candida has a term paper due in two weeks

Candida Has a Term Paper Due in 2 Weeks

Question 22

Candida has a term paper due in 2 weeks.She has had all semester long to work on it, but when she would try to work, other tasks became her priority.Candida was deliberately putting off her term paper.

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• Second Opinion

Candida Infection: Thrush

What is thrush.

Thrush is a fungal infection. It occurs in your mouth and throat.

Your mouth and throat normally contain millions of tiny organisms. These include bacteria and yeast. Most of these organisms do not cause any problems. In fact, they may help fight disease.

Yeasts are a type of fungus. A type of yeast called Candida normally lives on the mucous membranes of your mouth and throat. Usually, this yeast grows only in small numbers and is harmless. But under certain circumstances the Candida fungus can grow out of control and cause thrush.

Thrush does not usually affect healthy adults. It is more common in people with impaired immune systems. It is also more likely in people who take certain kinds of medicines. Thrush is normally not contagious.

There are 2 major kinds of thrush:

Pseudomembranous form. This is the more common form. It appears as white patches on your mouth, tongue, or back of your throat.

Atrophic form. This is the less common form. It is usually found in older adults. It typically appears as red patches underneath upper dentures.

Thrush is sometimes linked to other kinds of Candida infections. For example, people who have thrush sometimes have a Candida infection of the esophagus or vagina as well. The term thrush refers to a local infection of only the mouth and throat. But Candida sometimes causes infection in other areas of the body.

What causes thrush?

Thrush happens when the Candida fungus multiplies inside your mouth and throat. It crowds out other organisms. Circumstances that throw off the normal balance of organisms can trigger thrush. One example is when you take antibiotics. These medicines may kill some of the normal bacteria present in your mouth. Candida is unaffected by the antibiotics. So the fungus can then multiply freely. That is why people on antibiotics have an increased risk of thrush.

Other factors that can disrupt the normal balance of organisms and increase the risk of thrush are:

Chemotherapy

Radiation therapy

Organ transplantation

Corticosteroid use

Immune deficiency, such as from HIV/AIDS

Several types of Candida can cause an infection. But the most common one is Candida albicans.

Who is at risk for thrush?

You may have an increased risk for thrush if you have any of the above factors that disrupt the balance of organisms. Older adults and infants also have an increased risk for it.

What are the symptoms of thrush?

If you have thrush, you might have the following symptoms:

Cottony feeling in your mouth

Loss of taste

Sensitivity to spicy foods

Pain while eating or swallowing

White or red patches inside your mouth or on the back of your throat

Cracking at the corners of your mouth

Some people with thrush don’t have any symptoms.

How is thrush diagnosed?

Your healthcare provider will take your medical history. He or she will ask you about your symptoms and your past health information. Your healthcare provider will also look closely at your mouth and throat. If there are any white or red patches, your provider might scrape the affected area with a tongue depressor. Your healthcare provider may be able to diagnose thrush just from the appearance of the mouth sores (lesions). But a simple lab test of the sample can also often confirm it.

If you don’t have a known health problem that puts you at risk for thrush, you may need follow-up testing. For example, you may need an HIV test to figure out if you have a condition you don't yet know about.

Esophageal candidiasis often exists along with thrush (especially in people who have HIV/AIDS or an organ transplant). If you do have thrush, your healthcare provider may also check for this condition. You might need an upper endoscopy. It’s a procedure that allows your healthcare provider to look at your esophagus and also take a tissue sample for testing.

How is thrush treated?

Treatment will depend on your symptoms, age, and general health. It will also depend on how severe the condition is.

It is important to treat thrush early to relieve the pain and trouble swallowing, and to prevent spread of infection. 

Thrush is usually treated with antifungal medicine. These medicines could be in pill form. Or they may be put directly (topically) on your mouth and throat. They may include a swish and swallow medicine or an antifungal lozenge. They target the Candida overgrowth.

If the thrush doesn’t respond to topical treatment, your healthcare provider will likely switch treatment to an antifungal pill. This medicine is often stronger against Candida. It will also treat it in multiple locations in the body. The length and type of your therapy will depend on several factors. These include the severity of your infection and any other health problems. In rare cases, you may need to take medicine through an IV.

Some people may also need ongoing preventive treatment with oral antifungal medicines. You might need them if you are at continued high risk for thrush.

Typically, your healthcare provider can manage the diagnosis and treatment of thrush. But you may need to see an infectious disease specialist.

What are possible complications of thrush?

Systemic infection from thrush is very unlikely. But people who are debilitated and develop thrush usually have serious problems with their immune system. These people are at risk of the thrush spreading to the esophagus. And, rarely, they may develop a much more serious Candida infection throughout their body. Additional risk factors for systemic infection in very ill people include:

Central venous lines

IV nutrition

Broad-spectrum antibiotics

Kidney failure

Recent surgery

What can I do to prevent thrush?

You may be able to help prevent some cases of thrush. That is especially important if you have a health problem that increases your risk for it.

Practice good oral hygiene. Try using a chlorhexidine mouthwash.

Clean your dentures regularly as instructed. Make sure they fit you correctly.

After using a corticosteroid inhaler, rinse out your mouth with water or mouthwash.

Avoid broad-spectrum antibiotics. Use them only if you really need them.

Get proper treatment for health problems that increase your risk of thrush, like diabetes or HIV/AIDS.

When should I call my healthcare provider?

If you have a health problem that raises your risk of thrush, call your healthcare provider at the first sign of symptoms.

Key points about thrush

Thrush is a fungal infection of your mouth and throat. It is caused by an overgrowth of Candida yeast.

Antibiotics and immune system problems can raise your risk of thrush. It is uncommon in people without underlying conditions.

Thrush might cause a cottony feeling in your mouth, or a loss of taste.

Usually, antifungal medicine can treat thrush.

Sometimes untreated thrush may turn into a more serious infection, especially in people who are very ill. Prompt treatment for thrush can help prevent that.

Practicing good oral hygiene can prevent some cases of thrush.

Tips to help you get the most from a visit to your healthcare provider:

Know the reason for your visit and what you want to happen.

Before your visit, write down questions you want answered.

Bring someone with you to help you ask questions and remember what your provider tells you.

At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you.

Know why a new medicine or treatment is prescribed, and how it will help you. Also know what the side effects are.

Ask if your condition can be treated in other ways.

Know why a test or procedure is recommended and what the results could mean.

Know what to expect if you do not take the medicine or have the test or procedure.

If you have a follow-up appointment, write down the date, time, and purpose for that visit.

Know how you can contact your provider if you have questions.

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Find a Registered Dental Hygienist

Knowledge network, fact sheet: candidiasis (also known as “candidosis” and “moniliais”; and “thrush”; usually caused by overgrowth of yeast fungus candida albicans , but occasionally by other species of candida ), is the initiation of non-invasive dental hygiene procedures* contra-indicated, is the initiation of invasive dental hygiene procedures contra-indicated**, oral management implications, oral manifestations, related signs and symptoms, references and sources of more detailed information, is the initiation of non-invasive dental hygiene procedures* contra-indicated.

Is medical consult advised?  

• Yes, if the candidiasis has not yet been assessed by physician or dentist for definitive diagnosis (clinically or via microscopy of scraping) and management (including potential prescription medication).

Is the initiation of invasive dental hygiene procedures contra-indicated?**

Is medical consult advised? 

• See above. 

Is medical clearance required? 

Is antibiotic prophylaxis required?  

Is postponing treatment advised?

• Yes, until candidiasis has been treated and is resolved.

Oral management implications

• Mode of transmission is contact with secretions or excretions of mouth, skin, vagina, and feces, from patients/clients or carriers; by passage from mother to baby during childbirth; and by endogenous spread. Babies with oral thrush can pass the infection to their mothers’ nipples during breast-feeding. Because Candida yeasts are normal flora of the human mouth, a positive culture does not necessarily make the diagnosis.
• Good oral hygiene practices can help prevent oral candidiasis in people with weakened immune systems. Chlorhexidine mouthwash can prevent or reduce thrush in persons undergoing cancer treatment. People who use inhaled corticosteroids can reduce the risk of developing oral candidiasis by washing out the mouth with water or mouthwash after using an inhaler.
• Candida infections of the mouth and throat should be treated with antifungal medication prescribed by a physician or dentist. Oral candidiasis usually responds to topical treatments such as nystatin suspension (i.e., nystatin “swish and swallow”) and clotrimazole lozenges. Systemic antifungal medication such as fluconazole or itraconazole may be required for oropharyngeal infections that do not respond to topical treatments.
• Adults and children who have oral candidiasis but are otherwise healthy may also consider eating fresh culture yogurt or taking Lactobacillus acidophilus capsules or liquid to help restore normal bacterial flora, and hence decrease opportunistic Candida overgrowth.
• When oral leukoplakia is caused by candidiasis, it resolves when treated with antifungal medication. If the lesion does not respond to antifungal therapy, biopsy should be considered for diagnosis. 

Oral manifestations

• Candida organisms in small amounts are normal inhabitants of the mouth, throat, and the rest of the gastrointestinal tract, as well as other mucous membranes. Usually, these yeasts do not cause harm. However, if the microbial environment inside the mouth or throat becomes imbalanced, the organisms can multiply and cause overt infection; i.e., oral or oropharyngeal thrush.  
• Candida infections of the mouth and throat are uncommon among healthy adults. 
• Oral thrush  occurs most frequently in babies less than one month old (up to 7% prevalence), the elderly, and persons with immunodeficiency. Other factors associated with overgrowth of Candida species include HIV/AIDS; cancer chemotherapy ; organ transplantation (and associated use of immunosuppressive drugs); diabetes ; corticosteroid use (systemically, as well as topically via oral inhalation — e.g., for asthma management); dentures; broad-spectrum antibiotic use; xerostomia ; pregnancy (due to hormonal changes); oral contraceptive use; smoking; hypoparathyroidism; bone marrow malignancies ; and primary T-lymphocyte deficiency.
• The most common sign of oral candidiasis is creamy white, slightly raised patches or plaques on the tongue and other oral mucous membranes, including the buccal mucosa, hard and soft palates, tonsils, and gums. The lesions may bleed slightly when scraped or during tooth brushing. 
• Other signs and symptoms include redness and/or pain in the affected areas (especially in erythematous candidiasis ); difficulty swallowing (especially if there is also throat involvement); and cracking at the corners of the mouth (i.e., angular cheilitis ). In pseudomembranous candidiasis , a white, curdlike (“cottage cheese”) material is present on the mucosal surface. Chronic hyperplastic candidiasis (also known as candidal leukoplakia and hypertrophic candidiasis) appears as a white lesion which does not wipe off the mucosa.
• In denture stomatitis (also known as chronic atrophic candidiasis), erythematous change is limited to the mucosa covered by a full or partial denture. The lesions may vary from petechiae-like to more granular and generalized. Most common on the palate and alveolar ridge, denture stomatitis is asymptomatic and is usually discovered by the dental hygienist or dentist during a routine examination.
• Median rhomboid glossitis (a.k.a. central papillary atrophy) is sometimes associated with candidiasis. This condition appears as an erythematous, often rhombus-shaped, flat-to-raised area on the mid-line of the posterior dorsal tongue. Candida yeast are present in some lesions, which disappear with antifungal treatment.

Related signs and symptoms

• Candida infection is not restricted to the mouth and pharynx. It can occur in other parts of the body, causing fungal diaper rash in infants or vaginal yeast infections in women. Infants with oral thrush often have concurrent fungal diaper rash.
• Untreated oropharyngeal Candida infections can lead to invasive candidiasis 1 in susceptible persons, including spread to the esophagus, lungs, liver, and skin. This occurs most often in immunocompromised persons. Fever may be present.  
• Candida overgrowth in the esophagus is called Candida esophagitis, or esophageal candidiasis . It is associated with pain and difficulty swallowing. In particularly severe cases, intravenous antifungal therapy may be required.
• Chronic mucocutaneous candidiasis is a severe form of candidiasis, which typically occurs in patients/clients who are severely immunocompromised. The patient/client has skin lesions as well as chronic oral and genital mucosal candidiasis. The nails and skinfolds are usually involved.
• Breast-feeding women whose breasts are infected with Candida may experience red, sensitive, or itchy nipples; shiny or flaky skin on the areola; pain during nursing; painful nipples between feedings; and stabbing pains within the breast. Both mother and child should be treated with appropriate antifungal therapy in order to break the cycle of passing Candida back and forth between mother’s breasts and baby’s mouth.

References and sources of more detailed information

• Schwartz IS and Dingle TC. Candida auris. CMAJ . 2019;91(31):E865. https://doi.org/10.1503/cmaj.19043 3 
• Centers for Disease Control and Prevention https://www.cdc.gov/fungal/diseases/candidiasis/thrush/index.html https://www.cdc.gov/fungal/candida-auris/index.html  
• Mayo Clinic http://www.mayoclinic.com/health/oral-thrush/DS00408
• Heymann D (ed.). Control of Communicable Disease Manual (20 th edition).  Baltimore: American Public Health Association; 2015.
• Ibsen OAC and Phelan JA. Oral Pathology for the Dental Hygienist (6 th edition). St. Louis: Elsevier Saunders; 2014.
• Regezi JA, Sciubba JJ, Jordan RCK.  Oral Pathology – Clinical Pathologic Correlations (6 th edition). St. Louis: Elsevier Saunders; 2012.
• Bowen DM (ed.) and Pieren JA (ed.).  Darby and Walsh Dental Hygiene: Theory and Practice (5 th edition).  St. Louis:  Elsevier Saunders; 2020.

1 Invasive candidiasis can also be caused by the emerging, opportunistic pathogen Candida auris , particularly in the hospital setting. C. auris typically causes infections of the bloodstream, wounds, and ear, and many isolates are resistant to antifungals. However, oral thrush is not associated with this uncommon pathogen.

* Includes oral hygiene instruction, fitting a mouth guard, taking an impression, etc. ** Ontario Regulation 501/07 made under the Dental Hygiene Act, 1991. Invasive dental hygiene procedures are scaling teeth and root planing, including curetting surrounding tissue.

Vaginal Yeast Infection (Candidiasis)

• Diagnosis |
• Treatment |
• Prevention |

A vaginal yeast infection (also called candidiasis ) is caused by an infectious organism called Candida , usually Candida albicans .

A vaginal yeast infection may cause intense itching of the vagina and vulva, and women often have a thick, white, curd-like discharge.

If symptoms suggest a vaginal infection, doctors examine a sample of the discharge and may test it or fluid from the cervix for infectious organisms that can cause infection.

Antifungal medications—creams, vaginal suppositories, or oral medications—are effective treatment.

Being pregnant or having diabetes or a weakened immune system increases the risk of vaginal yeast infections.

(See also Overview of Vaginal Infections .)

Causes of Vaginal Yeast Infection

In women of childbearing age, yeast infections due to Candida albicans are particularly common. This yeast normally resides on the skin or in the intestine. From these areas, it can spread to the vagina. Yeast infections are not transmitted sexually.

Vaginal yeast infections are more likely to occur in women who

Are pregnant

Have diabetes

Have a weakened immune system —suppressed by medications (such as corticosteroids or chemotherapy drugs) or impaired by a disorder (such as AIDS )

Are taking antibiotics

Antibiotics taken by mouth tend to kill the bacteria that normally reside in the vagina and that prevent yeast from growing. Thus, using antibiotics increases the risk of developing a yeast infection.

Yeast infections are more likely to occur just before menstrual periods.

After menopause, yeast infections are uncommon except in women who take menopausal hormone therapy .

Symptoms of Vaginal Yeast Infection

The vagina and vulva may itch or burn, which may be particularly severe during sexual intercourse. The genital area may become red and swollen. Women may have a white discharge, often thick and curd-like.

Vaginal yeast infection symptoms may worsen the week before a menstrual period begins.

Did You Know...

Diagnosis of vaginal yeast infection.

A doctor's evaluation

Examination of a sample of the discharge and/or fluid from the cervix

If women have a vaginal discharge that is unusual or that lasts for more than a few days or have other vaginal symptoms, they should see a doctor.

Doctors suspect a yeast infection based on symptoms, such as a thick, white, curd-like discharge. They then ask questions about the discharge, other symptoms, possible causes (such as diabetes, other disorders, and use of antibiotics or hormones), and hygiene.

To confirm the diagnosis, doctors do a pelvic examination . While examining the vagina, the doctor takes a sample of the discharge with a cotton-tipped swab. The sample is examined under a microscope and sometimes cultured (placed in a substance that allows infectious organisms to grow). With information from these examinations, the doctor can often identify the cause of the symptoms.

Treatment of Vaginal Yeast Infection

Antifungal medications

Yeast infections are treated with antifungal medications. They may be used in the following ways:

Applied as a cream to the affected area

Inserted into the vagina as a suppository

Taken by mouth

Prevention of Vaginal Yeast Infection

Women who are at high risk of a yeast infection may need to take an antifungal medication by mouth to help prevent yeast infections. Such women include those with the following:

A need to take antibiotics for a long time

Repeated yeast infections, particularly in women with a weakened immune system

Keeping the vulva dry and wearing loose, absorbent cotton clothing that allows air to circulate can reduce moisture, which encourages the growth of yeast, and thus help prevent yeast from growing.

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Vaginal Yeast Infection (Candidiasis)

• What are vaginal yeast infections? |
• What are the symptoms of yeast infections? |
• How can my doctor tell if I have a yeast infection? |
• How do doctors treat yeast infections? |

What are vaginal yeast infections?

Yeast called Candida is a type of fungus. Some Candida live in your vagina all the time. Your vagina connects your uterus (where a baby grows when you're pregnant) to the outside of your body. Some people call it the birth canal. A vaginal yeast infection happens when too many yeast cells grow in your vagina.

These infections are very common and aren't usually serious

Yeast infections are most common when you’re pregnant, have diabetes , or are taking antibiotics

Symptoms may get worse the week before your monthly period starts and include vaginal itching and discharge

Antifungal medicines are used to treat yeast infections

Internal Female Genital Organs

What are the symptoms of yeast infections.

Itchiness of your vagina and vulva (the area on the outside of your body at the opening of your vagina)

A thick, white, curd-like vaginal discharge

Symptoms may get worse the week before your monthly period starts.

How can my doctor tell if I have a yeast infection?

Your doctor will suspect a yeast infection based on your symptoms. To tell for sure, your doctor will do a pelvic exam. During a pelvic exam, your doctor looks at your vulva and inside your vagina. In order to see inside, your doctor will hold your vagina open with a small instrument called a speculum. During the exam, your doctor will use a cotton swab to take a sample of discharge from your vagina and test it.

How do doctors treat yeast infections?

Yeast infections are treated with antifungal medicines. These are available as:

Creams, ointments, or suppositories that you put in your vagina (you can get these without a prescription)

Prescription pills you take by mouth

The oils in antifungal creams and ointments can weaken condoms made of latex. If you plan to have sex while using one of these medicines, use a different form of birth control, like a diaphragm, but also use a condom to prevent sexually transmitted infections (STIs).

If you have a high risk of getting yeast infections, you may need to take an antifungal medicine by mouth to prevent them. Needing to take antibiotics for a long time puts you at a high risk for yeast infections.

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• IDSA Foundation
• IDSA Academy
• Science Speaks

Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by IDSA

Published CID, 12/16/2015

Clinical Infectious Diseases , Volume 62, Issue 4, 15 February 2016, Pages e1–e50, https://doi.org/10.1093/cid/civ933

Published : 16 December 2015

Peter G. Pappas, Carol A. Kauffman, David R. Andes, Cornelius J. Clancy, Kieren A. Marr, Luis Ostrosky-Zeichner, Annette C. Reboli, Mindy G. Schuster, Jose A. Vazquez, Thomas J. Walsh, Theoklis E. Zaoutis, Jack D. Sobel

It is important to realize that guidelines cannot always account for individual variation among patients. They are not intended to supplant physician judgment with respect to particular patients or special clinical situations. IDSA considers adherence to these guidelines to be voluntary, with the ultimate determination regarding their application to be made by the physician in the light of each patient's individual circumstances.

Keywords:   candidemia, invasive candidiasis, fungal diagnostics, azoles, echinocandins

Executive Summary

Invasive infection due to Candida species is largely a condition associated with medical progress, and is widely recognized as a major cause of morbidity and mortality in the healthcare environment. There are at least 15 distinct Candida species that cause human disease, but >90% of invasive disease is caused by the 5 most common pathogens, C. albicans , C. glabrata , C. tropicalis , C. parapsilosis , and C. krusei . Each of these organisms has unique virulence potential, antifungal susceptibility, and epidemiology, but taken as a whole, significant infections due to these organisms are generally referred to as invasive candidiasis. Mucosal Candida infections—especially those involving the oropharynx, esophagus, and vagina—are not considered to be classically invasive disease, but they are included in these guidelines. Since the last iteration of these guidelines in 2009 [1], there have been new data pertaining to diagnosis, prevention, and treatment for proven or suspected invasive candidiasis, leading to significant modifications in our treatment recommendations.

Summarized below are the 2016 revised recommendations for the management of candidiasis. Due to the guideline's relevance to pediatrics, the guideline has been reviewed and endorsed by the American Academy of Pediatrics (AAP) and the Pediatric Infectious Diseases Society (PIDS). The Mycoses Study Group (MSG) has also endorsed these guidelines. The panel followed a guideline development process that has been adopted by the Infectious Diseases Society of America (IDSA), which includes a systematic method of grading both the quality of evidence (very low, low, moderate, and high) and the strength of the recommendation (weak or strong) [2] (Figure 1). [3] The guidelines are not intended to replace clinical judgment in the management of individual patients. A detailed description of the methods, background, and evidence summaries that support each recommendation can be found in the full text of the guideline.

Recommendations (Abridged)

I. what is the treatment for candidemia in nonneutropenic patients.

• An echinocandin (caspofungin: loading dose 70 mg, then 50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose 200 mg, then 100 mg daily) is recommended as initial therapy (strong recommendation; high-quality evidence) .
• Fluconazole, intravenous or oral, 800-mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily is an acceptable alternative to an echinocandin as initial therapy in selected patients, including those who are not critically ill and who are considered unlikely to have a fluconazole-resistant Candida species (strong recommendation; high-quality evidence) .
• Testing for azole susceptibility is recommended for all bloodstream and other clinically relevant Candida isolates. Testing for echinocandin susceptibility should be considered in patients who have had prior treatment with an echinocandin and among those who have infection with C. glabrata or C. parapsilosis (strong recommendation; low-quality evidence) .
• Transition from an echinocandin to fluconazole (usually within 5–7 days) is recommended for patients who are clinically stable, have isolates that are susceptible to fluconazole (eg, C. albicans ), and have negative repeat blood cultures following initiation of antifungal therapy (strong recommendation; moderate-quality evidence) .
• For infection due to C. glabrata , transition to higher-dose fluconazole 800 mg (12 mg/kg) daily or voriconazole 200–300 (3–4 mg/kg) twice daily should only be considered among patients with fluconazole-susceptible or voriconazole-susceptible isolates (strong recommendation; low-quality evidence) .
• Lipid formulation amphotericin B (AmB) (3–5 mg/kg daily) is a reasonable alternative if there is intolerance, limited availability, or resistance to other antifungal agents (strong recommendation; high-quality evidence) .
• Transition from AmB to fluconazole is recommended after 5–7 days among patients who have isolates that are susceptible to fluconazole, who are clinically stable, and in whom repeat cultures on antifungal therapy are negative (strong recommendation; high-quality evidence) .
• Among patients with suspected azole- and echinocandin-resistant Candida infections, lipid formulation AmB (3–5 mg/kg daily) is recommended (strong recommendation; low-quality evidence) .
• Voriconazole 400 mg (6 mg/kg) twice daily for 2 doses, then 200 mg (3 mg/kg) twice daily is effective for candidemia, but offers little advantage over fluconazole as initial therapy (strong recommendation; moderate-quality evidence). Voriconazole is recommended as step-down oral therapy for selected cases of candidemia due to C. krusei (strong recommendation; low-quality evidence) .
• All nonneutropenic patients with candidemia should have a dilated ophthalmological examination, preferably performed by an ophthalmologist, within the first week after diagnosis (strong recommendation; low-quality evidence) .
• Follow-up blood cultures should be performed every day or every other day to establish the time point at which candidemia has been cleared (strong recommendation; low-quality evidence) .
• Recommended duration of therapy for candidemia without obvious metastatic complications is for 2 weeks after documented clearance of Candida species from the bloodstream and resolution of symptoms attributable to candidemia (strong recommendation; moderate-quality evidence) .

II. Should Central Venous Catheters Be Removed in Nonneutropenic Patients With Candidemia?

• Central venous catheters (CVCs) should be removed as early as possible in the course of candidemia when the source is presumed to be the CVC and the catheter can be removed safely; this decision should be individualized for each patient (strong recommendation; moderate-quality evidence) .

III. What Is the Treatment for Candidemia in Neutropenic Patients?

• An echinocandin (caspofungin: loading dose 70 mg, then 50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose 200 mg, then 100 mg daily) is recommended as initial therapy (strong recommendation; moderate-quality evidence) .
• Lipid formulation AmB, 3–5 mg/kg daily, is an effective but less attractive alternative because of the potential for toxicity (strong recommendation; moderate-quality evidence) .
• Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily, is an alternative for patients who are not critically ill and have had no prior azole exposure (weak recommendation; low-quality evidence) .
• Fluconazole, 400 mg (6 mg/kg) daily, can be used for step-down therapy during persistent neutropenia in clinically stable patients who have susceptible isolates and documented bloodstream clearance (weak recommendation; low-quality evidence) .
• Voriconazole, 400 mg (6 mg/kg) twice daily for 2 doses, then 200–300 mg (3–4 mg/kg) twice daily, can be used in situations in which additional mold coverage is desired (weak recommendation; low-quality evidence) . Voriconazole can also be used as step-down therapy during neutropenia in clinically stable patients who have had documented bloodstream clearance and isolates that are susceptible to voriconazole (weak recommendation; low-quality evidence) .
• For infections due to C. krusei , an echinocandin, lipid formulation AmB, or voriconazole is recommended (strong recommendation; low-quality evidence) .
• Recommended minimum duration of therapy for candidemia without metastatic complications is 2 weeks after documented clearance of Candida from the bloodstream, provided neutropenia and symptoms attributable to candidemia have resolved (strong recommendation; low-quality evidence) .
• Ophthalmological findings of choroidal and vitreal infection are minimal until recovery from neutropenia; therefore, dilated funduscopic examinations should be performed within the first week after recovery from neutropenia (strong recommendation; low-quality evidence) .
• In the neutropenic patient, sources of candidiasis other than a CVC (eg, gastrointestinal tract) predominate. Catheter removal should be considered on an individual basis (strong recommendation; low-quality evidence) .
• Granulocyte colony-stimulating factor (G-CSF)–mobilized granulocyte transfusions can be considered in cases of persistent candidemia with anticipated protracted neutropenia (weak recommendation; low-quality evidence) .

IV. What Is the Treatment for Chronic Disseminated (Hepatosplenic) Candidiasis?

• Initial therapy with lipid formulation AmB, 3–5 mg/kg daily OR an echinocandin (micafungin: 100 mg daily; caspofungin: 70-mg loading dose, then 50 mg daily; or anidulafungin: 200-mg loading dose, then 100 mg daily), for several weeks is recommended, followed by oral fluconazole, 400 mg (6 mg/kg) daily, for patients who are unlikely to have a fluconazole-resistant isolate (strong recommendation; low-quality evidence) .
• Therapy should continue until lesions resolve on repeat imaging, which is usually several months. Premature discontinuation of antifungal therapy can lead to relapse (strong recommendation; low-quality evidence) .
• If chemotherapy or hematopoietic cell transplantation is required, it should not be delayed because of the presence of chronic disseminated candidiasis, and antifungal therapy should be continued throughout the period of high risk to prevent relapse (strong recommendation; low-quality evidence) .
• For patients who have debilitating persistent fevers, short-term (1–2 weeks) treatment with nonsteroidal anti-inflammatory drugs or corticosteroids can be considered (weak recommendation; low-quality evidence) .

V. What Is the Role of Empiric Treatment for Suspected Invasive Candidiasis in Nonneutropenic Patients in the Intensive Care Unit?

• Empiric antifungal therapy should be considered in critically ill patients with risk factors for invasive candidiasis and no other known cause of fever and should be based on clinical assessment of risk factors, surrogate markers for invasive candidiasis, and/or culture data from nonsterile sites (strong recommendation; moderate-quality evidence) . Empiric antifungal therapy should be started as soon as possible in patients who have the above risk factors and who have clinical signs of septic shock (strong recommendation; moderate-quality evidence) .
• Preferred empiric therapy for suspected candidiasis in nonneutropenic patients in the intensive care unit (ICU) is an echinocandin (caspofungin: loading dose of 70 mg, then 50 mg daily; micafungin: 100 mg daily; anidulafungin: loading dose of 200 mg, then 100 mg daily) (strong recommendation; moderate-quality evidence) .
• Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily, is an acceptable alternative for patients who have had no recent azole exposure and are not colonized with azole-resistant Candida species (strong recommendation; moderate-quality evidence) .
• Lipid formulation AmB, 3–5 mg/kg daily, is an alternative if there is intolerance to other antifungal agents (strong recommendation; low-quality evidence) .
• Recommended duration of empiric therapy for suspected invasive candidiasis in those patients who improve is 2 weeks, the same as for treatment of documented candidemia (weak recommendation; low-quality evidence) .
• For patients who have no clinical response to empiric antifungal therapy at 4–5 days and who do not have subsequent evidence of invasive candidiasis after the start of empiric therapy or have a negative non-culture-based diagnostic assay with a high negative predictive value, consideration should be given to stopping antifungal therapy (strong recommendation; low-quality evidence) .

VI. Should Prophylaxis Be Used to Prevent Invasive Candidiasis in the Intensive Care Unit Setting?

• Fluconazole, 800-mg (12 mg/kg) loading dose, then 400 mg (6 mg/kg) daily, could be used in high-risk patients in adult ICUs with a high rate (>5%) of invasive candidiasis (weak recommendation; moderate-quality evidence) .
• An alternative is to give an echinocandin (caspofungin: 70-mg loading dose, then 50 mg daily; anidulafungin: 200-mg loading dose and then 100 mg daily; or micafungin: 100 mg daily) (weak recommendation; low-quality evidence) .
• Daily bathing of ICU patients with chlorhexidine, which has been shown to decrease the incidence of bloodstream infections including candidemia, could be considered (weak recommendation; moderate-quality evidence) .

VII. What Is the Treatment for Neonatal Candidiasis, Including Central Nervous System Infection?

What is the treatment for invasive candidiasis and candidemia.

• AmB deoxycholate, 1 mg/kg daily, is recommended for neonates with disseminated candidiasis (strong recommendation; moderate-quality evidence) .
• Fluconazole, 12 mg/kg intravenous or oral daily, is a reasonable alternative in patients who have not been on fluconazole prophylaxis (strong recommendation; moderate-quality evidence) .
• Lipid formulation AmB, 3–5 mg/kg daily, is an alternative, but should be used with caution, particularly in the presence of urinary tract involvement (weak recommendation; low-quality evidence) .
• Echinocandins should be used with caution and generally limited to salvage therapy or to situations in which resistance or toxicity preclude the use of AmB deoxycholate or fluconazole (weak recommendation; low-quality evidence) .
• A lumbar puncture and a dilated retinal examination are recommended in neonates with cultures positive for Candida species from blood and/or urine (strong recommendation; low-quality evidence) .
• Computed tomographic or ultrasound imaging of the genitourinary tract, liver, and spleen should be performed if blood cultures are persistently positive for Candida species (strong recommendation; low-quality evidence) .
• CVC removal is strongly recommended (strong recommendation; moderate-quality evidence) .
• The recommended duration of therapy for candidemia without obvious metastatic complications is for 2 weeks after documented clearance of Candida species from the bloodstream and resolution of signs attributable to candidemia (strong recommendation; low-quality evidence) .

What Is the Treatment for Central Nervous System Infections in Neonates?

• For initial treatment, AmB deoxycholate, 1 mg/kg intravenous daily, is recommended (strong recommendation; low-quality evidence) .
• An alternative regimen is liposomal AmB, 5 mg/kg daily (strong recommendation; low-quality evidence) .
• The addition of flucytosine, 25 mg/kg 4 times daily, may be considered as salvage therapy in patients who have not had a clinical response to initial AmB therapy, but adverse effects are frequent (weak recommendation; low-quality evidence) .
• For step-down treatment after the patient has responded to initial treatment, fluconazole, 12 mg/kg daily, is recommended for isolates that are susceptible to fluconazole (strong recommendation; low-quality evidence) .
• Therapy should continue until all signs, symptoms, and cerebrospinal fluid (CSF) and radiological abnormalities, if present, have resolved (strong recommendation; low-quality evidence) .
• Infected central nervous system (CNS) devices, including ventriculostomy drains and shunts, should be removed if at all possible (strong recommendation; low-quality evidence) .

What Are the Recommendations for Prophylaxis in the Neonatal Intensive Care Unit Setting?

• In nurseries with high rates (>10%) of invasive candidiasis, intravenous or oral fluconazole prophylaxis, 3–6 mg/kg twice weekly for 6 weeks, in neonates with birth weights <1000 g is recommended (strong recommendation; high-quality evidence) .
• Oral nystatin, 100 000 units 3 times daily for 6 weeks, is an alternative to fluconazole in neonates with birth weights <1500 g in situations in which availability or resistance preclude the use of fluconazole (weak recommendation; moderate-quality evidence) .
• Oral bovine lactoferrin (100 mg/day) may be effective in neonates <1500 g but is not currently available in US hospitals (weak recommendation; moderate-quality evidence) .

VIII. What Is the Treatment for Intra-abdominal Candidiasis?

• Empiric antifungal therapy should be considered for patients with clinical evidence of intra-abdominal infection and significant risk factors for candidiasis, including recent abdominal surgery, anastomotic leaks, or necrotizing pancreatitis (strong recommendation; moderate-quality evidence) .
• Treatment of intra-abdominal candidiasis should include source control, with appropriate drainage and/or debridement (strong recommendation; moderate-quality evidence) .
• The choice of antifungal therapy is the same as for the treatment of candidemia or empiric therapy for nonneutropenic patients in the ICU (See sections I and V) (strong recommendation; moderate-quality evidence) .
• The duration of therapy should be determined by adequacy of source control and clinical response (strong recommendation; low-quality evidence) .

IX. Does the Isolation of Candida Species From the Respiratory Tract Require Antifungal Therapy?

• Growth of Candida from respiratory secretions usually indicates colonization and rarely requires treatment with antifungal therapy (strong recommendation; moderate-quality evidence) .

X. What Is the Treatment for Candida Intravascular Infections, Including Endocarditis and Infections of Implantable Cardiac Devices?

What is the treatment for candida endocarditis.

• For native valve endocarditis, lipid formulation AmB, 3–5 mg/kg daily, with or without flucytosine, 25 mg/kg 4 times daily, OR high-dose echinocandin (caspofungin 150 mg daily, micafungin 150 mg daily, or anidulafungin 200 mg daily) is recommended for initial therapy (strong recommendation; low-quality evidence) .
• Step-down therapy to fluconazole, 400–800 mg (6–12 mg/kg) daily, is recommended for patients who have susceptible Candida isolates, have demonstrated clinical stability, and have cleared Candida from the bloodstream (strong recommendation; low-quality evidence) .
• Oral voriconazole, 200–300 mg (3–4 mg/kg) twice daily, or posaconazole tablets, 300 mg daily, can be used as step-down therapy for isolates that are susceptible to those agents but not susceptible to fluconazole (weak recommendation; very low-quality evidence) .
• Valve replacement is recommended; treatment should continue for at least 6 weeks after surgery and for a longer duration in patients with perivalvular abscesses and other complications (strong recommendation; low-quality evidence) .
• For patients who cannot undergo valve replacement, long-term suppression with fluconazole, 400–800 mg (6–12 mg/kg) daily, if the isolate is susceptible, is recommended (strong recommendation; low-quality evidence) .
• For prosthetic valve endocarditis, the same antifungal regimens suggested for native valve endocarditis are recommended (strong recommendation; low-quality evidence). Chronic suppressive antifungal therapy with fluconazole, 400–800 mg (6–12 mg/kg) daily, is recommended to prevent recurrence (strong recommendation; low-quality evidence) .

What Is the Treatment for Candida Infection of Implantable Cardiac Devices?

• For pacemaker and implantable cardiac defibrillator infections, the entire device should be removed (strong recommendation; moderate-quality evidence) .
• Antifungal therapy is the same as that recommended for native valve endocarditis (strong recommendation; low-quality evidence) .
• For infections limited to generator pockets, 4 weeks of antifungal therapy after removal of the device is recommended (strong recommendation; low-quality evidence) .
• For infections involving the wires, at least 6 weeks of antifungal therapy after wire removal is recommended (strong recommendation; low-quality evidence) .
• For ventricular assist devices that cannot be removed, the antifungal regimen is the same as that recommended for native valve endocarditis (strong recommendation; low-quality evidence) . Chronic suppressive therapy with fluconazole if the isolate is susceptible, for as long as the device remains in place is recommended (strong recommendation; low-quality evidence) .

What Is the Treatment for Candida Suppurative Thrombophlebitis?

• Catheter removal and incision and drainage or resection of the vein, if feasible, is recommended (strong recommendation; low-quality evidence) .
• Lipid formulation AmB, 3–5 mg/kg daily, OR fluconazole, 400–800 mg (6–12 mg/kg) daily, OR an echinocandin (caspofungin 150 mg daily, micafungin 150 mg daily, or anidulafungin 200 mg daily) for at least 2 weeks after candidemia (if present) has cleared is recommended (strong recommendation; low-quality evidence) .
• Step-down therapy to fluconazole, 400–800 mg (6–12 mg/kg) daily, should be considered for patients who have initially responded to AmB or an echinocandin, are clinically stable, and have a fluconazole-susceptible isolate (strong recommendation; low-quality evidence) .
• Resolution of the thrombus can be used as evidence to discontinue antifungal therapy if clinical and culture data are supportive (strong recommendation; low-quality evidence) .

XI. What Is the Treatment for Candida Osteoarticular Infections?

What is the treatment for candida osteomyelitis.

• Fluconazole, 400 mg (6 mg/kg) daily, for 6–12 months OR an echinocandin (caspofungin 50–70 mg daily, micafungin 100 mg daily, or anidulafungin 100 mg daily) for at least 2 weeks followed by fluconazole, 400 mg (6 mg/kg) daily, for 6–12 months is recommended (strong recommendation; low-quality evidence) .
• Lipid formulation AmB, 3–5 mg/kg daily, for at least 2 weeks followed by fluconazole, 400 mg (6 mg/kg) daily, for 6–12 months is a less attractive alternative (weak recommendation; low-quality evidence) .
• Surgical debridement is recommended in selected cases (strong recommendation; low-quality evidence) .

What Is the Treatment for Candida Septic Arthritis?

• Fluconazole, 400 mg (6 mg/kg) daily, for 6 weeks OR an echinocandin (caspofungin 50–70 mg daily, micafungin 100 mg daily, or anidulafungin 100 mg daily) for 2 weeks followed by fluconazole, 400 mg (6 mg/kg) daily, for at least 4 weeks is recommended (strong recommendation; low-quality evidence) .
• Lipid formulation AmB, 3–5 mg/kg daily, for 2 weeks, followed by fluconazole, 400 mg (6 mg/kg) daily, for at least 4 weeks is a less attractive alternative (weak recommendation; low-quality evidence) .
• Surgical drainage is indicated in all cases of septic arthritis (strong recommendation; moderate-quality evidence) .
• For septic arthritis involving a prosthetic device, device removal is recommended (strong recommendation; moderate-quality evidence) .
• If the prosthetic device cannot be removed, chronic suppression with fluconazole, 400 mg (6 mg/kg) daily, if the isolate is susceptible, is recommended (strong recommendation; low-quality evidence) .

XII. What Is the Treatment for Candida Endophthalmitis?

What is the general approach to candida endophthalmitis.

• All patients with candidemia should have a dilated retinal examination, preferably performed by an ophthalmologist, within the first week of therapy in nonneutropenic patients to establish if endophthalmitis is present (strong recommendation; low-quality evidence) . For neutropenic patients, it is recommended to delay the examination until neutrophil recovery (strong recommendation; low-quality evidence) .
• The extent of ocular infection (chorioretinitis with or without macular involvement and with or without vitritis) should be determined by an ophthalmologist (strong recommendation; low-quality evidence) .
• Decisions regarding antifungal treatment and surgical intervention should be made jointly by an ophthalmologist and an infectious diseases physician (strong recommendation; low-quality evidence) .

What Is the Treatment for Candida Chorioretinitis Without Vitritis?

• For fluconazole-/voriconazole-susceptible isolates, fluconazole, loading dose, 800 mg (12 mg/kg), then 400–800 mg (6–12 mg/kg) daily OR voriconazole, loading dose 400 mg (6 mg/kg) intravenous twice daily for 2 doses, then 300 mg (4 mg/kg) intravenous or oral twice daily is recommended (strong recommendation; low-quality evidence) .
• For fluconazole-/voriconazole-resistant isolates, liposomal AmB, 3–5 mg/kg intravenous daily, with or without oral flucytosine, 25 mg/kg 4 times daily is recommended (strong recommendation; low-quality evidence) .
• With macular involvement, antifungal agents as noted above PLUS intravitreal injection of either AmB deoxycholate, 5–10 µg/0.1 mL sterile water, or voriconazole, 100 µg/0.1 mL sterile water or normal saline, to ensure a prompt high level of antifungal activity is recommended (strong recommendation; low-quality evidence) .
• The duration of treatment should be at least 4–6 weeks, with the final duration depending on resolution of the lesions as determined by repeated ophthalmological examinations (strong recommendation; low-quality evidence) .

What Is the Treatment for Candida Chorioretinitis With Vitritis?

• Antifungal therapy as detailed above for chorioretinitis without vitritis, PLUS intravitreal injection of either amphotericin B deoxycholate, 5–10 µg/0.1 mL sterile water, or voriconazole, 100 µg/0.1 mL sterile water or normal saline is recommended (strong recommendation; low-quality evidence) .
• Vitrectomy should be considered to decrease the burden of organisms and to allow the removal of fungal abscesses that are inaccessible to systemic antifungal agents (strong recommendation; low-quality evidence) .
• The duration of treatment should be at least 4–6 weeks, with the final duration dependent on resolution of the lesions as determined by repeated ophthalmological examinations (strong recommendation; low-quality evidence) .

XIII. What Is the Treatment for Central Nervous System Candidiasis?

• For initial treatment, liposomal AmB, 5 mg/kg daily, with or without oral flucytosine, 25 mg/kg 4 times daily is recommended (strong recommendation; low-quality evidence).
• For step-down therapy after the patient has responded to initial treatment, fluconazole, 400–800 mg (6–12 mg/kg) daily, is recommended (strong recommendation; low-quality evidence) .
• Therapy should continue until all signs and symptoms and CSF and radiological abnormalities have resolved (strong recommendation; low-quality evidence) .
• Infected CNS devices, including ventriculostomy drains, shunts, stimulators, prosthetic reconstructive devices, and biopolymer wafers that deliver chemotherapy should be removed if possible (strong recommendation; low-quality evidence) .
• For patients in whom a ventricular device cannot be removed, AmB deoxycholate could be administered through the device into the ventricle at a dosage ranging from 0.01 mg to 0.5 mg in 2 mL 5% dextrose in water (weak recommendation; low-quality evidence) .

XIV. What Is the Treatment for Urinary Tract Infections Due to Candida Species?

What is the treatment for asymptomatic candiduria.

• Elimination of predisposing factors, such as indwelling bladder catheters, is recommended whenever feasible (strong recommendation; low-quality evidence) .
• Treatment with antifungal agents is NOT recommended unless the patient belongs to a group at high risk for dissemination; high-risk patients include neutropenic patients, very low-birth-weight infants (<1500 g), and patients who will undergo urologic manipulation (strong recommendation; low-quality evidence) .
• Neutropenic patients and very low–birth-weight infants should be treated as recommended for candidemia (see sections III and VII) (strong recommendation; low-quality evidence) .
• Patients undergoing urologic procedures should be treated with oral fluconazole, 400 mg (6 mg/kg) daily, OR AmB deoxycholate, 0.3–0.6 mg/kg daily, for several days before and after the procedure (strong recommendation; low-quality evidence) .

What Is the Treatment for Symptomatic Candida Cystitis?

• For fluconazole-susceptible organisms, oral fluconazole, 200 mg (3 mg/kg) daily for 2 weeks is recommended (strong recommendation; moderate-quality evidence) .
• For fluconazole-resistant C. glabrata , AmB deoxycholate, 0.3–0.6 mg/kg daily for 1–7 days OR oral flucytosine, 25 mg/kg 4 times daily for 7–10 days is recommended (strong recommendation; low-quality evidence) .
• For C. krusei , AmB deoxycholate, 0.3–0.6 mg/kg daily, for 1–7 days is recommended (strong recommendation; low-quality evidence) .
• Removal of an indwelling bladder catheter, if feasible, is strongly recommended (strong recommendation; low-quality evidence) .
• AmB deoxycholate bladder irrigation, 50 mg/L sterile water daily for 5 days, may be useful for treatment of cystitis due to fluconazole-resistant species, such as C. glabrata and C. krusei (weak recommendation; low-quality evidence) .

What Is the Treatment for Symptomatic Ascending Candida Pyelonephritis?

• For fluconazole-susceptible organisms, oral fluconazole, 200–400 mg (3–6 mg/kg) daily for 2 weeks is recommended (strong recommendation; low-quality evidence) .
• For fluconazole-resistant C. glabrata , AmB deoxycholate, 0.3–0.6 mg/kg daily for 1–7 days with or without oral flucytosine, 25 mg/kg 4 times daily, is recommended (strong recommendation; low-quality evidence) .
• For fluconazole-resistant C. glabrata , monotherapy with oral flucytosine, 25 mg/kg 4 times daily for 2 weeks, could be considered (weak recommendation; low-quality evidence) .
• Elimination of urinary tract obstruction is strongly recommended (strong recommendation; low-quality evidence) .
• For patients who have nephrostomy tubes or stents in place, consider removal or replacement, if feasible (weak recommendation; low-quality evidence) .

What Is the Treatment for Candida Urinary Tract Infection Associated With Fungus Balls?

• Surgical intervention is strongly recommended in adults (strong recommendation; low-quality evidence) .
• Antifungal treatment as noted above for cystitis or pyelonephritis is recommended (strong recommendation; low-quality evidence) .
• Irrigation through nephrostomy tubes, if present, with AmB deoxycholate, 25–50 mg in 200–500 mL sterile water, is recommended (strong recommendation; low-quality evidence) .

XV. What Is the Treatment for Vulvovaginal Candidiasis?

• For the treatment of uncomplicated Candida vulvovaginitis, topical antifungal agents, with no one agent superior to another, are recommended (strong recommendation; high-quality evidence) .
• Alternatively, for the treatment of uncomplicated Candida vulvovaginitis, a single 150-mg oral dose of fluconazole is recommended (strong recommendation; high-quality evidence) .
• For severe acute Candida vulvovaginitis, fluconazole, 150 mg, given every 72 hours for a total of 2 or 3 doses, is recommended (strong recommendation; high-quality evidence) .
• For C. glabrata vulvovaginitis that is unresponsive to oral azoles, topical intravaginal boric acid, administered in a gelatin capsule, 600 mg daily, for 14 days is an alternative (strong recommendation; low-quality evidence) .
• Another alternative agent for C. glabrata infection is nystatin intravaginal suppositories, 100 000 units daily for 14 days (strong recommendation; low-quality evidence) .
• A third option for C. glabrata infection is topical 17% flucytosine cream alone or in combination with 3% AmB cream administered daily for 14 days (weak recommendation; low-quality evidence) .
• For recurring vulvovaginal candidiasis, 10–14 days of induction therapy with a topical agent or oral fluconazole, followed by fluconazole, 150 mg weekly for 6 months, is recommended (strong recommendation; high-quality evidence) .

XVI. What Is the Treatment for Oropharyngeal Candidiasis?

• For mild disease, clotrimazole troches, 10 mg 5 times daily, OR miconazole mucoadhesive buccal 50-mg tablet applied to the mucosal surface over the canine fossa once daily for 7–14 days are recommended (strong recommendation; high-quality evidence) .
• Alternatives for mild disease include nystatin suspension (100 000 U/mL) 4–6 mL 4 times daily, OR 1–2 nystatin pastilles (200 000 U each) 4 times daily, for 7–14 days (strong recommendation; moderate-quality evidence) .
• For moderate to severe disease, oral fluconazole, 100–200 mg daily, for 7–14 days is recommended (strong recommendation; high-quality evidence) .
• For fluconazole-refractory disease, itraconazole solution, 200 mg once daily OR posaconazole suspension, 400 mg twice daily for 3 days then 400 mg daily, for up to 28 days are recommended (strong recommendation; moderate-quality evidence) .
• Alternatives for fluconazole-refractory disease include voriconazole, 200 mg twice daily, OR AmB deoxycholate oral suspension, 100 mg/mL 4 times daily (strong recommendation; moderate-quality evidence) .
• Intravenous echinocandin (caspofungin: 70-mg loading dose, then 50 mg daily; micafungin: 100 mg daily; or anidulafungin: 200-mg loading dose, then 100 mg daily) OR intravenous AmB deoxycholate, 0.3 mg/kg daily, are other alternatives for refractory disease (weak recommendation; moderate-quality evidence) .
• Chronic suppressive therapy is usually unnecessary. If required for patients who have recurrent infection, fluconazole, 100 mg 3 times weekly, is recommended (strong recommendation; high-quality evidence) .
• For HIV-infected patients, antiretroviral therapy is strongly recommended to reduce the incidence of recurrent infections (strong recommendation; high-quality evidence) .
• For denture-related candidiasis, disinfection of the denture, in addition to antifungal therapy is recommended (strong recommendation; moderate-quality evidence) .

XVII. What Is the Treatment for Esophageal Candidiasis?

• Systemic antifungal therapy is always required. A diagnostic trial of antifungal therapy is appropriate before performing an endoscopic examination (strong recommendation; high-quality evidence) .
• Oral fluconazole, 200–400 mg (3–6 mg/kg) daily, for 14–21 days is recommended (strong recommendation; high-quality evidence) .
• For patients who cannot tolerate oral therapy, intravenous fluconazole, 400 mg (6 mg/kg) daily, OR an echinocandin (micafungin, 150 mg daily, caspofungin, 70-mg loading dose, then 50 mg daily, or anidulafungin, 200 mg daily) is recommended (strong recommendation; high-quality evidence) .
• A less preferred alternative for those who cannot tolerate oral therapy is AmB deoxycholate, 0.3–0.7 mg/kg daily (strong recommendation; moderate-quality evidence) .
• Consider de-escalating to oral therapy with fluconazole 200–400 mg (3–6 mg/kg) daily once the patient is able to tolerate oral intake (strong recommendation; moderate-quality evidence) .
• For fluconazole-refractory disease, itraconazole solution, 200 mg daily, OR voriconazole, 200 mg (3 mg/kg) twice daily either intravenous or oral, for 14–21 days is recommended (strong recommendation; high-quality evidence) .
• Alternatives for fluconazole-refractory disease include an echinocandin (micafungin: 150 mg daily; caspofungin: 70-mg loading dose, then 50 mg daily; or anidulafungin: 200 mg daily) for 14–21 days, OR AmB deoxycholate, 0.3–0.7 mg/kg daily, for 21 days (strong recommendation; high-quality evidence) .
• Posaconazole suspension, 400 mg twice daily, or extended-release tablets, 300 mg once daily, could be considered for fluconazole-refractory disease (weak recommendation; low-quality evidence) .
• For patients who have recurrent esophagitis, chronic suppressive therapy with fluconazole, 100–200 mg 3 times weekly, is recommended (strong recommendation; high-quality evidence) .

Introduction

In the first section, the panel summarizes background information relevant to the topic. In the second section, the panel poses questions regarding the management of candidiasis, evaluates applicable clinical trial and observational data, and makes recommendations using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework [2]. The following 17 questions were answered:

• What is the treatment for candidemia in nonneutropenic patients?
• Should central venous catheters be removed in nonneutropenic patients with candidemia?
• What is the treatment for candidemia in neutropenic patients?
• What is the treatment for chronic disseminated (hepatosplenic) candidiasis?
• What is the role of empiric treatment for suspected invasive candidiasis in nonneutropenic patients in the intensive care unit?
• Should prophylaxis be used to prevent invasive candidiasis in the intensive care unit setting?
• What is the treatment for neonatal candidiasis, including central nervous system infection?
• What is the treatment for intra-abdominal candidiasis?
• Does the isolation of Candida species from the respiratory tract require antifungal therapy?
• What is the treatment for Candida intravascular infections, including endocarditis and infections of implantable cardiac devices?
• What is the treatment for Candida osteoarticular infections?
• What is the treatment for Candida endophthalmitis?
• What is the treatment for central nervous system candidiasis?
• What is the treatment for urinary tract infections due to Candida species?
• What is the treatment for vulvovaginal candidiasis?
• What is the treatment for oropharyngeal candidiasis?
• What is the treatment for esophageal candidiasis?

Infections due to Candida species are major causes of morbidity and mortality in humans, causing a diverse spectrum of clinical disease ranging from superficial and mucosal infections to invasive disease associated with candidemia and metastatic organ involvement. As an entity, candidemia is one of the most common healthcare-associated bloodstream infections in US hospitals, typically ranking as the third or fourth most common cause of healthcare–associated bloodstream infection. A recent multicenter point-prevalence survey identified Candida species as the most commonly isolated healthcare-associated bloodstream pathogen [4]. Among patients with candidemia and other forms of invasive candidiasis, non-albicans Candida species constitute approximately 50% of all relevant isolates, representing a steady trend in many regions throughout the world for more than a decade [5–12].

Among the many clinical manifestations of candidiasis, candidemia and invasive candidiasis have been given the most attention in clinical trials. Candidemia is associated with up to 47% attributable mortality [5–13], and this is even higher among persons with septic shock [14]. Several authors have demonstrated that mortality is closely linked to both timing of therapy and/or source control [14–19]. That is, earlier intervention with appropriate antifungal therapy and removal of a contaminated central venous catheter (CVC) or drainage of infected material is generally associated with better overall outcomes [14–19]. CVCs are commonly linked with candidemia, but catheters are not always the source, especially among neutropenic patients in whom the gastrointestinal tract is a common source. Most experts agree that thoughtful patient-specific management of CVCs is critical in the overall management of the infection [19].

The continued reliance on blood cultures, which are notoriously insensitive as markers of disease, remains a significant obstacle to early intervention for this condition. The development of reliable nonculture assays is critical to providing the opportunity for earlier intervention and more targeted antifungal therapy among large numbers of patients in whom traditional blood cultures are insensitive or provide untimely results [20].

Species distribution is also a significant challenge for all forms of candidiasis, and there is considerable geographic, center-to-center, and even unit-to-unit variability in the prevalence of pathogenic Candida species [8–12]. Indeed, candidiasis is not one but rather several diseases, with each Candida species presenting its own unique characteristics with respect to tissue tropism, propensity to cause invasive disease, virulence, and antifungal susceptibility. A working knowledge of the local epidemiology and rates of antifungal resistance is critical in making informed therapeutic decisions while awaiting culture and susceptibility data.

Despite the overall robust nature of the randomized controlled trials examining treatment of candidemia and other forms of invasive candidiasis [21–34], no single trial has demonstrated clear superiority of one therapeutic agent over another. Careful analysis of these clinical data sometimes leads to conflicting conclusions. For instance, the use of amphotericin B (AmB) plus fluconazole is as least as effective as higher-dose (800 mg daily) fluconazole given alone for patients with candidemia [22], but there is little role for this combination in current practice, especially as echinocandins are such a safe and effective alternative. Similarly, voriconazole is as effective as the strategy of sequential AmB and fluconazole for candidemia, but few would choose voriconazole in this setting as there is little advantage and potentially greater toxicity associated with using this agent compared to other therapies [23].

The echinocandins have emerged as preferred agents for most episodes of candidemia and invasive candidiasis, with the exception of central nervous system (CNS), eye, and urinary tract infections due to these organisms. This preference is based on a strong safety profile, convenience, early fungicidal activity, a trend toward better outcomes based on data from individual studies and combined analyses of candidemia studies [19, 25], and the emergence of azole-resistant Candida species. The recent emergence of multidrug-resistant Candida species further complicates the selection of antifungal therapy for the immediate future [10, 12, 35–38] as there are no good prospective data to guide therapy.

There is an abundance of clinical data generated from large randomized clinical trials for candidemia, Candida esophagitis, oropharyngeal candidiasis, and prophylaxis studies in special populations, such as patients in intensive care units (ICUs), neonates, and selected transplant recipients, and these studies have led to important insights into optimal therapeutic approaches in these vulnerable populations. For those with less common manifestations of disease, such as osteomyelitis, endophthalmitis, and infective endocarditis, treatment recommendations are largely based on extrapolation from randomized studies of patients with other forms of disease, small retrospective series, and anecdotal reports. Thus, there is a critical need to assess these data in an ongoing manner to provide timely recommendations pertaining to the management of patients with these less common forms of candidiasis.

Panel Composition

The most recent version of the Infectious Diseases Society of America (IDSA) guideline on the management of patients with candidiasis was published in 2009 [1]. For this update, the IDSA Standards and Practice Guidelines Committee (SPGC) convened a multidisciplinary panel of 12 experts in the management of patients with candidiasis. The panel consisted of 12 members of IDSA, and included 11 adult infectious diseases physicians and 1 pediatric infectious diseases physician. All panel members were selected on the basis of their expertise in clinical and/or laboratory mycology with a focus on candidiasis.

Literature Review and Analysis

Panel members were each assigned to review the recent literature for at least 1 topic, evaluate the evidence, determine the strength of recommendations, and develop written evidence in support of these recommendations. PubMed, which includes Medline (1946 to present), was searched to identify relevant studies for the Candida guideline PICO (population/patient, intervention/indicator, comparator/control, outcome) questions. Search strategies were developed and built by 2 independent health sciences librarians from the Health Sciences Library System, University of Pittsburgh. For each PICO question, the librarians developed the search strategies using PubMed's command language and appropriate search fields. Medical Subject Headings (MeSH) terms and keywords were used for the main search concepts of each PICO question. Articles in all languages and all publication years were included. Initial searches were created and confirmed with input from the guideline committee chairs and group leaders from August to November 2013. The searches were finalized and delivered between late November 2013 and January 2014. After the literature searches were performed, authors continued to review the literature and added relevant articles as needed.

Process Overview

The panel met face-to-face twice and conducted a series of conference calls over a 2-year period. The panel reviewed and discussed all recommendations, their strength, and the quality of evidence. Discrepancies were discussed and resolved, and all final recommendations represent a consensus opinion of the entire panel. For the final version of these guidelines, the panel as a group reviewed all individual sections.

Evidence Review: The GRADE Method

GRADE is a systematic approach to guideline development that has been described in detail elsewhere [2, 39]. The IDSA adopted GRADE in 2008. In the GRADE system, the guideline panel assigns each recommendation with separate ratings for the underlying quality of evidence supporting the recommendation and for the strength with which the recommendation is made (Figure 1). Data from randomized controlled trials begin as “high” quality, and data from observational studies begin as “low” quality. However, the panel may judge that specific features of the data warrant decreasing or increasing the quality of evidence rating, and GRADE provides guidance on how such factors should be weighed [39]. The strength assigned to a recommendation chiefly reflects the panel's confidence that the benefits of following the recommendation are likely to outweigh potential harms. While the quality of evidence is an important factor in choosing recommendation strength, it is not prescriptive.

Guidelines and Conflicts of Interest

The expert panel complied with the IDSA policy on conflicts of interest, which requires disclosure of any financial or other interest that may be construed as constituting an actual, potential, or apparent conflict. Panel members were provided IDSA's conflicts of interest disclosure statement and were asked to identify ties to companies developing products that may be affected by promulgation of the guideline. Information was requested regarding employment, consultancies, stock ownership, honoraria, research funding, expert testimony, and membership on company advisory committees. Decisions were made on a case-by-case basis as to whether an individual's role should be limited as a result of a conflict. Potential conflicts of interests are listed in the Acknowledgments section.

Consensus Development Based on Evidence

The panel obtained feedback from 3 external peer reviewers. The guidelines were reviewed and endorsed by the MSG, the American Academy of Pediatrics (AAP) and the Pediatric Infectious Diseases Society (PIDS). The guideline was reviewed and approved by the IDSA SPGC and the IDSA Board of Directors prior to dissemination.

Revision Dates

At annual intervals, the panel chairs will be asked for their input on the need to update the guideline based on an examination of the current literature. The IDSA SPGC will consider this input and determine the necessity and timing of an update. If warranted, the entire panel or a subset thereof will be convened to discuss potential changes.

Antifungal Agents

Pharmacologic considerations for therapy for candidiasis.

Systemic antifungal agents shown to be effective for the treatment of invasive candidiasis comprise 4 major categories: the polyenes (amphotericin B [AmB] deoxycholate, liposomal AmB, AmB lipid complex [ABLC], and amphotericin B colloidal dispersion [ABCD, not available in the United States]), the triazoles (fluconazole, itraconazole, voriconazole, and posaconazole), the echinocandins (caspofungin, anidulafungin, and micafungin), and flucytosine. Data from a recently completed clinical trial comparing isavuconazole to an echinocandin for treatment of invasive candidiasis are unavailable at this time. Clinicians should become familiar with strategies to optimize efficacy through an understanding of relevant pharmacokinetic properties.

Amphotericin B

Most experience with AmB is with the deoxycholate preparation. Three lipid formulations of AmB have been developed and approved for use in humans: ABLC, ABCD, and liposomal AmB. These agents possess the same spectrum of activity as AmB deoxycholate, but daily dosing regimens and toxicity profiles differ for each agent. The 3 lipid formulation AmB agents have different pharmacological properties and rates of treatment-related adverse events and should not be interchanged without careful consideration. In this document, a reference to AmB, without a specific dose or other discussion of form, should be taken to be a reference to the general use of any of the AmB preparations. For most forms of invasive candidiasis, the typical intravenous dosage for AmB deoxycholate is 0.5–0.7 mg/kg daily, but dosages as high as 1 mg/kg daily should be considered for invasive Candida infections caused by less susceptible species, such as C. glabrata and C. krusei . The typical dosage for lipid formulation AmB is 3–5 mg/kg daily when used for invasive candidiasis. Nephrotoxicity is the most common serious adverse effect associated with AmB deoxycholate therapy, resulting in acute kidney injury in up to 50% of recipients and an electrolyte-wasting tubular acidosis in a majority of patients [40, 41]. Lipid formulations of AmB are more expensive than AmB deoxycholate, but all have considerably less nephrotoxicity [42, 43]. Most observers agree that lipid formulations, with the exception of ABCD, have fewer infusion-related reactions than AmB deoxycholate. The impact of the pharmacokinetics and differences in toxicity of lipid formulations of AmB have not been formally examined in clinical trials. We are not aware of any forms of candidiasis for which lipid formulations of AmB are superior to AmB deoxycholate in terms of clinical efficacy. In addition, we are not aware of any situation in which lipid formulations should not be used, with the exception of urinary tract infections, because of reduced renal excretion of these formulations. Animal model studies suggest a pharmacokinetic and therapeutic advantage for liposomal AmB in the CNS [44]. Data demonstrating that AmB deoxycholate–induced nephrotoxicity is associated with a 6.6-fold increase in mortality have led many clinicians to use lipid formulations of AmB in proven or suspected candidiasis, especially among patients in a high-risk environment, such as an ICU [45].

Fluconazole, itraconazole, voriconazole, posaconazole, and a new expanded-spectrum triazole, isavuconazole, demonstrate similar activity against most Candida species [46–51]. Each of the azoles has less activity against C. glabrata and C. krusei than against other Candida species. All of the azole antifungals inhibit cytochrome P450 enzymes to some degree [52]. Thus, clinicians must carefully consider the influence on a patient's drug regimen when adding or removing an azole. In large clinical trials, fluconazole demonstrated efficacy comparable to that of AmB deoxycholate for the treatment of candidemia [21, 22] and is also considered to be standard therapy for oropharyngeal, esophageal, and vaginal candidiasis, as well as urinary tract infections [53, 54]. Fluconazole is readily absorbed, with oral bioavailability resulting in concentrations equal to approximately 90% of those achieved by intravenous administration [55]. Absorption is not affected by food consumption, gastric pH, or disease state. Among the triazoles, fluconazole has the greatest penetration into the cerebrospinal fluid (CSF) and vitreous, achieving concentrations of >70% of those in serum [56–59]. For this reason, it is often used in the treatment of CNS and intraocular Candida infections. Fluconazole achieves urine concentrations that are 10–20 times the concentrations in serum and, thus, is the preferred treatment option for symptomatic cystitis [59]. For patients with invasive candidiasis, fluconazole should be administered with an average loading dose of 800 mg (12 mg/kg), followed by an average daily dose of 400 mg (6 mg/kg). The higher-dose level (800 mg daily, 12 mg/kg) is often recommended for therapy of susceptible C. glabrata infections, but this has not been validated in clinical trials. Fluconazole elimination is almost entirely renal; thus, a dose reduction is needed in patients with creatinine clearance <50 mL/minute.

Itraconazole is only available in oral formulations. It has not been well studied for invasive candidiasis, and is generally reserved for patients with mucosal candidiasis, especially those who have experienced treatment failure with fluconazole [60]. Gastrointestinal absorption is variable among patients and is greater for the oral solution compared with the capsule formulation. Histamine receptor antagonists and proton pump inhibitors result in decreased absorption of the capsule formulation, whereas acidic beverages enhance absorption [61]. Administration of the capsule formulation with food increases absorption, but the oral solution is better absorbed on an empty stomach [62]. Oral formulations are dosed in adults at 200 mg 3 times daily for 3 days, then 200 mg once or twice daily thereafter.

Voriconazole has demonstrated effectiveness for both mucosal and invasive candidiasis [23, 63]. Its clinical use has been primarily for step-down oral therapy in patients with infection due to C. krusei and fluconazole-resistant, voriconazole-susceptible C. glabrata . CSF and vitreous concentrations are >50% of serum concentration, and voriconazole has been shown to be efficacious in case series for these infection sites [64–66]. Voriconazole does not accumulate in active form in the urine and thus should not be used for urinary candidiasis. The oral bioavailability of voriconazole is excellent and is not affected by gastric pH, but it decreases when the drug is administered with food [67, 68]. In adults, the recommended oral dosing regimen for candidiasis includes a loading dose of 400 mg (6 mg/kg) twice daily for 2 doses, followed by 200–300 mg (3–4 mg/kg) twice daily.

Intravenous voriconazole is complexed to a cyclodextrin molecule; after 2 loading doses of 6 mg/kg every 12 hours, a maintenance dosage of 3–4 mg/kg every 12 hours is recommended. Because of the potential for cyclodextrin accumulation and possible nephrotoxicity among patients with significant renal dysfunction, intravenous voriconazole is not currently recommended for patients with a creatinine clearance <50 mL/minute. However, retrospective examination of intravenous voriconazole use in patients with varying degrees of renal function below this cutoff value has not identified toxic effects, mitigating some of these concerns [69, 70]. Oral voriconazole does not require dosage adjustment for renal insufficiency, but it is the only triazole that requires dosage reduction for patients with mild to moderate hepatic impairment [71].

Common polymorphisms in the gene encoding the primary metabolic enzyme for voriconazole result in wide variability of serum levels [72]. Drug–drug interactions are common with voriconazole and should be considered when initiating and discontinuing treatment with this compound [52]. Voriconazole has not been studied systematically in fluconazole-resistant Candida species, and with the exception of C. krusei , use is currently discouraged. Each of the triazoles can be associated with uncommon side effects. However, several effects are unique to voriconazole or more commonly associated with higher voriconazole concentrations, including hepatic injury, visual side effects, photosensitivity, periostitis, and CNS side effects [73–75].

Posaconazole does not have an indication for primary candidiasis therapy. It demonstrates in vitro activity against Candida species that is similar to that of voriconazole, but clinical data are inadequate to make an evidence-based recommendation for treatment of candidiasis other than oropharyngeal candidiasis [76]. Posaconazole is currently available as an extended-release tablet, an oral suspension, and an intravenous solution. The tablet formulation, given as 300 mg twice daily for 2 doses, then 300 mg daily produces predictable serum concentrations and excellent drug exposure and requires only once-daily dosing [77, 78]. The oral suspension has unpredictable bioavailability [79–81]. Intravenous posaconazole is given as 300 mg twice daily for 2 doses, then 300 mg daily.

Isavuconazole is a recently approved expanded-spectrum triazole antifungal with excellent in vitro activity against Candida species. Preliminary analysis of the recently completed large international double-blind trial comparing isavuconazole to an echinocandin for invasive candidiasis suggests that isavuconazole did not meet criteria for noninferiority (personal communication, Astellas US).

Echinocandins

Caspofungin, anidulafungin, and micafungin are available only as parenteral preparations [82–84]. The minimum inhibitory concentrations (MICs) of the echinocandins are low for most Candida species, including C. glabrata and C. krusei [48–50]. However, recent case series have described treatment failure associated with resistant strains of C. glabrata [85, 86]. Candida parapsilosis demonstrates innately higher MICs to the echinocandins than do most other Candida species, which raises the concern that C. parapsilosis may be less responsive to the echinocandins.

Each of these agents has been studied for the treatment of esophageal candidiasis [24, 87, 88] and invasive candidiasis [25–34], and each has demonstrated efficacy in these situations. Recent pooled analyses of almost exclusively nonneutropenic patients included in randomized invasive candidiasis treatment trials suggest a survival advantage associated with initial echinocandin therapy [19].

All echinocandins have minimal adverse effects. The pharmacologic properties in adults are also very similar, and each is administered once daily intravenously [82–84]. Echinocandins achieve therapeutic concentrations in all infection sites with the exception of the eye, CNS, and urine [59]. The major route of elimination is nonenzymatic degradation. None of the echinocandins require dosage adjustment for renal insufficiency or dialysis. Both caspofungin and micafungin undergo minimal hepatic metabolism, but neither drug is a major substrate for cytochrome P450. Caspofungin is the only echinocandin for which dosage reduction is recommended for patients with moderate to severe hepatic dysfunction. The usual intravenous dosing regimens for invasive candidiasis are as follows: caspofungin: loading dose 70 mg, then 50 mg daily; anidulafungin: loading dose 200 mg, then 100 mg daily; and micafungin: 100 mg daily (no loading dose needed).

Flucytosine

Flucytosine demonstrates broad antifungal activity against most Candida species, with the exception of C. krusei . The compound is available in the United States only as an oral formulation. The drug has a short half-life (2.4–4.8 hours) and is ordinarily administered at a dosage of 25 mg/kg 4 times daily for patients with normal renal function. Flucytosine demonstrates excellent absorption after oral administration (80%–90%), and most of the drug is excreted unchanged (microbiologically active) in the urine [89, 90]; dose adjustment is necessary for patients with renal dysfunction [91, 92].The compound exhibits high penetration into the CNS and eye. Concentration-dependent toxicity results in bone marrow suppression and hepatitis.

Flucytosine is usually given in combination with another antifungal agent due to a high rate of emergence of resistance during monotherapy [93]. The most common use of flucytosine in the setting of Candida infection is in combination with AmB for patients with more refractory infections, such as Candida endocarditis, meningitis, or endophthalmitis. Occasionally, it is used for the treatment of symptomatic urinary tract candidiasis due to fluconazole-resistant C. glabrata [94].

Pediatric Dosing

There is considerable variation in the pharmacokinetics of antifungal agents between adult and pediatric patients, and the data on dosing in pediatric patients are limited. The pharmacological properties of antifungal agents in children and infants have been reviewed in detail [95]. The optimal dose of AmB deoxycholate in neonates has not been clearly defined; a dosage of 1 mg/kg is generally used [96–98]. The safety, efficacy, area under the curve, and maximal concentration of ABLC 2–5 mg/kg day are similar in adults and children [99]. The pharmacokinetics of liposomal AmB in neonates and children suggest that both volume and clearance are affected by weight [100].

Flucytosine clearance is directly proportional to glomerular filtration rate, and infants with a very low birth weight may accumulate high plasma concentrations because of poor renal function due to immaturity [101]. Thus, the use of flucytosine without careful monitoring of serum drug levels is discouraged in this group of patients.

Fluconazole pharmacokinetics vary with age, and the drug is rapidly cleared in children. Thus, a daily fluconazole dose of 12 mg/kg is necessary for neonates and children [102–105]. Voriconazole pharmacokinetics are also highly variable in children [106–108]. To attain plasma exposures comparable to those in adults receiving 4 mg/kg every 12 hours, a loading dose of intravenous voriconazole of 9 mg/kg twice daily, followed by 8 mg/kg twice daily is recommended in children. The recommended oral dose is 9 mg/kg twice daily (maximum dose 350 mg) [95, 107]. There are no data on voriconazole dosing in children <2 years old, and there are no pediatric studies examining the pharmacokinetics of the intravenous formulation, the oral suspension, or the extended-release tablets of posaconazole.

Caspofungin and micafungin are approved by the US Food and Drug Administration (FDA) for use in children. Caspofungin dosing is based on body surface area rather than weight. Dosing in children is a loading dose of 70 mg/m2, followed by 50 mg/m2/day. Preliminary studies suggest an optimal dose of caspofungin in neonates of 25 mg/m2/day. The current recommendation for micafungin for invasive candidiasis is 2 mg/kg/day, with the option to increase to 4 mg/kg/day in children <40 kg. The optimal dose of micafungin in neonates is unknown, but likely to be 10 mg/kg/day or greater [109]. Anidulafungin should be dosed at 1.5 mg/kg/day for neonates and children [110–112].

Considerations During Pregnancy

AmB is the treatment of choice for invasive candidiasis in pregnant women [113]. Fluconazole, itraconazole, posaconazole, and isavuconazole should be avoided in pregnant women, especially those in the first trimester, because of the possibility of birth defects associated with their use. Voriconazole is contraindicated during pregnancy because of fetal abnormalities observed in animals. There are few data concerning the echinocandins; thus, their use is cautioned during pregnancy. Flucytosine is contraindicated during pregnancy because of fetal abnormalities observed in animals.

Therapeutic Drug Monitoring

Therapeutic drug monitoring (TDM) for itraconazole, voriconazole, posaconazole, and flucytosine has been shown to be useful for optimizing efficacy and limiting toxicity in patients receiving therapy for a variety of invasive fungal infections, including mucosal and invasive candidiasis [114]. The basis for TDM is widely variable concentrations among patients and a strong relationship between concentration and efficacy and/or toxicity.

For itraconazole, when measured by high-pressure liquid chromatography (HPLC), both itraconazole and its bioactive hydroxy-itraconazole metabolite are reported, the sum of which should be considered in assessing drug levels. Treatment success has been associated with concentrations ≥1 mg/L and toxicity with concentrations >5 mg/L. Bioassay levels are 3- to 7-fold higher than those measured by HPLC. Because of nonlinear pharmacokinetics in adults and genetic differences in metabolism, there is both intrapatient and interpatient variability in serum voriconazole concentrations [115–118]. TDM should be considered for patients receiving voriconazole, because drug toxicity has been observed at higher serum concentrations and reduced clinical response has been observed at lower concentrations [117, 118]. The therapeutic trough concentration window for voriconazole is 1–5.5 mg/L. Few data are available to support a specific concentration to optimize posaconazole efficacy. Flucytosine monitoring is predominantly used to prevent concentration-associated toxicity. Peak concentrations <100 mg/L are recommended to avoid the predictable liver and bone marrow effects [119].

Antifungal Susceptibility Testing

Intensive efforts to develop standardized, reproducible, and relevant susceptibility testing methods for fungi have resulted in the development of the Clinical and Laboratory Standards Institute (CLSI) M27-A3 and the European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodologies for susceptibility testing of yeasts [120]. Interpretive breakpoints for susceptibility take into account the MIC, as well as pharmacokinetic/pharmacodynamic data and animal model data. They are reported for each species. Breakpoints have been established for most, but not all, drugs for the 5 most common Candida species [47, 50, 121, 122] (Table 1).

In many instances, clinical breakpoints have decreased from those used previously. For example, the prior Candida clinical breakpoint for susceptibility to fluconazole was ≤8 mg/L. With the new interpretation, the susceptible value has been reduced to ≤2 mg/L for C. albicans . For C. glabrata , there is no breakpoint established for susceptibility to fluconazole, itraconazole, posaconazole, or voriconazole (Table 1).

When there is no clinical breakpoint established, the epidemiologic cutoff value (ECV) based on an examination of the distribution of MICs within a species can be used. The ECV is defined as the MIC value that excludes non–wild type strains, notably isolates that are likely to contain a resistant mutant [50, 123]. The addition of the ECV method is particularly useful for detecting emergence of resistance in a Candida species at an institution.

The susceptibility of Candida to the currently available antifungal agents is generally predictable if the species of the infecting isolate is known. Currently, antifungal resistance in C. albicans is uncommon. However, individual isolates may not necessarily follow this general pattern [124]. Recent surveillance studies suggest that triazole resistance among C. glabrata isolates has increased to a degree that is it difficult to rely upon these agents for therapy in the absence of susceptibility testing [12, 125, 126]. A similar trend has begun to emerge for a smaller proportion of C. glabrata isolates and the echinocandins [35, 85, 125]. The value of susceptibility testing for other Candida species is less clear, although resistance among C. tropicalis and C. parapsilosis has been reported from tertiary care institutions that have extensive use of antifungal agents [127, 128]. Because of these trends, susceptibility testing is increasingly used to guide the management of candidemia and invasive candidiasis.

Diagnosis of Candidiasis

Cultures of blood or other samples collected under sterile conditions have long been considered diagnostic gold standards for invasive candidiasis. Nonculture diagnostic tests, such as antigen, antibody, or β-D-glucan detection assays, and polymerase chain reaction (PCR) are now entering clinical practice as adjuncts to cultures. If used and interpreted judiciously, these tests can identify more patients with invasive candidiasis and better direct antifungal therapy. To fully realize the benefits of combining culture and nonculture tests, however, clinicians must carefully consider the types of invasive candidiasis, understand the strengths and limitations of each assay, and interpret test results in the context of the clinical setting.

Use of Cultures in the Diagnosis of Invasive Candidiasis

Invasive candidiasis encompasses 3 entities: candidemia in the absence of deep-seated candidiasis, candidemia associated with deep-seated candidiasis, and deep-seated candidiasis in the absence of candidemia [20]. The distribution of these entities is likely to differ among centers; on balance, data suggest that the groups are approximately equal in size [129].

The overall sensitivity of blood cultures for diagnosing invasive candidiasis is roughly 50% [20]. The limit of detection of blood cultures is ≤1 colony-forming unit/mL [130, 131]. The limit of detection for cultures is at or below that of PCR [132–135]. As such, blood cultures should be positive during the vast majority of active Candida bloodstream infections. They may be negative in cases of extremely low-level candidemia, intermittent candidemia, deep-seated candidiasis that persists after sterilization of the bloodstream, or deep-seated candidiasis resulting from direct inoculation of Candida in the absence of candidemia. Blood cultures are limited by slow turnaround times (median time to positivity of 2–3 days, ranging from 1 to ≥7 days), and the fact that they may become positive relatively late in the disease course [130, 136]. Cultures of tissues or fluid recovered from infected sites during deep-seated candidiasis also exhibit poor sensitivity (often <50%) and slow turnaround times, and require invasive sampling procedures that may be dangerous or contraindicated due to underlying medical conditions [137].

Antigen and Antibody Detection

Candida antigen and anti- Candida antibody detection has gained greater acceptance in Europe than the United States. In general, antigen detection is limited by rapid clearance from the bloodstream [138]. Concerns have been expressed about the reliability of antibody detection in immunosuppressed hosts, but assays have performed well in patients with neutropenia and cell-mediated immune defects (including hematopoietic cell and solid organ transplant recipients) [138, 139]. Serum immunoglobulin G (IgG) responses against specific antigens have typically performed better than immunoglobulin M (IgM) responses, suggesting that many patients mount amnestic responses or have ongoing, subclinical tissue invasion [139]. The best-studied test is a combined mannan/antimannan antibody assay, which is currently approved for use in Europe, but not the United States (Platelia Candida Ag and Ab; Bio-Rad). In a meta-analysis of 14 studies, the sensitivity/specificity for the diagnosis of invasive candidiasis of mannan and antimannan IgG individually were 58%/93% and 59%/83%, respectively [140]. Values for the combined assay were 83% and 86%, with best performances for C. albicans , C. glabrata , and C. tropicalis infections. In one study of candidemia, at least one test was positive before blood culture in 73% of patients [141]. In a study of hepatosplenic candidiasis, at least one test was positive before radiographic changes in 86% of patients [142]. This assay is not used widely in the United States, and its role in the diagnosis and management of invasive candidiasis is unclear.

β-D-Glucan detection

β-D-glucan is a cell wall constituent of Candida species, Aspergillus species, Pneumocystis jiroveci , and several other fungi. A serum β-D-glucan assay (Fungitell; Associates of Cape Cod, East Falmouth, Massachusetts) has been approved by the FDA as an adjunct to cultures for the diagnosis of invasive fungal infections. True-positive results are not specific for invasive candidiasis, but rather suggest the possibility of an invasive fungal infection. For this reason, among patient populations that are also at risk for invasive mold infections, such as hematopoietic cell transplant recipients, β-D-glucan offers a theoretical advantage over more narrow assays for candidiasis. β-D-glucan detection can identify cases of invasive candidiasis days to weeks prior to positive blood cultures, and shorten the time to initiation of antifungal therapy [143]. Prophylactic or empiric antifungal treatment is likely to impact test performance. On the one hand, antifungal agents may reduce diagnostic sensitivity [144–146], but decreasing β-D-glucan levels may also correlate with responses to antifungal therapy [147].

In meta-analyses of β-D-glucan studies, the pooled sensitivity and specificity for diagnosing invasive candidiasis were 75%–80% and 80%, respectively [144–146]. A number of issues complicate the interpretation of these data, including uncertainties about the best cutoff value for a positive result, number of positive tests required to establish a diagnosis, and optimal timing and frequency of testing among at-risk patients. There is marked heterogeneity among studies in how they address these issues, as well as in patient and control populations, range and type of fungal pathogens targeted, invasive candidiasis disease entities, distributions of Candida species, prior antifungal use, specific β-D-glucan assays employed, and other aspects of study design and statistical interpretation.

The major concern about β-D-glucan detection is the potential for poor specificity and false positivity, which may be particularly problematic in the patient populations for which nonculture diagnostics would be most helpful. For example, false-positive results are rare in healthy controls, but decidedly more common among patients in an ICU [148]. Causes of false positivity include other systemic infections, such as gram-positive and gram-negative bacteremia, certain antibiotics, such as intravenous amoxicillin-clavulanate (not available in the United States), hemodialysis, fungal colonization, receipt of albumin or immunoglobulin, use of surgical gauze or other material containing glucan, and mucositis or other disruptions of gastrointestinal mucosa [149–154]. The specificity of β-D-glucan can be improved by requiring consecutive positive results rather than a single result, but false positivity remains a significant limitation if the above-listed factors are common in the population tested. As an extreme example, the per-patient sensitivity/specificity and positive and negative predictive values of routine surveillance β-D-glucan testing in a recent study of lung transplant recipients were 64%/9% and 14%/50%, respectively [155]. Moreover, 90% of patients had at least one positive β-D-glucan result. Therefore, the test will be most useful if targeted to subgroups of patients whose clinical course or risk factors are particularly suggestive of invasive candidiasis or other fungal infection.

The role of β-D-glucan testing of samples other than serum in the diagnosis of invasive candidiasis is not established. Studies of β-D-glucan testing of CSF reported sensitivity and specificity of 100% and 95%–98%, respectively, for the diagnosis of non- Candida fungal CNS infections [156, 157]. β-D-glucan detection was highly sensitive and specific in a rabbit model of hematogenous C. albicans meningoencephalitis [158]. Limited data suggest that positive predictive values of β-D-glucan in bronchoalveolar lavage fluid are poor for diagnosing fungal pneumonia [159]. There are case reports for testing of samples collected from other sites of invasive Candida infection [160].

Limited data exist pertaining to the usefulness of β-D-glucan testing in children [161]. The optimal threshold for positivity of β-D-glucan testing in children is not known. In studies of uninfected immunocompetent individuals, mean β-D-glucan levels are slightly higher in children than adults [162]. Currently, it is not recommended to use β-D-glucan testing to guide pediatric clinical decision making.

Polymerase Chain Reaction

Candida PCR shares many of the potential benefits and shortcomings of β-D-glucan detection. Compared to cultures, PCR assays of various blood fractions have been shown to shorten the time to diagnosis of invasive candidiasis and initiation of antifungal therapy [134, 135]. The pooled sensitivity and specificity of PCR for suspected invasive candidiasis in a recent meta-analysis were 95% and 92%, respectively [134]. In probable invasive candidiasis, sensitivity of PCR and blood cultures was 85% and 38%, respectively. The impact of antifungal agents on diagnostic sensitivity was unclear. Data among patients colonized with Candida were surprisingly limited, but there was a trend toward lower specificity.

A major limitation of PCR studies is the lack of standardized methodologies and multicenter validation of assay performance. A multicenter US study assessing the performance of a self-contained instrument that amplifies and detects Candida DNA by PCR and T2 magnetic resonance (T2 Biosystems, Lexington, Massachusetts), respectively, has been completed [163]. This assay is FDA approved, but its role in the early diagnosis and management of candidemia remains unclear until more data are available. PCR has potential advantages over β-D-glucan or antigen-antibody assays, including the capacity for species identification, detection of molecular markers for drug resistance, and multiplex formatting. In Europe, a whole-blood, multiplex real-time PCR assay (SeptiFast, Roche) that detects 19 bacteria and 6 fungi ( C. albicans , C. glabrata , C. parapsilosis , C. tropicalis , C. krusei , and Aspergillus fumigatus ) has been investigated in several studies of sepsis and neutropenic fever. Among patients with candidemia in one study, the sensitivity of the test was 94%; the only negative result was observed with C. famata candidemia [164]. The role of PCR in testing samples other than blood is not established.

Nonculture Diagnostic Testing for Blood Culture–Negative Invasive Candidiasis

The overwhelming majority of studies have examined nonculture diagnostics in the setting of candidemia. More limited data on deep-seated candidiasis demonstrate how these tests may identify cases that are currently missed by blood cultures. In a single-center study of prospectively enrolled patients, the sensitivities/specificities of the Fungitell β-D-glucan assay and a real-time quantitative PCR assay (ViraCor-IBT, Lee's Summit, Missouri) for invasive candidiasis were 56%/73% and 80%/70%, respectively [132]. More importantly, the sensitivities of contemporaneously collected blood cultures, β-D-glucan assay, and PCR samples among patients with deep-seated candidiasis (mostly intra-abdominal candidiasis) were 21%, 67%, and 88%, respectively. The combination of either a positive blood culture or positive β-D-glucan assay had sensitivity for invasive candidiasis of 79%; a positive blood culture or positive PCR sample was 98% sensitive. A second study investigated the serum β-D-glucan assay, Candida score (a predictive score for invasive candidiasis based on clinical parameters and burden of Candida colonization), and Candida colonization indices (predictive scores based on burden of colonization) among prospectively enrolled patients who were in surgical ICUs at 2 hospitals and who were at particularly high risk for intra-abdominal candidiasis [143]. The sensitivity/specificity of 2 consecutive positive β-D-glucan results was 65%/78%. In contrast, the sensitivity of blood cultures was only 7%. In addition to identifying cases missed by blood cultures, the β-D-glucan assay was positive a median of 5 and 6 days prior to positive intra-abdominal cultures and institution of antifungal therapy, respectively. The sensitivities of Candida scores and colonization indices were comparable to β-D-glucan, but specificities were poorer (≤43%).

The interpretation of specificity in these studies was complicated by the fact that negative controls were also at risk for invasive candidiasis. Therefore, it is unclear if positive test results for controls were false positives (as defined in the studies) or true positives that were missed due to the poor sensitivity of intra-abdominal and blood cultures. Indeed, this is a central challenge in assessing new diagnostics for invasive candidiasis: How can test performance be accurately measured when the gold standard is inadequate?

Full Recommendations

Recommendations, evidence summary, recommendation.

Central venous catheters and other intravascular devices are important risk factors in the development and persistence of candidemia in nonneutropenic patients [5, 7–9, 184]. A CVC is present in at least 70% of nonneutropenic patients with candidemia at the time that the diagnostic blood culture is obtained [5, 7–9, 170, 184–187]. The relationship of candidemia to CVCs has been assumed on the basis of observation, clinical experience, and an understanding of the role of biofilm in the genesis of bloodstream infections [188, 189]. That candidemia in nonneutropenic patients is commonly due to contaminated CVCs is undeniable, but there remains controversy as to how best to distinguish a catheter-associated candidemia from one that is related to another source, such as the gastrointestinal tract.

There have been no prospective clinical studies designed to examine CVC management as a primary measurement related to outcome. Moreover, several retrospective analyses have led to very different conclusions regarding the necessity and timing of CVC removal in the candidemic patient [19, 190–193]. Thus, the controversy continues, with some groups arguing for a strictly individualized approach to each patient [190] and others for an approach that removes CVCs in all nonneutropenic candidemic patients in whom it is safe and feasible to do so [19]. No prospective study has demonstrated a survival benefit to early CVC removal in patients who have candidemia, but most studies have demonstrated a shorter duration of candidemia and/or a trend toward improved outcomes [14, 21–23, 27, 28, 168, 192–200]. The recent combined analysis of 7 candidemia trials observed a survival benefit among those who underwent CVC removal at some time during treatment for candidemia [19]. The survival benefit applied to patients across all levels of severity of illness as determined by APACHE II scores.

The Expert Panel members strongly believe that CVCs should be removed if this can be performed safely when candidemia is documented in the nonneutropenic patient. It is intuitive that each patient with candidemia must be managed individually with respect to CVC removal or retention, but on balance, the bulk of data supports an approach that leads to early removal among nonneutropenic patients in whom the catheter is a likely source of infection.

Among neutropenic patients, the role of the gastrointestinal tract as a source for disseminated candidiasis is evident from autopsy studies, but in an individual patient, it is difficult to determine the relative contributions of the gastrointestinal tract vs the CVC as the primary source of candidemia [195, 201]. An exception is made for candidemia due to C. parapsilosis, which is very frequently associated with CVCs [188, 189, 200, 202]. A recent retrospective analysis that included mostly nonneutropenic patients underscored the influence of early CVC removal, specifically among patients with C. parapsilosis bloodstream infection, on clinical outcome [176].

Candidemia that develops in neutropenic patients is a life-threatening infection associated with acute disseminated candidiasis, a sepsis-like syndrome, multiorgan failure, and death. Outcomes are particularly poor in people with protracted neutropenia, such as that which develops after induction therapy for hematologic malignancies [190, 203, 204]. Candidemia associated with C. tropicalis is associated with particularly poor outcomes in neutropenic hosts. Chronic disseminated candidiasis (hepatosplenic candidiasis) can ensue as a complication of candidemia in neutropenic patients, especially when patients with gastrointestinal tract mucositis do not receive antifungal prophylaxis. There are no adequately powered randomized controlled trials of treatment of candidemia in neutropenic patients. The data are largely derived from single-arm studies, small subsets of randomized controlled studies that have enrolled mostly nonneutropenic patients, and pooled outcomes from randomized trials [205, 206].

Historically, candidemia in neutropenic patients was treated with an AmB formulation. The availability of voriconazole and the echinocandins has led to greater use of these agents, but without compelling clinical data. The extensive use of fluconazole for prophylaxis to prevent invasive candidiasis in neutropenic patients and the lack of meaningful prospective data has led to a diminished therapeutic role for this agent among these patients, except for use as maintenance, or step-down therapy after organism species and susceptibilities are obtained in clinically stable patients [207].

The numbers of neutropenic patients included in candidemia treatment studies are small. In these trials, 50% of caspofungin recipients vs 40% of AmB deoxycholate recipients [25], 68% of micafungin recipients vs 61% of liposomal AmB recipients [26], and 69% of micafungin recipients vs 64% of caspofungin recipients [28] with neutropenia at onset of therapy were successfully treated. The randomized controlled trial of anidulafungin vs fluconazole enrolled too few neutropenic patients with candidemia to generate meaningful data regarding efficacy [27]. In 2 retrospective studies, successful outcomes for primary treatment of neutropenic patients were reported in 64% of those receiving AmB deoxycholate, 64% of those receiving fluconazole, and 68% of those receiving caspofungin [29, 208].

Additional insights can be gleaned from data derived from studies of empiric antifungal therapy involving febrile patients with neutropenia who had candidemia at baseline. In these studies, baseline candidemia was cleared in 73% of those treated with AmB deoxycholate vs 82% of those treated with liposomal AmB [209] and in 67% of those treated with caspofungin vs 50% of those treated with liposomal AmB [210]. Data from a large randomized trial also suggest that voriconazole is a reasonable choice for febrile patients with neutropenia and suspected invasive candidiasis for whom additional mold coverage is desired [211].

A systematic review was conducted to analyze available data generated in treatment trials and empiric therapy trials that enrolled neutropenic patients [205]. This included 17 trials that randomized 342 neutropenic patients with documented invasive candidiasis. Pooling of results favored use of nonpolyenes to AmB-containing comparators. Another pooled analysis that summarized results of treating with micafungin or comparators (liposomal AmB or caspofungin) for candidemia in the setting of malignancy-associated neutropenia from 2 randomized trials demonstrated success rates ranging from 53% to 85%, but no significant differences among treatment groups [206].

On the basis of these limited data, the success rates of antifungal therapy for candidemia in patients with neutropenia do not appear to be substantially different from those reported in the large randomized trials of nonneutropenic patients. However, conclusions may be limited by significant enrollment bias of selected patients. Although these data do not suggest less favorable outcomes associated with fluconazole and voriconazole, many experts prefer lipid formulation AmB or an echinocandin, which are fungicidal, as first-line agents. Similar to the approach in nonneutropenic patients, the recommended duration of therapy for candidemia in neutropenic patients is for 14 days after resolution of attributable signs and symptoms and clearance of the bloodstream of Candida species, provided that there has been recovery from neutropenia. When neutropenia is protracted, an antifungal drug should be continued until engraftment. This recommendation is based on limited data from prospective randomized trials and has been associated with few complications and relapses [209, 210].

The management of intravascular catheters in neutropenic patients with candidemia is less straightforward than in their nonneutropenic counterparts. Distinguishing gut-associated from vascular catheter–associated candidemia can be difficult in these patients [201]. The data for catheter removal are less compelling, and catheter removal often creates significant intravenous access problems. An analysis of 842 patients enrolled in 2 phase 3 treatment trials failed to demonstrate significant clinical benefits of catheter removal in multivariable analyses that adjusted for other measures of prognostic significance [190]. The Expert Panel suggests that catheter removal should be considered on an individual basis, taking into account feasibility and risk of removal.

An extremely important factor influencing the outcome of candidemia in neutropenic patients is the recovery of neutrophils during therapy. In multiple cohort studies of patients with cancer who had candidemia, and pooled analyses of randomized trials, persistent neutropenia was associated with a greater chance of treatment failure [190, 203, 204, 212]. This has led to improvement of strategies to harvest granulocytes from donors (including community volunteers), using G-CSF mobilization, which has been shown to be safe and feasible [213]. Analysis of subsets of people within phase 1/2 granulocyte infusion studies, retrospective observations, and small cohort studies suggest that G-CSF–mobilized granulocyte transfusions may be of benefit in patients with persistent candidemia and prolonged neutropenia [213–215]. In a randomized controlled trial, granulocyte infusions were associated with few toxicities, but small numbers of patients in infection subgroups limited conclusions of efficacy [216]. The panel recommends consideration of granulocyte infusions in select situations, when such technology is feasible.

Chronic disseminated candidiasis is an uncommon syndrome seen almost entirely in patients who have hematologic malignancies and who have just recovered from neutropenia [217–219]. Candida albicans is the species most commonly isolated, but C. tropicalis , C. glabrata , C. krusei , and other Candida species also have been implicated. Fever, right upper quadrant discomfort, nausea, and elevation of liver enzymes occur following return of neutrophils and persist for months unless treatment is initiated. Contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography-CT (PET-CT), and sometimes ultrasound have all been shown to be useful for diagnosis and for follow-up [217, 218, 220, 221]. Biopsy of lesions may reveal budding yeasts and hyphae, but organisms may not be seen on biopsy specimens and often do not grow in culture, leading some to suggest that chronic disseminated candidiasis represents an immune reconstitution syndrome [219].

Approaches to the treatment of chronic disseminated candidiasis are based on anecdotal case reports and open-label series. Early experience with AmB was discouraging; as many as one-third of patients died within 3 months with active infection, and the overall mortality was 74% [222]. With the use of newer antifungal agents, mortality has decreased to 21% overall and is highly linked to relapse of leukemia [223]. Lipid formulations of AmB have proved more efficacious, perhaps related to better tissue concentrations [217, 218, 224, 225]. Fluconazole alone or following AmB induction has been shown to be effective [226, 227]. Increasingly, patients are receiving fluconazole prophylaxis, and thus have an increased risk of developing infection with a fluconazole-resistant organism. In this population, a broader-spectrum azole or an echinocandin is more appropriate therapy. Only a few reports note experience with voriconazole or posaconazole for this condition, but echinocandins are increasingly used to treat this infection [219, 223, 228–231].

Antifungal therapy should be given until all lesions have resolved radiographically in order to prevent relapse. MRI or PET-CT appear to be the most sensitive follow-up modalities, but are expensive [220, 221]; standard contrast-enhanced CT is less expensive and is adequate for follow-up. Additional chemotherapy and hematopoietic cell transplant should be pursued when clinically appropriate and not delayed because of candidiasis. However, antifungal therapy must be continued during the period of immunosuppression to prevent relapse of infection [219, 223, 228–231].

There is evidence that this syndrome could possibly be a form of immune reconstitution and that corticosteroids or anti-inflammatory agents might have a role in selected patients. Several investigators have reported rapid defervescence and improvement in liver enzyme tests when corticosteroids have been given in conjunction with antifungal agents [219, 223, 232, 233]. The dosage of corticosteroids has generally been 0.5–1 mg/kg daily of oral prednisone. The duration of steroid treatment, although highly variable, in most cases has been several weeks, given as a tapering dose [232, 233]. However, the role of corticosteroids in this disease is still not clear.

Candida species are an increasing cause of invasive infection in nonneutropenic patients in the ICU; half to two-thirds of all episodes of candidemia occur in an ICU [5, 14, 167, 170, 234]. Candida bloodstream infections are associated with increased ICU and hospital stay [129, 235]. Most estimates of attributable mortality rates for invasive candidiasis in this setting are 30%–40% [167, 170]. In those patients who have septic shock due to Candida species and who do not have adequate source control or antifungal therapy begun within 24 hours, the mortality approaches 100% [14]. Prompt initiation of appropriate antifungal therapy has been associated with as much as a 50% reduction in mortality [14, 17, 18, 236]. Prompt and appropriate antifungal therapy is often delayed because of the relative insensitivity of blood cultures, the time needed for blood cultures to yield growth, the possibility of negative blood cultures with invasive abdominal candidiasis, and the lack of specific clinical signs and symptoms. Strategies for initiating empiric antifungal therapy include an evaluation of risk factors and use of surrogate markers.

Optimal utilization of risk factors and colonization status to derive clinical scoring systems and the interpretation of non-culture-based diagnostic tests to identify patients with invasive candidiasis to initiate early empiric antifungal therapy have been the subjects of many investigations. Retrospective and single-center studies have yielded conflicting results, depending on unique patient populations. Well-designed prospective clinical trials in this area have been difficult to perform, and many unanswered questions remain.

Risk factors for development of invasive candidiasis include Candida colonization, severity of illness, exposure to broad-spectrum antibiotics, recent major surgery, particularly abdominal surgery, necrotizing pancreatitis, dialysis, parenteral nutrition, corticosteroids, and the use of CVCs [237, 238]. Empiric therapy based solely on colonization with Candida species appears inadequate [16, 239]. Prospective studies evaluating the extent of Candida colonization with scores or indices have not been shown to change management, and they are labor intensive and expensive [234].

Several studies have looked at prediction models to identify patients at highest risk. These studies are characterized by high specificity, but low sensitivity, thus missing many patients with candidiasis [240–242]. A subset of postsurgical patients, particularly those with recurrent gastrointestinal perforation, anastomotic leaks, or acute necrotizing pancreatitis may be at uniquely high risk for candidiasis [238, 240, 243, 244]. The most important combination of factors in an individual patient has not been established.

Surrogate markers that have been evaluated in the ICU setting include β-D-glucan, mannan-antimannan antibodies, and PCR testing. β-D-glucan appears to be more sensitive than Candida colonization scores or indices, but appears to have low positive predictive value [245–248]. False-positive results are a problem, as noted in the Background section. The optimal timing and number of samples is unknown. In a recent prophylaxis trial of high-risk ICU patients, β-D-glucan testing performed twice weekly identified 87% of patients with proven candidiasis [249]. Small studies basing preemptive therapy on β-D-glucan testing suggest that the high negative predictive value of this test could be useful in excluding invasive candidiasis in the ICU setting [151, 248, 250–252].

Combined mannan-antimannan testing has variable sensitivity and specificity [142, 253]. Real-time PCR appears to have similar sensitivity to β-D-glucan for the diagnosis of candidemia, but may be more sensitive for the diagnosis of other forms of invasive candidiasis [132]. Tests using magnetic biosensor technology for the rapid detection of Candida species from whole-blood samples (T2 Biosystems) are also promising [163]. Recommendations for the clinical use of these tests are challenging without robust data in the at-risk ICU population.

Limited clinical studies have evaluated the efficacy of empiric strategies. Retrospective studies indicate potential for higher survival when empiric antifungal therapy is given to high-risk patients [254]. Prospective clinical trials of empiric antifungal therapy in the ICU are difficult to conduct and have yielded conflicting results. Selected older studies, including those in specific patient populations, such as those with prior gastrointestinal surgery or bowel perforation, demonstrated potential benefit [255, 256]. In a randomized clinical trial of ICU patients at risk for invasive candidiasis and with unexplained fever, empiric fluconazole (800 mg daily for 14 days) was not associated with better outcomes when compared with placebo [257]. A recent study comparing caspofungin to placebo among ICU patients with signs of infection, Candida colonization, and clinical risk factors for invasive candidiasis was stopped prematurely due to poor patient accrual, confirming the difficulty in conducting these trials [249].

Widespread use of antifungal agents must be balanced against the cost, the risk of toxicity, and the emergence of resistance. None of the existing clinical trials have been adequately powered to assess the risk of the emergence of azole or echinocandin resistance. Empiric antifungal therapy should be considered in critically ill patients with risk factors for invasive candidiasis and no other known cause of fever. Preference should be given to an echinocandin in hemodynamically unstable patients, those previously exposed to an azole, and in those colonized with azole-resistant Candida species. Fluconazole may be considered in hemodynamically stable patients who are colonized with azole-susceptible Candida species or who have no prior exposure to azoles. There are no data guiding the appropriate duration of empiric antifungal therapy among patients who have a clinical response to therapy, but it is logical that it should not differ from the treatment of documented candidemia. Conversely, therapy can be stopped after several days in the absence of clinical response if cultures and surrogate markers are negative.

Time to appropriate therapy in candidemia appears to have a significant impact on the outcome of patients with this infection [14, 17, 18]. However, insensitivity and significant delays using culture techniques, as well as limitations of rapid diagnostic tests, remain for this common cause of bloodstream infection among patients in the ICU [258, 259]. A safe and effective prophylactic strategy to prevent candidemia among high-risk patients could be of great benefit [260]. The approach to prophylaxis has been either broad, in which all patients within the ICU setting are treated [261, 262], or selective, in which only specific high-risk groups of patients are targeted for prophylaxis [249, 263, 264].

For ICUs that show very high rates of invasive candidiasis, in excess of the expected rates of <5% of patients, antifungal prophylaxis may be warranted in selected patients who are at highest risk [260]. Two randomized, placebo-controlled trials have shown a reduction in the incidence of invasive candidiasis in single units or single hospitals when fluconazole prophylaxis was used broadly in the ICU; one study targeted all patients in a surgical ICU [262] and, in the other, all patients receiving mechanical ventilation [261]. In both studies, Candida urinary tract infections, as well as invasive candidiasis and candidemia, were included as endpoints.

In a blinded placebo-controlled trial that enrolled a small number of patients, fluconazole prophylaxis was shown to decrease Candida intra-abdominal infections in high-risk patients in the surgical ICU [263]. A noncomparative, open-label trial using caspofungin prophylaxis in a small number of similar high-risk surgical patients also showed benefit [264]. A recent multicenter placebo-controlled, blinded clinical trial of caspofungin prophylaxis targeting only those ICU patients who met specific criteria for high risk for invasive candidiasis showed a trend toward reduction of invasive candidiasis, but was limited by the sample size [249].

Several meta-analyses have assessed the issue of fluconazole prophylaxis in ICU patients [265–268]. Not surprisingly, there were methodological differences among the studies, and there was variation among the study populations. All 4 meta-analyses showed that fluconazole prophylaxis was associated with a reduction in invasive candidiasis, but only 2 showed a reduction in candidemia [267, 268]. Importantly, only one analysis showed a reduction in mortality from invasive candidiasis [268]. None of the meta-analyses assessed the issues of adverse effects of antifungal agents, the emergence of resistance to fluconazole, or major ecological shifts in Candida species, topics of great importance in the ICU setting. A Cochrane analysis confirmed the importance of focusing prophylactic efforts on high-risk patients, noting that the number needed to treat to prevent one case of invasive candidiasis in the ICU setting varied from 9 in high-risk patients to 188 in low-risk patients [269].

Few data exist on risk factors for candidemia in pediatric intensive care unit (PICU) patients. A population-based, case-control study conducted in a large tertiary care pediatric center found an incidence of candidemia of 3.5 per 1000 PICU admissions [270]. The presence of a CVC, a diagnosis of malignancy, and receipt of either vancomycin or an antianaerobic antimicrobial agent for >3 days were independently associated with the development of candidemia. Children who had ≥3 of these risk factors in different combinations had a predicted probability of developing candidemia of between 10% and 46%.

Data are accruing on the use of skin decolonization with antiseptic agents in the ICU to decrease bloodstream infections, including those caused by Candida species [271–274]. Several multicenter randomized clinical trials have shown that daily bathing of ICU patients with chlorhexidine decreases the incidence of both catheter-associated and non-catheter-associated hospital-acquired bloodstream infections [271–273]. These studies were aimed primarily at evaluating the impact on multidrug-resistant bacterial infections and provide few data on Candida infections. However, at least one of these trials found a significant reduction in catheter associated Candida bloodstream infections [272]. A meta-analysis on the effects of daily chlorhexidine bathing included 10 studies performed in an ICU setting, only one of which was a randomized controlled trial. The conclusion was that chlorhexidine bathing reduced the incidence of bloodstream infections, including catheter-associated bacterial infections [274]. Although not proven to prevent candidemia, there is little risk to the use of chlorhexidine in ICU patients, and this practice may prove beneficial.

There are limited data to guide therapy for CNS Candida infections in the neonate. All AmB preparations, including the lipid formulations, penetrate the CNS and have fungicidal activity in the CNS [44]. AmB deoxycholate and liposomal AmB were found to have greater antifungal efficacy when studied in a rabbit model of Candida meningoencephalitis compared with the other formulations [44]. The clinician must weigh the benefits and drawbacks of using liposomal AmB with its good CSF penetration but poor urine levels vs using AmB deoxycholate with less good CSF levels but better urine levels.

The benefit of adding flucytosine for neonates with CNS candidiasis is uncertain. In the largest prospective study evaluating treatment outcomes of CNS candidiasis in neonates, the median time to clear CSF was longer for those who received flucytosine plus AmB deoxycholate (17.5 days; 6 infants), compared with those who received only AmB deoxycholate (6 days; 18 infants) [279]. In addition, flucytosine is poorly tolerated, and gastrointestinal side effects may hinder oral feeding in neonates. In general, flucytosine is used only in neonates who have not responded to AmB alone.

Data supporting the use of echinocandins in neonates are emerging; however, several key issues require further clarification. The optimal dose of echinocandins in neonates remains uncertain [109, 284, 293–297]. Furthermore, there are concerns regarding the penetration of echinocandins into the CSF. Echinocandins appear to penetrate brain tissue, but not the CSF, and achieve concentrations in brain shown to be effective in animal models when dosages higher than those recommended for humans have been used [298, 299]. Limited clinical data suggest that the echinocandins may be effective for the treatment of CNS infections in neonates, but are not adequate to recommend their use at this time [293].

Numerous studies examining fluconazole prophylaxis for the prevention of invasive candidiasis in neonates have consistently demonstrated efficacy and possibly reduced mortality [300–310]. Fluconazole, 3 mg/kg or 6 mg/kg twice weekly, significantly reduced rates of invasive candidiasis in premature neonates weighing <1000 g in nurseries with a very high incidence of Candida infections [300, 302]. A 2007 Cochrane review of clinical trials of fluconazole prophylaxis demonstrated efficacy, with a typical relative risk of 0.23 and number needed to treat of 9. The number needed to treat varied substantially depending on the incidence of invasive candidiasis in a particular ICU. The majority of studies have demonstrated the safety of fluconazole prophylaxis and lack of emergence of resistance.

Enteral or orally administered nystatin has been shown to be effective in reducing invasive candidiasis in preterm infants [303, 311–313]. In one study, nystatin prophylaxis was also associated with a reduction in all-cause mortality [313]. However, there remains a paucity of data on nystatin prophylaxis in infants <750 grams (the group at highest risk), and nystatin may not always be able to be administered when there is an ileus, gastrointestinal disease, feeding intolerance, or hemodynamic instability. These clinical situations are very common in low-gestational-age premature infants and limit the broad applicability of nystatin prophylaxis as a preventive strategy.

Lactoferrin is a mammalian milk glycoprotein involved in innate immunity. In a randomized trial of bovine lactoferrin in infants <1500 g, the incidence of late-onset sepsis was significantly lower in the lactoferrin group than in the placebo group [314]. A secondary analysis of the clinical trial showed that lactoferrin also reduced the incidence of invasive fungal infections compared with placebo [314]. Further confirmation of the efficacy and safety of oral bovine lactoferrin for the prevention of invasive candidiasis is needed, especially in infants <750 g, because there were only a few neonates in this category in this trial.

Intra-abdominal candidiasis in patients who have had recent abdominal surgery or intra-abdominal events refers to a heterogeneous group of infections that includes peritonitis, abdominal abscess, and purulent or necrotic infection at sites of gastrointestinal perforation or anastomotic leak. Up to 40% of patients with secondary or tertiary peritonitis, as defined by a multinational consensus panel, may develop intra-abdominal candidiasis with a high mortality rate [243, 244, 315, 316]. A subset of postsurgical patients, particularly those with recurrent gastroduodenal perforation, anastomotic leaks, or acute necrotizing pancreatitis, are at uniquely high risk for invasive candidiasis [243, 244, 263, 316–320]. In other settings, such as perforated appendicitis, invasive candidiasis appears to be a rare complication [316, 319]. Infections are often polymicrobial, with yeast noted in as high as 20% of all cases and 40% in patients with a recent gastroduodenal perforation [319, 320].

Diagnosis is hampered by the lack of specific clinical signs and symptoms. Blood cultures are often negative [321]. A laboratory report of yeast isolated from an abdominal specimen must be evaluated to distinguish between contamination, colonization, and invasive infection. Swabs of superficial wounds and specimens taken from intra-abdominal catheters that have been in place for >24 hours do not provide useful information and should not be performed. In contrast, the presence of yeast obtained from normally sterile intra-abdominal specimens (operative room specimens, and/or drains that have been placed within 24 hours) in patients with clinical evidence for infection should be considered indicative of intra-abdominal candidiasis.

The role of surrogate markers and Candida risk scores in this setting has not been established. There are limited data on the utility of using β-D-glucan in postsurgical patients with suspected intra-abdominal candidiasis. In one study, β-D-glucan had a 72% positive predictive value and an 80% negative predictive value for distinguishing colonization from intra-abdominal invasive candidiasis and performed better than Candida colonization scores or indices [143].

Clinical evidence for the use of antifungal therapy for patients with suspected intra-abdominal invasive candidiasis is limited. Most studies are small, uncontrolled, single-center, or performed in specific populations. Patients who have Candida species isolated from normally sterile abdominal cultures or drains placed within 24 hours and who have clinical evidence of infection should be treated for intra-abdominal candidiasis. Patients who have had gastroduodenal perforations, anastomotic leaks, necrotizing pancreatitis, or other intra-abdominal events without the isolation of Candida species and who are doing poorly despite treatment for bacterial infections may benefit from empiric antifungal therapy. Several meta-analyses of antifungal prophylaxis in high-risk surgical ICU patients have yielded conflicting results [265–268].

Source control with adequate drainage and/or debridement is an important part of therapy of intra-abdominal candidiasis [14]. The choice of antifungal agent should be guided by the Candida species isolated and knowledge of the local epidemiology, including antifungal susceptibility patterns. Duration of antifungal therapy should be guided by clinical response and the adequacy of source control.

The isolation of Candida species from the respiratory tract is commonly encountered among patients who are in the ICU and are intubated or have a chronic tracheostomy. This almost always reflects colonization of the airways and not infection. Candida pneumonia and lung abscess are very uncommon [322, 323]. Only rarely after aspiration of oropharyngeal material has primary Candida pneumonia or abscess been documented [324, 325]. Pneumonia due to Candida species is generally limited to severely immunocompromised patients who develop infection following hematogenous spread to the lungs. CT scan of the thorax usually shows multiple pulmonary nodules. Isolation of Candida species from respiratory samples in a patient who is severely immunosuppressed should trigger a search for evidence of invasive candidiasis.

Although the diagnosis of Candida pneumonia is supported by isolation of the organism from a bronchoalveolar lavage (BAL) specimen, a firm diagnosis requires histopathological evidence of invasive disease. Multiple prospective and retrospective autopsy studies consistently demonstrate the poor predictive value of the growth of Candida from respiratory secretions, including BAL fluid [326–328]. In one prospective study, none of 77 patients who died in an ICU and who had clinical and radiologic evidence of pneumonia and a positive culture for Candida species from BAL or sputum demonstrated evidence of Candida pneumonia at autopsy [328]. Because of the rarity of Candida pneumonia, the extremely common finding of Candida in respiratory secretions, and the lack of specificity of this finding [329–331], a decision to initiate antifungal therapy should not be made on the basis of respiratory tract culture results alone.

Recent observations suggest that colonization of the airway with Candida species is associated with the development of bacterial colonization and pneumonia [332–336]. Candida airway colonization was also associated with worse clinical outcomes and higher mortality in these studies. However, it is not clear if Candida airway colonization has a causal relationship to poorer outcomes or is simply a marker of disease severity.

The incidence of Candida endocarditis has increased concurrent with the general increase in Candida infections [337]. Endocarditis should be suspected when blood cultures are persistently positive, when a patient with candidemia has persistent fever despite appropriate treatment, or when a new heart murmur, heart failure, or embolic phenomena occur in the setting of candidemia [338]. Most cases occur following cardiac valvular surgery, but other risk factors include injection drug use, cancer chemotherapy, prolonged presence of CVCs, and prior bacterial endocarditis. The signs, symptoms, and complications are generally similar to those of bacterial endocarditis, except for the frequent occurrence of large emboli to major vessels. Cases are fairly evenly divided between C. albicans and non- albicans Candida species [339].

Medical therapy of Candida endocarditis has occasionally been curative [340–348], but the optimum therapy for both native and prosthetic valve endocarditis in adults is a combination of valve replacement and a long course of antifungal therapy based on case reports, case series, cohort studies, a meta-analysis, and clinical experience [339, 349]. Valve repair and vegetectomy are alternatives to valve replacement. Most of the cases reported in the literature have been treated with AmB deoxycholate, with or without flucytosine [339, 342, 349–355]. Fluconazole monotherapy is associated with an unacceptably high rate of relapse and mortality [354]. However, fluconazole is useful for step-down therapy.

AmB deoxycholate and azoles have decreased activity when compared with echinocandins against biofilms formed by Candida in vitro, and they penetrate poorly into vegetations. Echinocandins and lipid formulations of AmB demonstrate more potent activity against Candida biofilms [356]. A prospective, open-label clinical trial, cohort studies, and several case reports show a role for the echinocandins in the treatment of endocarditis [228, 346, 348, 357–365]. Higher dosages of the echinocandins are thought to be necessary to treat endocarditis [228, 365]. Caspofungin has been used as monotherapy and in combination with AmB, azoles, or flucytosine in single case reports, but data are limited for the other echinocandins [346, 360, 361, 363, 365, 366].

Lifelong suppressive therapy with fluconazole has been used successfully after a course of primary therapy in patients for whom cardiac surgery is contraindicated; it has also been advocated to prevent late recurrence of Candida prosthetic valve endocarditis [360, 367, 368]. Because Candida endocarditis has a propensity to relapse months to years later, follow-up should be maintained for several years after treatment [350, 351].

There are a few case reports and a single retrospective review of Candida infections of pacemakers and cardiac defibrillators [369–374]. The entire device should be removed and antifungal therapy given for 4–6 weeks depending on whether the infection involves the wires in addition to the generator pocket [369, 371–374]. Medical therapy alone has failed [370].

There are isolated case reports and a few case series on Candida infections of ventricular assist devices [375–378]. The Expert Panel believes that suppressive azole therapy after a full course of initial antifungal therapy is warranted. Many of these devices cannot be removed and suppression will be lifelong. The role of antifungal prophylaxis to prevent infection in all patients receiving an assist device remains controversial [378].

Most experience treating suppurative thrombophlebitis has been with AmB deoxycholate. Fluconazole and caspofungin have also been successful in some cases [379–381], but other agents used for primary treatment of candidemia, including echinocandins and voriconazole, should be effective [382]. Higher-than-usual doses of echinocandins should be used, similar to therapy for endocarditis.

Surgical excision of the vein plays an important role in the treatment of peripheral-vein Candida thrombophlebitis. When a central vein is involved, surgery is usually not an option. In some cases, systemic anticoagulation or thrombolytic therapy has been used as adjunctive therapy, but there are insufficient data to recommend their use. Thrombolytic therapy, in conjunction with antifungal therapy, has been used successfully in the management of an infected thrombus attached to a CVC in a patient with persistent candidemia [381].

Most patients with osteomyelitis present with a subacute to chronic course [383, 384]. The most common mechanism of infection is hematogenous dissemination, but direct inoculation and contiguous spread of infection also occur. Involvement of 2 or more bones is common, and therefore, when a single focus of infection is identified, there should be a search for other sites of involvement. The axial skeleton, especially the spine, is the most common site of involvement in adults; in children, the long bones are more commonly involved [228, 384–388]. Neither the clinical picture nor the findings on radiographic imaging are specific for Candida infection. Candida albicans remains the dominant pathogen. However, 2 retrospective reviews of a large number of cases found that non- albicans Candida were an increasingly frequent cause of Candida osteomyelitis and mixed infections with bacteria, especially Staphylococcus aureus , were not uncommon, underscoring the need for biopsy and culture [384, 389].

Treatment recommendations are based on case reports and case series. Historically, AmB deoxycholate has been the most commonly used agent [388]. Recent literature favors the use of fluconazole or an echinocandin over AmB [228, 384–386]. Fluconazole has been used successfully as initial therapy for patients who have susceptible isolates, but treatment failures have also been reported [390–393]. There are case reports of the successful treatment of osteomyelitis with itraconazole, voriconazole, posaconazole, and caspofungin [228, 229, 394–396].

Cure rates appear to be significantly higher when an antifungal agent is administered for at least 6 months [384, 385]. The addition of AmB deoxycholate or fluconazole to bone cement has been suggested to be of value as adjunctive therapy in complicated cases and appears to be safe, but this practice is controversial [397, 398].

Surgical debridement is frequently performed in conjunction with antifungal therapy. Some reports have found surgical therapy important for Candida vertebral osteomyelitis [387], but others have not found that to be the case [388]. Surgery is indicated in patients who have neurological deficits, spinal instability, large abscesses, or persistent or worsening symptoms during therapy [384].

On the basis of a small number of cases, Candida mediastinitis and sternal osteomyelitis in patients who have undergone sternotomy can be treated successfully with surgical debridement followed by either AmB or fluconazole [391, 399]. Irrigation of the mediastinal space with AmB is not recommended, because it can cause irritation. Antifungal therapy of several months' duration, similar to that needed for osteomyelitis at other sites, is appropriate.

Adequate drainage is critical to successful therapy of Candida arthritis. In particular, Candida arthritis of the hip requires open surgical drainage. Case reports have documented cures with AmB, fluconazole, and caspofungin therapy in combination with adequate drainage [400–402]. Administration of either AmB or fluconazole produces substantial synovial fluid levels, so that intra-articular injection of antifungal agents is not necessary.

Candida prosthetic joint infection generally requires resection arthroplasty, although success with medical therapy alone has been described rarely [403, 404]. The combination of removal and reimplantation of the prosthesis in 2 stages separated by 3–6 months and a prolonged period of antifungal therapy for at least 12 weeks after the resection arthroplasty and at least 6 weeks after prosthesis implantation is suggested on the basis of limited data [405–407]. The efficacy of antifungal-loaded cement spacers is controversial [408]. If the prosthetic device cannot be removed, chronic suppression with an antifungal agent, usually fluconazole, is necessary.

Endophthalmitis refers to infections within the eye, usually involving the posterior chamber and sometimes also the anterior chamber. Candida endophthalmitis can be exogenous, initially affecting the anterior chamber and occurring following trauma or a surgical procedure. More often, Candida species cause endogenous infection in which the organism reaches the posterior chamber of the eye via hematogenous spread. Endogenous infections can be manifested as isolated chorioretinitis or as chorioretinitis with extension into the vitreous, leading to vitritis [409–412]. Candida albicans is the species most commonly responsible for endogenous endophthalmitis, but all Candida species that cause candidemia have been reported to cause this complication [411–414]. Outcomes in terms of visual acuity depend on the extent of visual loss at the time of presentation and macular involvement [415].

Several basic principles are important in the approach to treatment of Candida infections of the eye. It should first be determined whether infection involves the anterior and/or posterior segment of the eye and whether the macula or vitreous are involved [70, 416–418]. Achieving adequate concentrations of the appropriate antifungal agent in the area of the eye that is infected is crucial to success [419, 420]. Infections involving the chorioretinal layer are more easily treated because this area of the posterior chamber is highly vascular; many systemic antifungal agents likely reach adequate concentrations within the choroid and the retina [420–422]. The antifungal susceptibilities of the infecting species are important. Species that are susceptible to fluconazole or voriconazole are more easily treated because these agents achieve adequate concentrations in the posterior segment of the eye, including the vitreous [419, 420, 422]. Treatment must be systemic to treat candidemia and other organ involvement, if present, in addition to the ocular infection.

Sight-threatening lesions near the macula or invasion into the vitreous usually necessitate intravitreal injection of antifungal agents, usually AmB deoxycholate or voriconazole, with or without vitrectomy, in addition to systemic antifungal agents [412, 419, 422–425]. The ophthalmologist plays a key role in following the course of endogenous Candida endophthalmitis, deciding when and if to perform intravitreal injections and vitrectomy.

The approach to the patient who has candidemia has evolved over time, and standard practice now includes consultation with an ophthalmologist to do a dilated retinal examination. The basis for the recommendation to perform an ophthalmological evaluation is not a result of randomized controlled trials showing the benefits of such an assessment, but rather clinical judgment that the result of missing and not appropriately treating Candida endophthalmitis could be of great consequence to the patient. The issue of whether an ophthalmological examination of all candidemic patients is cost-effective has been raised [183, 426]. The members of the Expert Panel believe that the risk of missing Candida endophthalmitis outweighs the cost of obtaining an ophthalmological examination. We are concerned about the greater risk of loss of visual acuity in patients who are examined only after manifesting ocular symptoms [415], and note that other centers report higher rates of endophthalmitis than reports from the centers cited by those who question the routine use of ocular examination [417, 418, 421].

The greatest clinical experience for treatment of Candida endophthalmitis has been with intravenous AmB deoxycholate, only because it has been available for the longest time. However, this agent does not achieve adequate concentrations in the posterior chamber [419, 420, 427, 428]. In animal experiments in inflamed eyes, liposomal AmB achieved higher concentrations in the eye than either AmB deoxycholate or AmB lipid complex [427]. A few patients have been treated successfully with lipid formulations of AmB, but concentrations in the vitreous in humans have not been reported [429].

Flucytosine provides adjunctive synergistic activity when used with AmB; it should not be used as monotherapy because of development of resistance and reports of decreased efficacy in animal models [428]. It attains excellent levels in the ocular compartments, including the vitreous [412, 430]. Toxicity is common, and flucytosine serum levels must be monitored weekly to prevent dose-related toxicity.

Fluconazole is frequently used for the treatment of Candida endophthalmitis. In experimental animals, this agent achieves excellent concentrations throughout the eye, including the vitreous [428]. In humans, concentrations in the vitreous are approximately 70% of those in the serum [57]. Clinical and microbiological response rates in animals with experimental infection are somewhat conflicting, with most reports showing efficacy of fluconazole, but some noting better efficacy with AmB than fluconazole [428, 431, 432]. Early reports in humans noted the efficacy of fluconazole, but some patients had received intravitreal injection of antifungal agents, as well as systemic fluconazole [433, 434]. Despite the fact that no large published series has defined the efficacy of fluconazole therapy, this agent is routinely used for the treatment of Candida endophthalmitis [410, 411, 415, 421].

Voriconazole has played an increasing role in the treatment of endophthalmitis [419]. Concentrations in the vitreous in humans are approximately 40% of serum concentrations; the drug is relatively safe, and, like fluconazole, can be given by the oral or intravenous route [435–438]. It is more active than fluconazole against C. glabrata , although resistance is increasing and may preclude its use for some patients; it is uniformly active against C. krusei. Efficacy of voriconazole in treating Candida endophthalmitis has been documented, but not compared with fluconazole [429, 436, 438]. Serum and (presumably) intraocular concentrations of voriconazole are quite variable, and serum trough levels should be routinely monitored to achieve concentrations between 2 µg/mL and 5 µg/mL to enhance efficacy and avoid toxicity [118].

There are few data regarding the use of posaconazole for Candida endophthalmitis. Intraocular penetration is poor, this agent has been used in very few patients, and it is not approved for the treatment of candidemia [419].

Echinocandins are first-line agents for the treatment of candidemia. Whether they can effectively treat chorioretinitis without vitreal involvement cannot be answered with the data available. Penetration of all echinocandins into the different chambers of the eye is poor, and is especially poor in the vitreous [412, 419, 420]. When levels have been achieved in experimental animal models and in one study in humans with micafungin, the dosages needed have been higher than those currently licensed for use [112, 439–443]. Only a few case reports of the use of an echinocandin as monotherapy have been published, and the results are contradictory [444, 445]. With the availability of other agents that achieve adequate concentrations in the vitreous, there is little reason to recommend the use of echinocandins for Candida endophthalmitis.

Because involvement of the macula is sight-threatening and concentrations of antifungal agents in the posterior chamber do not immediately reach therapeutic levels, many ophthalmologists perform an intravitreal injection of either AmB deoxycholate or voriconazole to quickly achieve high antifungal activity in the posterior chamber. AmB is the agent that has been used most often for intravitreal injection [422, 423]. A dosage of 5–10 µg given in 0.1 mL sterile water is generally safe [419]. Intravitreal injection of lipid formulations of AmB has been compared with AmB deoxycholate in rabbits; all formulations showed toxicity at higher doses, but at 10 µg, the least toxic was liposomal AmB [446], confirming a prior study using a noncommercial liposomal formulation [447].

Voriconazole is increasingly used for intravitreal injection for both Candida and mold endophthalmitis [438, 448]. It has been shown to be safe in animal eyes at concentrations <250 µg/mL [449]. The usual dose given to humans is 100 µg in 0.1 mL sterile water or normal saline (achieving a final concentration of 25 µg/mL) [419, 438]. In vitrectomized eyes, the half-life of both AmB and voriconazole is shortened, and repeated injections may be required [450, 451].

Candida endophthalmitis that has extended into the vitreous results in worse visual outcomes than chorioretinitis without vitritis [415]. This may be related to the inability of many antifungal agents to achieve adequate concentrations in the vitreous body. Poor outcomes could also be due to an increased burden of organisms in the posterior chamber or the existence of an abscess that cannot be visualized through the vitreal haziness. Additionally, in cases of endophthalmitis in which fungemia is not documented and the organism is unknown, vitrectomy provides material for culture that is superior to needle aspiration and allows the proper antifungal agent to be used [422, 424].

The treatment when vitritis is documented is similar to that recommended for chorioretinitis without vitreal involvement, with the added recommendations to (1) inject either AmB deoxycholate or voriconazole into the vitreous to achieve high drug concentrations in the posterior chamber and to (2) consider performing a pars plana vitrectomy. Several small series have noted success in patients in whom early pars plana vitrectomy was accomplished [415, 423, 424, 452]. Removal of the vitreous is usually accompanied by intravitreal injection of antifungal agents, and as noted above, the half-life of injected antifungal agents is shortened with vitrectomy [450, 451]. The risk of retinal detachment, a severe late complication of endophthalmitis with vitreal involvement, is decreased with early vitrectomy [412, 415]. To have the best outcomes, Candida endophthalmitis with vitritis must be managed with close cooperation between ophthalmologists and infectious diseases specialists.

CNS Candida infections can occur as a manifestation of disseminated candidiasis, as a complication of a neurosurgical procedure, especially when an intracranial device is inserted, or rarely as an isolated chronic infection [453–462]. Meningitis is the most common presentation, but multiple small abscesses throughout the brain parenchyma, large solitary brain abscesses, and epidural abscesses have been reported [462]. Low-birth-weight neonates are at high risk to have CNS infection as a complication of candidemia; neonatal CNS candidiasis is dealt with in the section on neonatal Candida infections. Most infections are due to C. albicans , with few reports of C. glabrata and other species causing infection [453–457, 459, 461, 462]. Treatment is based on the antifungal susceptibilities of the infecting species and the ability of the antifungal agent to achieve appropriate concentrations in the CSF and brain.

No randomized controlled trials have been performed to evaluate the most appropriate treatment for these uncommon infections. Single cases and small series are reported. Most experience has accrued with the use of AmB deoxycholate, with or without flucytosine [453–455, 457, 459, 460, 462]. Liposomal AmB (AmBisome) has been found to attain higher levels in the brain than amphotericin B lipid complex (ABLC) or AmB deoxycholate in a rabbit model of Candida meningoencephalitis [44].

The combination of AmB and flucytosine is recommended because of the in vitro synergism noted with the combination and the excellent CSF concentrations achieved by flucytosine. However, flucytosine's toxic effects on bone marrow and liver must be carefully monitored, preferably with frequent serum flucytosine levels. The optimal length of therapy with AmB alone or in combination with flucytosine has not been studied. Several weeks of therapy are suggested before transitioning to oral azole therapy.

Fluconazole achieves excellent levels in CSF and brain tissue and has proved useful as step-down therapy [453, 454, 459]. Fluconazole also has been used as monotherapy; both success and failure have been noted, and for this reason it is not recommended as first-line therapy [453, 454, 463–465]. Fluconazole combined with flucytosine has been reported to cure Candida meningitis in a few patients [459], and this is a possible regimen for step-down therapy. There are no reports of the use of voriconazole or posaconazole for CNS candidiasis. Voriconazole achieves excellent levels in CSF, and should be considered for the rare case of C. glabrata that is not voriconazole resistant or C. krusei meningitis after initial treatment with AmB with or without flucytosine. Posaconazole does not reach adequate concentrations in the CSF, and this agent is not recommended.

Echinocandins have been used infrequently for CNS candidiasis. There are case reports noting success [466], but CNS breakthrough infections in patients receiving an echinocandin for candidemia have been reported [467]. There are experimental animal data noting that anidulafungin and micafungin can successfully treat C. albicans meningitis, but the doses required in humans are much higher than currently recommended for candidemia [296, 299]. At present, echinocandins are not recommended for CNS candidiasis.

Infected CNS devices should be removed to eradicate Candida . Most experience has been with external ventricular drains and ventriculoperitoneal shunts that have become infected with Candida species [460, 463]. In recent years, infected devices include deep brain stimulators and Gliadel biopolymer wafers that have been placed into the site of a brain tumor to deliver chemotherapy locally. Although difficult to remove, experience has shown that these devices must be taken out for cure of the infection [456, 468, 469].

Intraventricular administration of antifungal agents is not usually necessary for treatment of CNS Candida infections. In patients in whom the removal of a ventricular shunt or external ventriculostomy drain is too risky because of significantly elevated intracranial pressure, or among patients who have not responded to systemic antifungal therapy, intraventricular AmB deoxycholate has proved useful [453, 454, 460, 463, 469]. The dose of intraventricular AmB deoxycholate is not standardized, and recommendations vary from 0.01 mg to 1 mg in 2 mL of 5% dextrose in water daily [455, 463, 466, 469]. Toxicity—mainly headache, nausea, and vomiting—is a limiting factor when administering AmB by this route [454, 463].

The presence of candiduria is the usual trigger for a physician to consider whether a patient has a urinary tract infection due to Candida species. The patients at most risk for candiduria are those who are elderly, female, diabetic, have indwelling urinary devices, are taking antibiotics, and have had prior surgical procedures [470–475]. In the asymptomatic patient, candiduria almost always represents colonization, and elimination of underlying risk factors, such as indwelling catheters, is often adequate to eradicate candiduria [471].

Multiple studies have noted that candiduria does not commonly lead to candidemia [471, 472, 476–480]. Several of these studies have shown that candiduria is a marker for greater mortality, but death is not related to Candida infection and treatment for Candida infection does not change mortality rates [476, 480, 481]. A prospective study in renal transplant recipients found that although mortality was higher in patients who had candiduria, treatment did not improve outcomes, suggesting again that candiduria is a marker for severity of underlying illness [482].

Several conditions require an aggressive approach to candiduria in asymptomatic patients. These include neonates with very low birth weight, who are at risk for invasive candidiasis that often involves the urinary tract [281, 483]. Many physicians who care for neutropenic patients treat those who have fever and candiduria because the candiduria may indicate invasive candidiasis. However, a recent study from a cancer hospital of a small number of patients, 25% of whom were neutropenic, found that these patients did not develop candidemia or other complications of candiduria [484]. Several reports have documented a high rate of candidemia when patients undergo urinary tract instrumentation [485, 486], which has led to recommendations to treat with antifungal agents periprocedure.

Candida UTI can develop by 2 different routes [487]. Most symptomatic UTIs evolve as an ascending infection beginning in the lower urinary tract, similar to the pathogenesis of bacterial UTI. Patients with ascending infection can have symptoms of cystitis or pyelonephritis. The other route of infection occurs as a consequence of hematogenous spread to the kidneys in a patient who has candidemia. These patients usually have no urinary tract symptoms or signs, and are treated for candidemia.

Diagnostic tests on urine often are not helpful in differentiating colonization from infection or in pinpointing the involved site within the urinary tract [488, 489]. For example, pyuria in a patient with an indwelling bladder catheter cannot differentiate Candida infection from colonization. Similarly, the colony count in the urine, especially when a catheter is present, cannot be used to define infection [488, 489]. Imaging of the urinary tract by ultrasound or CT scanning is helpful in defining structural abnormalities, hydronephrosis, abscesses, emphysematous pyelonephritis, and fungus ball formation [490–492]. Aggregation of mycelia and yeasts (fungus balls) in bladder or kidney leads to obstruction and precludes successful treatment of infection with antifungal agents alone [94]. Rarely, Candida species cause localized infections in prostate, epididymis, or testicles [491, 493–495].

Several basic principles are important in the approach to treatment of Candida UTI. The ability of the antifungal agent to achieve adequate concentrations in the urine is as important as the antifungal susceptibilities of the infecting species [94]. Candida albicans , the most common cause of fungal UTI, is relatively easy to treat because it is susceptible to fluconazole, which achieves high concentrations in the urine. In contrast, UTIs due to fluconazole-resistant C. glabrata and C. krusei can be extremely difficult to treat.

Fluconazole is the drug of choice for treating Candida UTI. It was shown to be effective in eradicating candiduria in the only randomized, double-blind, placebo-controlled trial that has been conducted in patients with candiduria [496]. It is important to note that the patients in this trial were asymptomatic or had minimal symptoms of cystitis. Fluconazole is available as an oral formulation, is excreted into the urine in its active form, and easily achieves urine levels exceeding the MIC for most Candida isolates [94].

Flucytosine demonstrates good activity against many Candida species, with the exception of C. krusei, and is excreted as active drug in the urine [94]. Treatment with flucytosine is limited by its toxicity and the development of resistance when it is used as a single agent.

AmB deoxycholate is active against most Candida species (although some C. krusei isolates are resistant) and achieves concentrations in the urine that exceed the MICs for most isolates, and even low doses have been shown to be effective in treating Candida UTI [497]. The major drawbacks are the need for intravenous administration and toxicity. The lipid formulations of AmB appear to not achieve urine concentrations that are adequate to treat UTI and should not be used [498].

All other antifungal drugs, including the other azole agents and echinocandins, have minimal excretion of active drug into the urine and generally are ineffective in treating Candida UTI [94]. However, there are several reports of patients in whom echinocandins were used, primarily because of UTI due to fluconazole-resistant organisms, and both success and failure were reported [499–502]. Infection localized to the kidney, as occurs with hematogenous spread, probably can be treated with echinocandins because tissue concentrations are adequate even though these agents do not achieve adequate urine concentrations [499].

Irrigation of the bladder with AmB deoxycholate resolves candiduria in 80%–90% of patients, as shown in several open-label trials, but in those studies, recurrent candiduria within several weeks was very common [503–505]. This approach is useful only for bladder infections and generally is discouraged, especially in patients who would not require an indwelling catheter for any other reason [94, 506, 507]. Cystitis due to C. glabrata or C. krusei can sometimes be treated with amphotericin B bladder irrigation and endoscopic removal of any obstructing lesions [94].

Fungus balls are an uncommon complication of Candida UTI except in neonates, in whom fungus ball formation in the collecting system commonly occurs as a manifestation of disseminated candidiasis [483]. In adults, surgical or endoscopic removal of the obstructing mycelial mass is central to successful treatment [94, 508, 509]. In neonates, some series documented resolution of fungus balls with antifungal treatment alone [510], but others found that endoscopic removal was necessary [511, 512]. There are anecdotal reports of a variety of techniques used to remove fungus balls from the renal pelvis; these include endoscopic removal via a percutaneous nephrostomy tube, infusion of streptokinase locally, and irrigation with antifungal agents through a nephrostomy tube [511–513]. Fungus balls in the bladder and lower ureter usually can be removed endoscopically [509].

Vulvovaginal candidiasis can be classified as either uncomplicated, which is present in about 90% of cases, or complicated, which accounts for only about 10% of cases, on the basis of clinical presentation, microbiological findings, host factors, and response to therapy [514]. Complicated vulvovaginal candidiasis is defined as severe or recurrent disease, infection due to non-albicans species, and/or infection in an abnormal host. Candida albicans is the usual pathogen, but other Candida species can also cause this infection.

A diagnosis of vulvovaginal candidiasis can usually be made clinically when a woman presents with symptoms of pruritus, irritation, vaginal soreness, external dysuria, and dyspareunia, often accompanied by a change in vaginal discharge. Signs include vulvar edema, erythema, excoriation, fissures, and a white, thick, curdlike vaginal discharge. Unfortunately, these symptoms and signs are nonspecific and can be the result of a variety of infectious and noninfectious etiologies. Before proceeding with empiric antifungal therapy, the diagnosis should be confirmed by a wet-mount preparation with use of saline and 10% potassium hydroxide to demonstrate the presence of yeast or hyphae and a normal pH (4.0–4.5). For those with negative findings, vaginal cultures for Candida should be obtained.

A variety of topical and systemic oral agents are available for treatment of vulvovaginal candidiasis. No evidence exists to show the superiority of any one topical regimen [515, 516], and oral and topical antifungal formulations have been shown to achieve entirely equivalent results [517]. Uncomplicated infection can be effectively treated with either single-dose fluconazole or short-course fluconazole for 3 days, both of which achieve >90% response [517, 518]. Treatment of vulvovaginal candidiasis should not differ on the basis of human immunodeficiency virus (HIV) infection status; identical response rates are anticipated for HIV-positive and HIV-negative women.

Complicated vulvovaginal candidiasis requires that therapy be administered intravaginally with topical agents for 5–7 days or orally with fluconazole 150 mg every 72 hours for 3 doses [54, 514]. Most Candida species, with the exception of C. krusei and C. glabrata , respond to oral fluconazole. Candida krusei responds to all topical antifungal agents. However, treatment of C. glabrata vulvovaginal candidiasis is problematic [514, 516]. The most important decision to make is whether the presence of C. glabrata in vaginal cultures reflects colonization in a patient who has another disease, or whether it indicates true infection requiring treatment. Azole therapy, including voriconazole, is frequently unsuccessful [519]. A variety of local regimens have sometimes proved effective. These include boric acid contained in gelatin capsules and nystatin intravaginal suppositories [520]. Topical 17% flucytosine cream can be used alone or in combination with 3% AmB cream in recalcitrant cases [520, 521]. These topical formulations, as well as boric acid gelatin capsules, must be compounded by a pharmacist for specific patient use. Azole-resistant C. albicans infections are extremely rare. However, recent evidence has emerged documenting fluconazole and azole class resistance in women following prolonged azole exposure [522].

Recurrent vulvovaginal candidiasis, defined as ≥4 episodes of symptomatic infection within one year, is usually caused by azole-susceptible C. albicans [514, 523]. Contributing factors, such as diabetes, are rarely found. Treatment should begin with induction therapy with a topical agent or oral fluconazole for 10–14 days, followed by a maintenance azole regimen for at least 6 months [523–525]. The most convenient and well-tolerated regimen is 150 mg fluconazole once weekly. This regimen achieves control of symptoms in >90% of patients [523]. After cessation of maintenance therapy, a 40%–50% recurrence rate can be anticipated. If fluconazole therapy is not feasible, topical clotrimazole cream, 200 mg twice weekly, clotrimazole vaginal suppository 500 mg once weekly, or other intermittent oral or topical antifungal treatment is recommended [526, 527].

Oropharyngeal and esophageal candidiasis occur in association with HIV infection, diabetes, leukemia and other malignancies, steroid use, radiation therapy, antimicrobial therapy, and denture use [528, 529], and their occurrence is recognized as an indicator of immune dysfunction. In HIV-infected patients, oropharyngeal candidiasis is most often observed in patients with CD4 counts <200 cells/µL [528–530]. The advent of effective antiretroviral therapy has led to a dramatic decline in the prevalence of oropharyngeal candidiasis and a marked diminution in cases of refractory disease [531].

Fluconazole or multiazole resistance is predominantly the consequence of previous repeated and long-term exposure to fluconazole or other azoles [530–533]. Especially in patients with advanced immunosuppression and low CD4 counts, C. albicans resistance has been described, as has gradual emergence of non- albicans Candida species, particularly C. glabrata , as a cause of refractory mucosal candidiasis [532, 533].

Most cases of oropharyngeal candidiasis are caused by C. albicans , either alone or in mixed infections. Symptomatic infections caused by C. glabrata , C. dubliniensis , and C. krusei alone have been described [532–534]. Multiple randomized prospective studies of oropharyngeal candidiasis have been performed involving patients with AIDS and patients with cancer. Most patients will respond initially to topical therapy [532, 535, 536]. In HIV-infected patients, symptomatic relapses occur sooner and more frequently with topical therapy than with fluconazole [535]. In a multicenter randomized study among HIV-infected individuals, 50-mg mucoadhesive buccal tablets of miconazole applied once daily to the mucosal surface over the canine fossa were as effective as 10-mg clotrimazole troches used 5 times daily [537].

Fluconazole tablets and itraconazole solution are superior to ketoconazole and itraconazole capsules [538–540]. Local effects of oral solutions may be as important as the systemic effects. Posaconazole suspension is also as efficacious as fluconazole in patients with AIDS [541]. Posaconazole, 100-mg delayed release tablets, given as 300 mg daily as a single dose, are FDA approved for the prophylaxis of fungal infections in high-risk patients. The tablets provide a stable bioavailability (approximately 55%), once-daily dosing, and the convenience of less stringent food requirements for absorption. This formulation has not been fully evaluated for mucosal candidiasis, but, with further study, could replace the oral suspension for this purpose.

Recurrent infections typically occur in patients who have persistent immunosuppression, especially those who have AIDS and low CD4 cell counts (<50 cells/µL) [530–533]. Long-term suppressive therapy with fluconazole has been shown to be effective in the prevention of oropharyngeal candidiasis [53, 542, 543]. In a large multicenter study of HIV-infected patients, long-term suppressive therapy with fluconazole was compared with the episodic use of fluconazole in response to symptomatic disease. Continuous suppressive therapy reduced the relapse rate more effectively than did intermittent therapy, but was associated with increased in vitro resistance. The frequency of refractory disease was the same for both groups [53]. Oral AmB deoxycholate, nystatin solution, and itraconazole capsules are less effective than fluconazole in preventing oropharyngeal candidiasis [544, 545].

Fluconazole-refractory infections should be treated initially with itraconazole solution; between 64% and 80% of patients will respond to this therapy [546, 547]. Posaconazole suspension is efficacious in approximately 75% of patients with refractory oropharyngeal or esophageal candidiasis [548], and voriconazole also is efficacious for fluconazole-refractory infections [549]. Intravenous caspofungin, micafungin, and anidulafungin have been shown to be effective alternatives to azole agents for refractory candidiasis [24, 87, 88, 550]. Oral or intravenous AmB deoxycholate is also effective in some patients; however, a pharmacist must compound the oral formulation [551]. Immunomodulation with adjunctive granulocyte-macrophage colony-stimulating factor or interferon-γ have been occasionally used in the management of refractory oral and esophageal candidiasis [552, 553].

Decreasing rates of oral carriage of Candida species and a reduced frequency of symptomatic oropharyngeal candidiasis are seen among HIV-infected patients on effective antiretroviral therapy [554]. Thus, antiretroviral therapy should be used whenever possible for HIV-infected patients with oropharyngeal or esophageal candidiasis.

Chronic mucocutaneous candidiasis is a rare condition that is characterized by chronic, persistent onychomycosis and/or mucocutaneous lesions due to Candida species. Some patients have a thymoma or autoimmune polyendocrinopathy syndrome type 1 [555]. Fluconazole should be used as initial therapy for candidiasis in these patients. Response to antifungal therapy may be delayed when there is extensive skin or nail involvement. Because of the intrinsic immunodeficiency, most patients require chronic suppressive antifungal therapy and frequently develop azole-refractory infections [556]. Patients with fluconazole-refractory Candida infections should be treated the same as patients with AIDS who develop azole refractory infections [528].

Esophageal candidiasis typically occurs at lower CD4 counts than oropharyngeal disease [528–530]. The advent of effective antiretroviral therapy has led to a dramatic decline in the prevalence of esophageal candidiasis and a marked diminution in cases of refractory disease [531]. Most cases of esophageal candidiasis are caused by C. albicans . However, symptomatic infections caused by C. glabrata , C. dubliniensis , and C. krusei have been described [534].

The presence of oropharyngeal candidiasis and dysphagia or odynophagia in an immunocompromised host is frequently predictive of esophageal candidiasis, although esophageal candidiasis can present as odynophagia without concomitant oropharyngeal candidiasis. A therapeutic trial with fluconazole for patients with presumed esophageal candidiasis is a cost-effective alternative to endoscopic examination. In general, most patients with esophageal candidiasis will have improvement or resolution of their symptoms within 7 days after the initiation of antifungal therapy [557].

Fluconazole is superior to ketoconazole, itraconazole capsules, and flucytosine, and is comparable to itraconazole solution for the treatment of esophageal candidiasis [558, 559]; up to 80% of patients with fluconazole-refractory infections will respond to itraconazole solution [547]. Voriconazole is as efficacious as fluconazole and has shown success in the treatment of fluconazole-refractory mucosal candidiasis [63, 549].

The echinocandins are as effective as fluconazole but are associated with higher relapse rates than those observed with fluconazole [24, 87, 88, 550]. Thus, higher doses of echinocandins are recommended for use for esophageal disease than are used for candidemia to decrease relapses. Higher doses have been studied for micafungin [560]. Fluconazole-refractory disease responds to caspofungin, and it is likely that micafungin and anidulafungin are as effective as caspofungin. In patients with advanced AIDS, recurrent infections are common, and long-term suppressive therapy with fluconazole is effective in decreasing the recurrence rates [53]. The use of effective antiretroviral therapy has dramatically decreased the incidence of esophageal candidiasis in HIV-infected patients.

Acknowledgments

The Expert Panel expresses its gratitude for thoughtful reviews of an earlier version by Anna Thorner and Pranatharthi Chandrasekar; and David van Duin as liaison of the IDSA Standards and Practice Guidelines Committee (SPGC). The panel also greatly appreciates the work of Charles B. Wessels and Michele Klein Fedyshin of the Health Sciences Library System of the University of Pittsburgh for the development and execution of the systematic literature searches for this guideline.

Financial support

Support for this guideline was provided by the Infectious Diseases Society of America.

Potential conflicts of interest

The following list is a reflection of what has been reported to IDSA. To provide thorough transparency, IDSA re­quires full disclosure of all relationships, regardless of relevancy to the guideline topic. Evaluation of such relationships as potential conflicts of interest (COI) is determined by a review process that includes assessment by the SPGC Chair, the SPGC liaison to the development panel, and the Board of Directors liaison to the SPGC and, if necessary, the COI Task Force of the Board. This assessment of disclosed relationships for possible COI will be based on the relative weight of the financial relationship (ie, monetary amount) and the relevance of the relationship (ie, the degree to which an association might reasonably be interpreted by an independent observer as related to the topic or recommendation of consideration). The reader of these guidelines should be mindful of this when the list of disclosures is reviewed. For activities outside of the submitted work, P. G. P. served as a consultant to Merck, Astellas (past), Gilead, T2 Biosystems, Scynexis, Viamet, IMMY Diagnostics, and Pfizer (past) and has received research grants from T2 Biosystems, Gilead, Merck, Astellas, Scynexis, and IMMY. For activities outside of the submitted work, C. A. K. has received research grants from VA Cooperative Studies, Merck, the Centers for Disease Control and Prevention (CDC) and The National Institute on Aging (all past), and has received royalties from UpToDate. For activities outside of the submitted work, D. A. has served a consultant to Merck, Astellas, Pfizer, Seachaid, Mayne, Roche, Theravance, Viamet, and Scynexis and has received research grants from Merck, Pfizer, MSG, Actellion, Theravance, Scynexis, and Astellas. For activities outside of the submitted work, C. J. C. has consulted for Merck, and received research grants from Pfizer, Merck, Astellas, CSL Behring, and T2 Diagnostics. For activities outside of the submitted work, K. A. M. has received research grants from Pfizer, Astellas, Merck, and the National Institutes of Health (NIH) and served as a consultant for Astellas, Chimerix, Cidara, Genentech, Merck, Revolution Medicines, and Theravance. She has a licensed patent to MycoMed Technologies. For activities outside of the submitted work, L. O.-Z. has served as a consultant to Viracor (past), Novadigm (past), Pfizer (past), Astellas, Cidara, Scynexis, and Merck and has received research grants from Merck (past), Astellas, Pfizer (past), Immunetics, Associates of Cape Cod (past), and T2 Biosystems, and has been on the speakers' bureau for Merck and Pfizer. For activities outside of the submitted work, A. C. R. has received research grants from Merck and T2 Biosystems, and royalties from UpToDate. For activities outside of the submitted work, J. A. V. has served as a consultant for Astellas, Forest, served on promotional speakers' bureau for Astellas, Pfizer, Forest, and Astra Zeneca, and has received research grants from Astellas, Pfizer, Merck, MSG, T2 Biosystems, and NIH/National Institute of Dental and Craniofacial Research. For activities outside of the submitted work, T. J. W. has served as a consultant for Astellas, Drais (past), Novartis, Pfizer, Methylgene, SigmaTau, Merck, ContraFect Trius, and has received research grants from SOS Kids Foundation, Sharpe Family Foundation, Astellas, Cubist, Theravance, Medicines Company, Actavis, Pfizer, Merck, Novartis, ContraFect, and The Schueler Foundation. For activities outside of the submitted work, T. E. Z. has served as a consultant for Astellas, Pfizer, Merck, and Cubist (all past) and has received research grants from Merck (past), Cubist (past), Agency for Health Research and Quality, CDC, NIH, and the Thrasher Foundation. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

For the full list of references, please visit the Oxford University Press website .

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Eliminating Candida Overgrowth on Different Body Parts

Candida is a group of fungi that exists (usually harmlessly) in areas such as the skin, the mouth, the vagina, and the gastrointestinal tract.

Candidiasis is an infection caused by Candida fungus, usually Candida Albicans . Candida infection, also known as a yeast infection , is rarely serious in people with healthy immune systems but can sometimes spread to other parts of the body in immunocompromised people.

Symptoms depend on the area of infection . On the skin, an overgrowth may cause a rash, while a vaginal yeast infection can cause itching, burning, and abnormal discharge. An oral yeast infection can cause white patches on the tongue, while an overgrowth of Candida in the gut can cause gastrointestinal complaints such as bloating.

This article will discuss symptoms of Candida overgrowth, how to stop Candida overgrowth, the role diet plays in Candidiasis, causes of persistent Candida overgrowth, and how to prevent Candidiasis when immunocompromised.

Longhua Liao / Getty Images

Candida Overgrowth Symptoms by Body Part

Candidiasis can cause a range of symptoms depending on the location and severity. It is usually mild. Although rare, it can become serious enough to affect the heart or brain.

The symptoms of Candida overgrowth can be similar to those of other health conditions. Always see your healthcare provider to get an accurate diagnosis.

Here is how Candida overgrowth can affect different areas of the body.

Candidiasis of the skin (cutaneous Candidiasis or cutaneous Moniliasis ) often develops in the skinfolds of areas such as:

• Under the breasts
• Folds of the buttocks
• Area covered by a diaper
• Webbing between toes/fingers

It may also occur on the scalp (which could lead to hair loss), face, fingertips, trunk, or anus (called perianal Candidiasis).

This photo contains content that some people may find graphic or disturbing.

Reproduced with permission from ©DermNet NZ and ©Waikato District Health Board www.dermnetnz.org 2022

Symptoms of Candidiasis of the skin include:

• Rash with redness and skin breakdown
• Clearly defined red lesions/patches that are typically rimmed with small, red-based pustules
• Oozing clear fluid from patches
• Itching or burning

Symptoms of vaginal Candidiasis (commonly called a vaginal yeast infection ) include:

• Abnormal discharge (may be white, yellow, clumpy/curd-like, and/or watery)
• Reddened and/or swollen tissues of the vulva and vagina
• Vaginal/vulva itching, irritation, and/or soreness
• Pain or discomfort during sexual intercourse and/or during urination

Symptoms can vary by person. For instance, not everyone with a vaginal yeast infection experiences abnormal discharge.

Symptoms of Candidiasis of the penis include:

• Painful rash on the underside of the penis
• Redness on the underside of the penis
• Scaling on the underside of the penis

Candidiasis of the penis is more common in those whose female sexual partners have vaginal Candidiasis, and in those who have diabetes mellitus .

Reproduced with permission from ©DermNet NZ www.dermnetnz.org 2022

Candidiasis in the mouth ( thrush ) has two main forms, which are:

• Pseudomembranous : More common form; affects mouth, tongue, or back of the throat
• Atrophic form.  Less common form, usually found in older adults; typically appears underneath upper dentures

Symptoms of thrush include:

• White patches on the tongue. inner cheeks, roof of the mouth, and/or throat
• Pain while eating or swallowing (difficulty swallowing may indicate thrush in the esophagus)
• A cottony feeling in the mouth
• Redness and cracking of the corners of the mouth
• Loss of taste
• Sensitivity to spicy foods

Yeast in the gastrointestinal tract is normal, but an overgrowth has the potential to cause problems . Broad-spectrum antibiotics have been linked to increased colonization of Candida species in the gut.

Gastrointestinal symptoms of Candidiasis may include:

• Constipation
• Abdominal pain

Candidiasis can occur under the fingernails or toenails .

Symptoms of Candida infection around the nails ( Candidal paronichia ) may include:

• White or yellow coloring of the nail
• Separation of the nail from the nail bed

Systemic Candidiasis and invasive Candidiasis can affect many parts of the body. This infection is serious.

Systemic/invasive Candidiasis can affect the:

• Other areas

The most common symptoms are fever and chills that don't improve after being treated with antibiotics for suspected bacterial infections, but other symptoms more specific to the area of infection can occur.

Systemic/invasive Candidiasis tends to occur in people who are hospitalized, immunocompromised , or who have other medical conditions.

How to Stop Candida Overgrowth 

Candida overgrowth is usually treated with antifungal medications such as:

• Clotrimazole
• Fluconazole

Oral thrush is typically treated with antifungal medicine applied to the inside of the mouth for seven to 14 days.

Oral thrush may also be treated with a medicated mouthwash or lozenges that dissolve in the mouth. Candidiasis of the esophagus is usually treated with oral or intravenous antifungal medications.

Yeast infections of the vagina or penis may be treated with antifungal creams, medicated suppositories, or oral medications.

Candidiasis of the skin may be treated with antifungal powders or creams.

Candida infections of the nails are often treated with oral antifungal medications.

Severe Candidiasis may require oral antifungal medications, especially for people with weakened immune systems.

If the Candida infection stems from or is worsened by medication use, such as antibiotics, corticosteroids, or immunosuppressants, your healthcare provider may look for alternative medications or treatments for you to use.

Measures that may help prevent Candidiasis include:

• Practice good oral hygiene (especially for people who wear dentures), including regular brushing and flossing, and using mouthwash as needed.
• Keep skin dry and try to reduce friction in areas where skin rubs against skin.
• Wear cotton underwear.
• Change diapers frequently and keep the skin dry (avoid petroleum jelly and talcum powder).

What Are "Good" and "Bad" Bacteria?

Most types of bacteria don't make people sick, and many types are beneficial. Certain types of bacteria help to:

• Digest food
• Destroy disease-causing cells
• Give the body vitamins it needs
• Make foods like yogurt and cheese

The gut is colonized by 10 times more microbes (including bacteria) than human cells. Gut bacteria are important for keeping people healthy.

Infectious bacteria can reproduce quickly in the body and cause illness. Types of infectious bacteria that cause infections include:

• Streptococcus
• Staphylococcus
• Escherichia coli ( E. coli )

Some bacteria help keep Candida from overgrowing. Taking antibiotics can kill these bacteria and cause a buildup of Candida. Taking probiotics of bacteria such as lactobacillus acidophilus or bifidobacterium when taking antibiotics may help restore a balance of bacteria, but the evidence is mixed. If you need to take antibiotics, talk to your healthcare provider about how to ensure you take them correctly, and whether probiotics may be useful for you.

Using Diet to Cleanse Candida Overgrowth

While there isn't a consensus on a "Candida diet", some studies and/or practitioners suggest it may help prevent yeast infections by reducing or avoiding foods such as:

• Dairy products and foods with high concentrations of yeast (like cheese, peanuts, and alcohol)
• Processed foods

Eating certain foods may help prevent yeast infections , including:

• Yogurt with live probiotic cultures
• Whole grains

While some people feel better following the "Candida diet," that effect may be due to eating healthier foods, which benefits overall health.

Causes of Persistent (Chronic) Candida Overgrowth

Chronic Candidiasis more commonly affects people who:

• Have predisposing health conditions (such as diabetes mellitus)
• Have immune deficiencies
• Are pregnant

Between 5% and 9% of people with vaginas experience recurrent vaginal yeast infections (three or more confirmed infections annually). Most vaginal yeast infections are caused by a type of fungus called Candida albicans. Still, recurrent or persistent yeast infections may be caused by a less common type of Candida, such as Candida glabrata or Candida krusei .

Vaginal cultures (samples of vaginal discharge tested in a lab) should be done to look for these less common species in people with recurrent or persistent yeast infection symptoms.

Factors that may increase a person's chances of developing recurrent vaginal yeast infections include:

• Blood sugar levels
• Insulin resistance
• Overall immune risk
• Presence of vaginal inflammation
• Chronic stress
• Microbiota (microbes in a specific environment, such as the vagina)

Chronic or recurrent Candida infections may be due to familial Candidiasis. This is an inherited tendency to develop Candida infections, caused by mutations in any of several genes identified with the condition.

A rare and severe form of Candidiasis called chronic mucocutaneous Candidiasis, usually developed in infancy, can cause chronic infection of the:

• Mucus membranes

Talk to your primary healthcare provider if you are experiencing recurrent or persistent Candida infections. If this is not an option, you can try services such as Zocdoc or Minute Clinic .

What Are SIBO and SIFO?

Small intestinal bacterial overgrowth (SIBO) involves an excessive amount of bacteria in the small intestine and gastrointestinal symptoms, such as bloating, abdominal pain, diarrhea, and distention.

Small intestinal fungal overgrowth (SIFO) refers to an excessive number of fungal organisms in the small intestine associated with gastrointestinal symptoms similar to those of SIBO.

Preventing Candida Overgrowth When Immunocompromised

For an existing, severe Candida infection that could be life-threatening to someone who is immunocompromised, an intravenous (IV) medication called amphotericin B may be used.

Antifungal prophylaxis (antifungal medication given to prevent the infection) may be recommended for people at high risk for developing invasive Candidiasis.

Candidiasis is an overgrowth of the Candida fungus. It usually occurs on the skin, in the mouth, in the vagina or on or around the penis , in the gut, or under the nails. Rarely, it can be systemic, affecting areas such as the blood, brain, or heart.

Candida infections are usually treated with antifungal medications such as creams, powders, rinses, lozenges, oral or IV medicines.

While not proven, avoiding or reducing sugar, food and drinks high in yeast and processed foods may help prevent yeast infections. It may also help to eat foods and spices such as garlic, yogurt with probiotic cultures, whole grains, nuts, cinnamon, sage, oregano, and cloves.

Chronic Candida overgrowth may result from compromised immune systems, infection with less common forms of Candida , familial Candidiasis, and Chronic Mucocutaneous Candidiasis.

Antifungal medication may be given as a preventative measure against Candida infection for people at risk for developing invasive Candidiasis.

Yu D, Liu Z. The research progress in the interaction between Candida albicans and cancers . Front Microbiol . 2022;13:988734. doi:10.3389/fmicb.2022.988734

National Organization for Rare Disorders. Candidiasis .

Johns Hopkins. Yeast infection .

Centers for Disease Control and Prevention. Vaginal candidiasis .

UpToDate. Patient education: vaginal yeast infection (beyond the basics) .

Cedars-Sinai. Candida infection: thrush .

Centers for Disease Control and Prevention. Candida infections of the mouth, throat, and esophagus .

Seelbinder B, Lohinai Z, Vazquez-Uribe R, et al. Candida expansion in the gut of lung cancer patients associates with an ecological signature that supports growth under dysbiotic conditions . Nat Commun . 2023;14(1):2673. doi:10.1038/s41467-023-38058-8

MedlinePlus. Familial candidiasis .

Centers for Disease Control and Prevention. Invasive candidiasis risk & prevention .

MedlinePlus. Bacterial infections .

Zhang YJ, Li S, Gan RY, Zhou T, Xu DP, Li HB. Impacts of gut bacteria on human health and diseases . IJMS. 2015;16(12):7493-7519. doi:10.3390/ijms16047493

Mount Sinai. Candidiasis .

Li WR, Shi QS, Dai HQ, et al. Antifungal activity, kinetics and molecular mechanism of action of garlic oil against Candida albicans . Sci Rep . 2016;6(1):22805. doi:10.1038/srep22805

Akimoto-Gunther L, Bonfim-Mendonça P de S, Takahachi G, et al. Highlights regarding host predisposing factors to recurrent vulvovaginal candidiasis: chronic stress and reduced antioxidant capacity . Coste AT , ed. PLoS ONE. 2016;11(7):e0158870. doi:10.1371/journal.pone.0158870

Rao SSC, Tan G, Abdulla H, Yu S, Larion S, Leelasinjaroen P. Does colectomy predispose to small intestinal bacterial (Sibo) and fungal overgrowth (Sifo)? Clinical and Translational Gastroenterology. 2018;9(4):e146. doi:10.1038/s41424-018-0011-x

Erdogan A, Rao SSC. Small intestinal fungal overgrowth . Curr Gastroenterol Rep . 2015;17(4):16. doi:10.1007/s11894-015-0436-2

By Heather Jones Jones is a freelance writer with a strong focus on health, parenting, disability, and feminism.

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3 Causes of Recurring Candida & What to Do

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Science Based

Written by  Amy Myers, MD

Are you battling with stubborn and recurring Candida overgrowth? Have you tried the Candida diet, Candida-fighting supplements, and other lifestyle changes, only to have your symptoms reappear as soon as you stop treatment? You’re not the only one. This is something I helped to address all the time in my clinic.

There are a few underlying causes of recurring Candida overgrowth I suspect could be to blame. Fortunately, once you pinpoint and address the root cause, you can enjoy lasting relief from chronic symptoms and say goodbye to your ongoing struggle with recurrent infections.

In this article, I’ll cover the three most common culprits for recurring Candida, and what you can do to break out of this vicious cycle and banish your symptoms once and for all.

1. How Your Diet Still Affects Recurring Candida

I know you’re probably thinking, “Wait, I already did the Candida diet!” I bet it worked for a time too. However, if you start eating the way you did before your Candida protocol, it should come as no surprise that the overgrowth is back.

Diet is never a quick fix. It’s why I call my program “The Myers Way®”— it’s a way of life, not a temporary solution. You can reintroduce certain foods and be a little more flexible once you’ve finished the Candida protocol. However, if you are susceptible to gut infections you might have to be more careful with what you put on your plate or in your cup.

Sugar is the number one offender when it comes to Candida overgrowth. If you’ve ditched refined sugar and Candida still won’t go away, you might also have to ease off all-natural sweeteners such as coconut sugar, honey, and maple syrup. Save sweet treats for special occasions, and try to stick to ones made with stevia or monk fruit. Pure Stevia is 200-300 times sweeter than regular sugar, while pure monk fruit is 150-200 times sweeter, meaning you’ll use them in such small quantities that they’ll be less likely to feed an overgrowth.

In addition to added sugars, you may have to watch out for fruit. Although fruit is filled with nutrients, it’s also very high in natural sugars and should be kept to a minimum if you struggle with recurring Candida. Keep it to 1 cup or less per day of low-sugar fruits such as berries.

Liquid sugar can be just as bad — if not worse — than sugar itself. Certain types of alcohol such as beer, wine, and champagne are not only packed with sugar, they’re fermented as well. What is used to ferment these drinks? Yeast. The combination of yeast and sugar creates a feeding frenzy for Candida. Not to mention alcohol is a toxin , so I recommend ditching it completely. However, if you choose to indulge, opt for a clear liquor such as vodka, which undergoes a rigorous distillation process to remove all the yeast.

Fermented Foods

Speaking of fermentation processes, you’ll want to avoid fermented foods as well. Especially if you can’t seem to get Candida under control. This includes even “healthy” fermented foods and drinks such as kombucha, sauerkraut, and non-dairy yogurt. To help foster good gut bacteria without feeding Candida, take a high-quality probiotic supplement with at least 100 billion CFUs.

Starchy Vegetables

Sweet potatoes, squash, and other starchy vegetables are high in carbs, which get converted into sugars in your gut. Although you may not think of these seemingly harmless foods when fighting Candida, they may be behind recurrent infections. Fill your plate with non-starchy vegetables instead, including leafy greens , broccoli, cauliflower, cucumber, asparagus, and zucchini.

Cutting down on sugar is certainly an adjustment, especially if you’ve been eating the Standard American Diet, which is chock full of sugar and starches in nearly everything we eat. However, you will feel SO much better once you ditch sugar , and the reward will be relief from your symptoms and recurring Candida overgrowth! To help you on your journey, I highly recommend Leaky Gut Revive® for curbing sugar cravings while you ease your way into this low-sugar way of eating.

For more information, take this short symptoms quiz to determine which foods are best for your conditions, and which foods you should eliminate. 

Foods to Enjoy, Foods to Toss Quiz

No matter your situation, the foods you eat are a key component in your overall health. Giving your body the fuel it needs to thrive is one of the best ways to take back control of your health.

However, it can be overwhelming trying to decide which foods are best for you to eat. After all, there is a lot of information available when it comes to what we should and shouldn’t be eating.

If you’ve been struggling to determine which foods are triggering your condition, or just want a simple list to bring with you the grocery store, take this short quiz to find out which foods are best for you to enjoy, and what to toss.

Digestive Tract

Head/node/lungs, joint/muscle, autoimmunity or thyroid conditions.

Your results will be delivered to your inbox in just a few moments!

2. Mycotoxin Exposure and Candida Overgrowth

Mycotoxin exposure is always in the back of my mind as the cause of chronic symptoms that have no other explanation. If you’ve gone through everything — optimized your diet, repaired your gut, etc. — and you’re still struggling with recurring Candida overgrowth, that’s when I suspect mycotoxins.

Mycotoxins are gas-like toxins, similar to volatile organic compounds (VOCs), given off by molds. They can be found in common foods such as peanuts, coffee, and corn, as well as in your environment.

Symptoms of Mycotoxin Exposure

• Eczema or psoriasis
• Depression, anxiety, and other mood imbalances
• Cognitive impairment, brain fog, memory loss
• Fibromyalgia , muscle weakness, joint pain
• Neurological issues
• ADD or ADHD
• Lyme disease symptoms (yet tested negative for Lyme)
• Autoimmune diseases

Mycotoxins are toxic to 25% of the population who have a susceptible gene. However, I also tell people that each of us has a cup of water that is our health. Each day, we put drops of water in — whether from our diet, leaky gut, toxins, infections, or stress — and at some point, that cup will overflow. This “overflow” is what turns that gene on, and once it’s on it stays on.

If you suspect mycotoxins are coming from your environment if at all possible you must leave that environment for a week or two and see if your symptoms resolve. If that environment is your home, you will need to bring in a certified mold remediator to clean up the mold before returning. This is a HUGE project! For that reason, I recommend getting yourself tested first.

I use a urine test from Real Time Labs out of Dallas to assess for 3 main types of mycotoxins. They can also do a filter test where you cut out a piece of the air filter from your home and test it for those same mycotoxins.

As for treatment, you can work with your doctor to get a prescription antifungal. If you choose to self-treat, you can ensure your liver detoxification pathways are working optimally using Acetyl-Glutathione. Caprylic acid and certain clays, such as bentonite, can be helpful for binding to toxins, although they are not going to be as powerful as prescription antifungals.

I go into detail about mycotoxin exposure and how to recover from it in my podcast.

3. Mercury Overload’s Connection to Candida

There hasn’t been a lot of research regarding the connection between mercury overload and Candida overgrowth. Unfortunately, conventional medicine often misses this critical root cause. However, it is something I have come across time and again in my patients with recurring Candida overgrowth.

One reason for this connection is that Candida can bind with mercury in your intestines, so the mercury can’t get into your bloodstream. 1

While this is a helpful protective action (as your organs will be less exposed to mercury) the mercury also kills off the good bacteria that normally keep Candida in check. This allows Candida to proliferate more easily. 2

There is also some scientific evidence suggesting that mercury can disrupt your natural gut environment, encouraging Candida and bad bacteria to overgrow. 3

Mercury may also damage your gut lining to such an extent that Candida can easily make its way into other areas of your body. 4

Symptoms of Mercury Overload

• Chemical sensitivity and allergies
• Anxiety , depression and brain fog
• Infertility, irregular menstrual cycles
• Fatigue and sleep disturbance in children
• Unexplained numbness and tingling
• Hair loss and hearing loss
• Cardiovascular disease

Testing for and addressing mercury overload can be a bit complex, so I recommend ruling out all other root causes before diving into treatment. If you suspect mercury overload is indeed the cause of your recurring Candida, you’ll find your next steps outlined in here .

How to Beat Recurring Candida for Good in 3 Easy Steps

Recurring Candida infections can be frustrating to say the least, especially if you think you’ve tried everything to clear your infection. Fortunately, addressing the root cause underlying the overgrowth — whether it’s optimizing your diet, clearing your body of mold toxins, or detoxing from mercury overload — will put you on the right path to a healthy and Candida-free body.

Need some extra support as you work to overcome Candida overgrowth? Try my Candida Breakthrough® Program and join thousands of others who have successfully taken back their health. You will learn my 3-step proven protocol for beating Candida, including an entire module focused on recurring Candida, where we’ll cover:

• The strategies you need to create a gut-healthy lifestyle
• The paradigm shift required to stick with it
• Recipes for celebrations, so you’re always prepared

You’ll get all of the powerful supplements, easy-to-make meal plans, and other resources in my Candida Breakthrough® Program so that you can take back your health and live your best life.

Article Sources

• https://phys.org/news/2017-07-genetically-yeast-heavy-metal-pollution.html .
• //brendawatson.com/gut-health/candidiasis/ .
• https://www.ncbi.nlm.nih.gov/pubmed/8280208 .
• //www.townsendletter.com/Jan2017/mercury0117_3.html .

Amy Myers,  MD

Amy Myers, MD is a two-time New York Times bestselling author and an internationally acclaimed functional medicine physician. Dr. Myers specializes in empowering those with autoimmune, thyroid, and digestive issues to reverse their conditions and take back their health. In addition, she is a wife, mother, and the successful  founder and CEO of  Amy Myers MD ® .

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Vulvovaginal Candidiasis: A Review of the Evidence for the 2021 Centers for Disease Control and Prevention of Sexually Transmitted Infections Treatment Guidelines

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Paul Nyirjesy, Carolyn Brookhart, Gweneth Lazenby, Jane Schwebke, Jack D Sobel, Vulvovaginal Candidiasis: A Review of the Evidence for the 2021 Centers for Disease Control and Prevention of Sexually Transmitted Infections Treatment Guidelines, Clinical Infectious Diseases , Volume 74, Issue Supplement_2, 15 April 2022, Pages S162–S168, https://doi.org/10.1093/cid/ciab1057

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Vulvovaginal candidiasis (VVC) is a common cause of vulvovaginal itching and discharge. This article discusses the latest CDC STI Treatment Guidelines for VVC.

A literature search of relevant topics was performed, and a team of experts was convened to discuss (1) diagnosis/testing modalities; treatment of (2) uncomplicated VVC , (3) complicated VVC, and (4) VVC caused by non- albicans yeast; (5) alternative treatment regimens; (6) susceptibility testing of yeast; Special Populations: (7) pregnancy and (8) HIV and VVC.

Yeast culture remains the gold standard for diagnoses. Newer molecular assays have been developed for the diagnosis of VVC and perform well. Azole antifungals remain the treatment of choice for uncomplicated VVC. Two new drugs, TOL-463 and recently FDA-approved ibrexafungerp, appeared promising in clinical trials. For recurrent VVC, oteseconazole, not yet commercially available, may represent a new option. For non- albicans yeast infections in symptomatic patients, boric acid appears useful. No evidence supports the use of alternative treatments, including probiotics. Fluconazole during pregnancy may be associated with spontaneous abortion and craniofacial and heart defects. In women with HIV infection, lower CD4+ T-cell counts are associated with increased rates of VVC, and VVC is associated with increased viral shedding. Treatment measures in women with HIV infection are identical to those women without HIV infection.

There has been significant new knowledge generated about VVC since the 2015 CDC Guidelines which have led to changing recommendations.

One of the most common causes of vulvovaginal itching and discharge worldwide, vulvovaginal candidiasis (VVC) is a condition characterized by yeast colonization, most frequently by Candida albicans . In the United States, VVC represents the second most common cause of vaginal infections, affecting 70–75% of women during their lifetime and resulting in an estimated 1.4 million outpatient visits each year [ 1 , 2 ]. At an annual treatment cost of at least $368 million for VVC [ 1 ] and lost productivity costs of over $4.8 billion for recurrent VVC alone [ 3 ], VVC represents a significant economic burden on the American healthcare system as well as a serious public health issue.

Although most women with vaginal yeast colonization are asymptomatic, many experience varying degrees of vaginal itching, the symptom most specific to VVC [ 2 ]. Some patients may also experience vaginal soreness, swelling, dyspareunia, dysuria, or increased discharge [ 2 ]. VVC may be diagnosed clinically, via microscopy, or with yeast culture, and the vast majority of cases are treated with azole antifungals [ 4 ].

Although much is known about the presentation, diagnosis, and management of VVC, knowledge continues to be generated. Thus periodic reviews of the literature are required to ensure that treatment guidelines reflect the most recent findings. To update the treatment guidelines for vulvovaginal candidiasis, a team of experts was convened to review the literature concerning several key topic areas: (1) data concerning diagnosis and testing modalities; (2) treatment of uncomplicated VVC; (3) treatment of complicated VVC; (4) VVC caused by non- albicans yeast species; (5) alternative regimens for treatment of VVC; (6) susceptibility testing of yeast and its role in treatment; (7) pregnancy and VVC; and (8) human immunodeficiency virus (HIV) and VVC. This article serves as a supplement to the updated 2021 Centers for Disease Control and Prevention of Sexually Transmitted Infections (CDC STI) treatment guidelines for vulvovaginal candidiasis and highlights clinically important findings relevant to the aforementioned key questions. Additionally, it poses areas for further research necessary for the continued development of our understanding of this common but complex condition.

Using the PubMed database of the US National Library of Medicine, we conducted a search of the literature published between January 2013 and June 2019, restricting results to English-language articles concerning human subjects. To identify studies of interest, we used the following search and Medical Subject Heading (MeSH) terms: (candidiasis, “vulvovaginal” [MeSH Terms] OR “candidiasis” [All Fields] AND “vulvovaginal” [All Fields]) OR “vulvovaginal candidiasis” [All Fields] OR (“yeast” [All Fields] AND “vaginitis” [All Fields]) OR “yeast vaginitis” [All Fields]) AND (“therapy” [Subheading] OR “therapy” [All Fields] OR “treatment” [All Fields] OR “therapeutics” [MeSH Terms] OR “therapeutics” [All Fields]). Given the complexities associated with diagnosing and treating Candida glabrata , we additionally searched for studies concerning this species: (“candida glabrata” [MeSH Terms] OR (“candida” [All Fields] AND “glabrata” [All Fields]) OR “candida glabrata” [All Fields]) AND (“vaginitis” [MeSH Terms] OR “vaginitis” [All Fields]). Additionally, we searched for articles addressing VVC and pregnancy: (“vaginitis” [MeSH Terms] OR “vaginitis” [All Fields]) AND (“yeasts” [MeSH Terms] OR “yeasts” [All Fields] OR “yeast” [All Fields] OR “saccharomyces cerevisiae” [MeSH Terms] OR (“saccharomyces” [All Fields] AND “cerevisiae” [All Fields]) OR “saccharomyces cerevisiae” [All Fields]) AND (“pregnancy” [MeSH Terms] OR “pregnancy” [All Fields]). Finally, we searched for studies concerning both VVC and HIV: (“candidiasis, vulvovaginal” [MeSH Terms] OR (“candidiasis” [All Fields] AND “vulvovaginal”[All Fields]) OR “vulvovaginal candidiasis”[All Fields] OR (“vulvovaginal” [All Fields] AND “candidiasis” [All Fields])) AND (“hiv” [MeSH Terms] OR “hiv” [All Fields] OR “hiv seropositivity” [MeSH Terms] OR (“hiv” [All Fields] AND “seropositivity” [All Fields]) OR “hiv seropositivity” [All Fields]). A total of 816 manuscripts were identified and screened, 70 selected for review, and ultimately 45 were included in the qualitative synthesis for the panel consideration.

Using online searches of pharmacies, phone calls to pharmacies, and physical visits to pharmacies, we reviewed the availability of the regimens suggested by the 2015 treatment guidelines ( Table 1 ).

Recommended Regimens for Treatment of Vulvovaginal Candidiasis

From Workowski KA et al; Centers for Disease Control and Prevention. Sexually transmitted infections treatment guidelines, 2021. MMWR Recomm Rep. 2021;70(4):1–187.

Diagnosis of Vulvovaginal Candidiasis

Although microscopy and clinical suspicion have been used to diagnose VVC for decades, culture has remained the gold standard for diagnosis of vaginal fungal infections. While valuable tools, all 3 diagnostic methods have drawbacks. Both microscopy and clinical diagnosis have poor sensitivity, while yeast cultures can lead to a delay in diagnosis and treatment. Culture of most Candida species takes a minimum of 48–72 hours, precluding early treatment for the approximately 50% of infected patients with negative microscopy. Given this delay, many providers rely on microscopy or clinical diagnosis for patients presenting with symptoms consistent with VVC. This approach may result in misdiagnosis and unnecessary treatment. In fact, less than half of patients who are treated for VVC are diagnosed with an objective assay [ 5 ].

Given the limitations of current methods of VVC diagnosis and the growing popularity of molecular testing for the STI diagnosis, a growing number of commercial laboratories have developed molecular tests for VVC. Until recently, the performance characteristics of molecular testing for VVC were unknown. In a multi-site prospective cohort study, polymerase chain reaction (PCR) for the Candida group ( C. albicans , C. dubliniensis , C. parapsilosis , and C. tropicalis ) was found to have high clinical accuracy (sensitivity 90.9%, specificity 94.1%, PPV 87.8%, and NPV 95.7%) [ 6 ]. Sensitivity was lower for C. glabrata (75.9%) but specificity, PPV, and NPV remained high for this species (99.7%, 81.6%, and 99.6% respectively). A later study of this same population compared real-time PCR to clinical microscopy and found that for the Candida group, PCR yielded higher sensitivity (90.7% vs 57.5%), specificity (93.6% vs 89.4%), PPV (87.2% vs 72.2%) and NPV (95.5% vs 81.4%) than clinical diagnosis [ 7 ]. Clinicians should be aware that some commercially available PCR tests for yeast are not Food and Drug Administration (FDA) cleared and have not published their performance characteristics. Thus, providers who choose PCR methods to diagnose VVC should be familiar with the performance characteristics. In general, molecular diagnostic methods appear promising and may replace culture as the gold standard in the future. However, even FDA-cleared tests may miss less common species of yeasts that infrequently cause VVC. Unlike culture, PCR does not make the organism available for susceptibility testing.

Treatment of Vulvovaginal Candidiasis

VVC can be classified as either uncomplicated or complicated ( Table 2 ) depending on factors including infection severity, yeast species, and immune system integrity [ 1 ]. In general, complicated VVC is less likely to respond to treatment and requires more aggressive regimens to completely resolve. Given the significant prognostic differences between uncomplicated and complicated VVC, the differentiation between these two conditions is necessary.

Classification of Vulvovaginal Candidiasis

Abbreviation s: HIV, human immunodeficiency virus; VVC, vulvovaginal candidiasis.

Treatment of Uncomplicated Vulvovaginal Candidiasis

Azole antifungals continue to be the backbone of VVC treatment and are adequate to completely resolve Candida infections in most cases of uncomplicated VVC. These medications come in a variety of formulations and can be administered orally or topically as vaginal creams, ointments, or suppositories. Our search of available regimens for the treatment of VVC found that, to date, none of the recommended medications have been removed from the market, and no additional formulations have been introduced. As such, the recommended treatment of uncomplicated VVC remains unchanged.

Recently approved is the oral antifungal agent ibrexafungerp (formerly SCY-078), a semi-synthetic triterpenoid antifungal glucan synthase inhibitor which affects cell wall metabolism. In a small randomized controlled trial, subjects with moderate to severe VVC were treated with 3 or 5 days of either ibrexafungerp or 150mg oral fluconazole. Those on the ibrexafungerp regimens had numerically higher clinical (78.1% vs 65.6%) and mycological (70.3% vs 68.8%) cure rates and identical therapeutic cure rates (56.3%) at 24 days post-treatment [ 8 ]. At 120 days post-treatment, the ibrexafungerp regimens continued to perform well, with clinical cure rates of 88% compared to 65% in the fluconazole arm. Additionally, the recurrence rate at 120 days was lower for the ibrexafungerp groups than the fluconazole group (4% vs 15%) [ 8 ]. This drug may end up being particularly useful for azole intolerant or resistant VVC.

In development is TOL-463, a novel boric acid-based vaginal anti-infective enhanced with ethylenediaminetetraacetic acid (EDTA). In a small phase 2 randomized controlled trial of women with either VVC, bacterial vaginosis (BV) or both, participants were assigned to take TOL-463 as either a vaginal gel or an insert. In the women with VVC, the insert showed higher rates of cure than the gel (92% vs 81% clinical cure rate, 85% vs 81% mycological cure rate). Both methods were found to be effective and safe [ 9 ], but without evidence of superiority over available antifungal therapies.

For both of these medications, further research is needed to determine the role they will ultimately play in treating VVC.

Treatment of Recurrent Vulvovaginal Candidiasis

Recurrent VVC (RVVC) is defined as three or more symptomatic episodes of VVC over 12 months [ 10 ]. In the past, RVVC was defined as four or more episodes over 12 months, but current treatment protocols, whose synopses can be reviewed on clinicaltrials.gov, confirm that three or more has become the accepted case definition. Usually thought to affect a small proportion of women (<5%), a recent internet survey of more than 6000 women from five European countries and the United States found the prevalence of self-reported RVVC to be 9%, with the highest prevalence in women 25 to 34 years old (12%) [ 11 ]. Although self-report is prone to bias, this study suggests that RVVC is more common than traditionally thought, especially among young women, and that additional studies of its prevalence that use validated methods of diagnosing VVC are warranted and necessary. RVVC is associated with significant morbidity. In addition to the itching, burning, swelling, and discomfort often associated with VVC, women with recurrent VVC often also suffer from low self-esteem, loss of confidence, challenges participating in their regular interests, and difficulty in their sexual and intimate life [ 3 ]. Missed days of work and the resultant economic burden compound these issues, contributing to a cycle of stress and anxiety. In the United States, recurrent VVC is estimated to affect 6 million women, causing approximately $4.7 billion in lost productivity annually [ 3 ].

Little is known about host factors that contribute to RVVC in women; possible factors include genetic predisposition in cases of idiopathic RVVC, as well as drug resistance or under-dosing. A recent retrospective study to assess differences in in vivo antifungal potency used the first positive yeast cultures from more than 200 women with recurrent VVC. The efficacy of six antifungals (fluconazole, itraconazole, miconazole, clotrimazole, terconazole, and nystatin) against various yeast species was tested at both pH 4 (normal vaginal pH) and pH 7 (commonly used by labs when doing susceptibility testing). All medications tested were found to have higher minimum inhibitory concentrations (MICs) at pH 4 than at pH 7 [ 12 ]. The impact of pH differed by antifungal agent and yeast species, with the most significant difference in MIC was seen when terconazole was used to treat C. glabrata . In these cases, the MIC was more than 388-fold higher at pH 4 than at pH 7. The reduced susceptibility of C. glabrata at low pH confirms the findings of a previous study [ 13 ], and suggests that the activity of antifungal drugs should be tested at a vaginal pH of 4 rather than the laboratory standard of pH 7 as there may be clinically relevant and unrecognized azole drug resistance that may contribute to recurrence of VVC.

Maintenance fluconazole, the first line treatment for RVVC, has been shown to improve quality of life in 96% of women [ 14 ]; it is, however, uncommonly curative and recurrence occurs more frequently than was previously thought, with one study finding that more than 63% of women who had completed maintenance therapy continued to have ongoing infections [ 15 ]. For all of these reasons, recurrent VVC represents a significant public health issue in need of new treatment approaches.

In terms of treatment, oteseconazole (formerly known as VT-1161) is a promising, novel oral highly-selective inhibitor of fungal lanosterol demethylase (CYP51) medication which has a very long plasma half-life. In a double blind placebo-controlled randomized controlled trial of women with RVVC, patients treated with VT-1161 at either a high or low dose for 12 or 24 weeks showed remarkably lower rates of recurrence than those on placebo at the 48 week study time point (4% vs 52%) [ 16 ]. Analysis of phase 3 trials is expected to be available soon.

A novel approach to treating RVVC, a vaccine targeting a hyphal virulence factor of Candida albicans , has also been evaluated for the treatment of RVVC [ 17 ]. Clinical data has shown it to be safe, immunogenic, and capable of reducing the frequency of symptomatic VVC for up to 12 months, but only in a subset of women under 40 years of age.

Unlike treatment of urinary tract or bloodstream infections where susceptibility testing is routine for determining the best treatment, susceptibility testing for yeast infections has not been widely used. With growing concerns about resistance of both albicans and non- albicans Candida , susceptibility testing may help guide therapeutic choice, particularly at a pH of 4.0 which mimics the vaginal environment in premenopausal women with VVC. Susceptibility testing is most valuable in patients with VVC refractory to treatment (eg, still symptomatic with a positive culture immediately after treatment).

Treatment of VVC caused by non- albicans Candida

Candida albicans is the species most commonly found to be causative of VVC. Vulvovaginal yeast infections can also be caused by non- albicans yeast including other species of Candida or even yeast used in baking, like Saccharomyces cerevisiae [ 18 ]. These other species can be more challenging to diagnose and treat; as such these women meet the diagnostic criteria for complicated VVC.

Evidence suggests that at least 50% of women colonized with non-a lbicans Candida species experience minimal or no symptoms of VVC [ 19 ]. Relatively few studies have investigated clinical outcomes in non- albicans cases [ 20–23 ]. Since the last published guidelines, a retrospective analysis of non- albicans cases at a tertiary care center [ 24 ] found that yeast seemed to be responsible for symptoms in 29/55 cases of C. glabrata , 16/24 cases of C. parapsilosis , 4/7 cases of C. tropicalis , 3/5 cases of C. lusitaniae and 2/2 cases of C. krusei . In total, non- albicans yeast accounted for symptoms in 55.7% of the 97 investigated cases. The same study found that a majority of non- albicans VVC can be effectively treated with either fluconazole or boric acid. Fluconazole resulted in a mycologic cure in 81% of C. parapsilosis cases and 60% of C. glabrata cases, while an initial 21–30 day course of boric acid effected a cure in 75% of C. parapsilosis cases, 78% of C. glabrata cases, 100% of C. tropicalis cases, 80% of C. lusitaniae cases, and 100% of C. krusei cases [ 24 ].

Of 49 C. parapsilosis cases at another tertiary care center, 60% were symptomatic [ 25 ]. Of those symptomatic cases, the clinician felt that 65% were symptomatic due to colonization with C. parapsilosis . Although the dose and duration was not specified in this study, treatment with boric acid was reported as effective in all treated cases, while only 70% of isolates were susceptible to fluconazole. Given the challenges associated with treating non- albicans yeast because of drug resistance and the low virulence of many of these species of yeast, women who are found to be asymptomatically colonized should forgo drug treatment.

Alternative Treatments

Many women who suffer from VVC, especially recurrent VVC, turn to alternative treatments. The growing public interest and investment in alternative treatment regimens for treating VVC necessitates a review of the efficacy of these modalities.

Since the last update to the treatment guidelines for VVC, several international studies investigated alternative treatments, including the use of honey-based ointments and gels, combined ginger-clotrimazole vaginal cream, and essential oils including tea tree, laurel, anise, basil, bergamot, lavender, mint, oregano, grapefruit, rosemary, winter savory, and ginger [ 26–29 ]. Although some of these interventions had beneficial impacts such as reducing discharge or partial reduction of symptoms, in general they were equal or inferior to prescribed medications. Given the lack of regulation of these treatments and their associated vehicles, as well as the availability of FDA-approved alternatives that show higher rates of cure, we do not recommend their use for the treatment of VVC.

In addition to increasing popularity of herbal alternative treatments, there has been a surge in the popularity of probiotics in recent years, especially for the treatment of digestive and vaginal health issues. Between 2007 and 2012, the number of adults in the US taking probiotics or prebiotics quadrupled [ 30 ], and in 2015, consumers worldwide spent an estimated $35 billion on probiotic supplements with the number expected to rise [ 31 ]. Several international groups have investigated the use of oral or vaginal probiotics for treatment or prophylaxis against VVC. Studies from Italy, Iran, Sweden, and Canada examined the impact of probiotics including Lactobacillus fermentum, L. acidophilus, L. plantarum, L. rhamnosus, L. reuteri, L. gasseri, Bifidobacterium bifidum, and B. longum [ 32–36 ]. All of these studies suffered from methodological issues. As such, the use of alternative treatments including essential oils and oral or vaginal probiotics is not recommended for the treatment of VVC.

Special Populations

Pregnancy is a known risk factor for VVC, likely due to pregnancy-related factors including increased estrogen levels, increased vaginal glycogen, and alterations in the immune system [ 37 ]. Given the risk of teratogenesis during this vulnerable period, all medications must be thoroughly studied before they are recommended for use during pregnancy.

A systematic review of congenital malformations and fluconazole use during the first trimester found a potential association between fluconazole and overall malformations (odds ratio [OR] 1.10, 95% confidence interval [CI] .98–1.25), heart defects (OR 1.29, 95% CI 1.05–1.58), and craniofacial defects (OR 1.25, 95% CI .88-–1.77). The increased rates of overall malformations and craniofacial defects failed to meet significance [ 38 ]. The link between fluconazole use during pregnancy and the risk of craniofacial and cardiac defects was also seen in a case-control study from a database of more than 40000 mothers and their newborns, which found significant epidemiologic associations between fluconazole use during pregnancy and cleft lip and/or palate (OR 5.53, 95% CI 1.68–18.24) as well as dextro-transposition of the great arteries (OR 7.56, 95% CI 1.22–35.45) [ 39 ].

Fluconazole use during pregnancy has also been associated with spontaneous abortion [ 40 , 41 ], although no increased risk was seen if fluconazole use occurred in the year prior to pregnancy or if a topical azole was used [ 40 ]. Several studies with significant methodological flaws, primarily the use of microscopy instead of culture for diagnosis, demonstrated an association between VVC and preterm delivery [ 42–44 ]. Additional higher quality studies are needed to further investigate this relationship and to determine the degree of risk of preterm delivery among women with both symptomatic and asymptomatic yeast colonization. Current guidelines state that only topical azole therapy should be used to treat VVC in pregnancy.

Human Immunodeficiency Virus

Several international studies have evaluated the relationship between HIV infection and VVC. A retrospective cohort study from South Africa found that rates of VVC increased when CD4 + T-cell counts were <200 cells/mm 3 and plasma HIV RNA load was >10000 copies/mL [ 45 ]. VVC was also associated with increased vaginal viral shedding. In contrast, women on combination ART were 4-fold less likely to develop VVC. Although no studies yielded robust findings, the link between worsening viral control and VVC is echoed in studies from Brazil, Namibia, and the United States [ 46–48 ]. The treatment guidelines for women with HIV infection and VVC remain unchanged.

Future Needs

Significant knowledge about VVC has been generated since the publication of the last update to the CDC Treatment Guidelines, but there is still much that remains unknown or that requires further investigation. Specifically, home self-tests that are accurate for yeast are one intervention that might decrease VVC-associated healthcare spending and would expedite treatment for many women. In the same vein, widely available validated molecular testing would expedite diagnosis of VVC and identification of the causative species, allowing for timely and targeted treatment of infections while decreasing rates of misdiagnosis.

A study of the clinical utility and cost effectiveness of the various diagnostic methods and susceptibility testing available is vital as healthcare costs continue to rise. Identifying the most effective clinical workup, including the role of in vitro susceptibility testing, for patients with either uncomplicated or complicated VVC is one way to maximize quality of care while also minimizing costs to the patient and to standardizing best practices among providers.

There is a growing need for treatment options for non- albicans yeast and C. albicans infections resistant to azole. Although vaginal boric acid and possibly nystatin have been very useful, the only other medication that reliably treats non- albicans yeast is a compounded cream containing flucytosine, which is prohibitively expensive for many patients. Additionally, effective medications that do more than simply control cases of recurrent VVC are still lacking from our current armamentarium. Use of ineffective medications in these patients runs the risk of increasing antifungal resistance, making complete eradication of their infection even more challenging. Better therapies must be developed to treat recurrent VVC.

Finally, further studies should be conducted concerning the larger implications of VVC on human health and disease. Like many other causes of vaginitis, VVC and its impact on patients is often trivialized. As a result, the role that is plays in other diseases, chronic or acute, has been at best largely glossed over, at worst completely ignored. This significant public health issues requires serious research and inquiry if it is to be combatted on the national and global scale.

Supplement sponsorship. This supplement is sponsored by The Centers for Disease Control and Prevention.

Potential conflicts of interest. P. N. has received research support from Mycovia Pharmaceuticals, Curatek Pharmaceuticals, Scynexis, Inc, and Hologic; he has served as a consultant for Mycovia Pharmaceuticals, Lupin Pharmaceuticals, Hologic, Scynexis, Inc, Daré Bioscience, Inc, and Becton Dickinson (BD). G. L. reports that she is on Sanaria’s Data Safety and Monitoring Board for Malaria Vaccination and serves as the Treasurer-Elect of the Infectious Diseases Society for Obstetrics and Gynecology. J. S. has received research funding and consulting fees from Mycovia, Toltec, Scynexis, BD Diagnostics, Lupin, Talis, PhagoMed, and Hologic; J. S. also reports honoraria from Hologic and Scynexis, patents planned, issued, or pending with UAHSF, travels fees from Scynexis, stock or stock options from Talis. J. D. S. has served as a consultant to Mycovia Pharmaceuticals, Scynexis and Lupin Pharmaceuticals. C. B. reports no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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Bérard A , Sheehy O , Zhao J , et al.  . Associations between low- and high-dose oral fluconazole and pregnancy outcomes: 3 nested case-control studies. CMAJ 2019 ; 191 : E17 – E187 .

Farr A , Kiss H , Holzer I , Husslein P , Hagmann M , Petricevic L. Effect of asymptomatic vaginal colonization with Candida albicans on pregnancy outcome. Acta Obstet Gynecol Scand 2015 ; 94 : 989 – 96 .

Roberts CL , Algert CS , Rickard KL , Morris JM. Treatment of vaginal candidiasis for the prevention of preterm birth: a systematic review and meta-analysis. Syst Rev 2015 ; 21 : 4 – 31 .

Holzer I , Farr A , Kiss H , Hagmann M , Petricevic L. The colonization with Candida species is more harmful in the second trimester of pregnancy. Arch Gynecol Obstet 2017 ; 295 : 891 – 5 .

Apalata T , Carr WH , Sturm WA , Longo-Mbenza B , Moodley P. Determinants of symptomatic vulvovaginal candidiasis among human immunodeficiency virus type 1 infected women in rural KwaZulu-natal, South Africa. Infect Dis Obstet Gynecol 2014 ; 2014 : 387070 – 10 .

Alczuk SSD , Bonfim-Mendonça PS , Rocha-Brischiliari SC , et al.  . Effect of highly active antiretroviral therapy on vaginal Candida spp. isolation in HIV-infected compared to HIV-uninfected women. Rev Inst Med Trop Sao Paulo 2015 ; 57 : 169 – 74 .

Gaston D , Madeleine S , Steve G , et al.  . Prevalence and correlates of genital infections among newly diagnosed human immunodeficiency virus-infected adults entering human immunodeficiency virus care in Windhoek, Namibia. Sex Transm Dis 2016 ; 43 : 698 .

Merenstein D , Hu H , Wang C , et al.  . Colonization by Candida species of the oral and vaginal mucosa in HIV-infected and noninfected women. AIDS Res Hum Retroviruses 2013 ; 29 : 30 .

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Information for Healthcare Professionals About Invasive Candidiasis

Signs and symptoms of invasive candidiasis are often non-specific and include fever and chills that do not respond to antibacterial treatment. Candidemia is the most common form of invasive candidiasis; other forms include endocarditis, peritonitis, meningitis, osteomyelitis, arthritis, and endophthalmitis. Invasive candidiasis is associated with an in-hospital all-cause mortality of approximately 30%.

Candida auris has emerged globally since 2009, including in the United States from mid-2015, and is very concerning because it is highly antimicrobial resistant, causes invasive infections associated with high mortality, and spreads easily between patients in healthcare settings.

Candida albicans , C. glabrata , C. parapsilosis , C. tropicalis , and C. krusei are most common. Species distribution varies by patient population and geographic region.

Candida is a commensal organism of the gastrointestinal tract and skin.

Most infections arise from the endogenous flora of patients with risk factors following disruption of skin and mucosal barriers. Less commonly, Candida can be transmitted via healthcare workers’ hands or contaminated medical devices.

Invasive candidiasis is primarily diagnosed with blood culture. Newer culture-independent diagnostic methods are promising but are not yet widely used. The Beta-D-glucan assay is approved as an adjunctive diagnostic tool but is not a very specific test for Candida . Determining the species of Candida causing the infection is important to guide appropriate antifungal treatment.

For most adult patients with candidemia, an echinocandin is recommended as initial therapy, with transition to fluconazole once the infecting species and antifungal susceptibility are known and blood cultures have cleared. Fluconazole is an acceptable alternative to an echinocandin as initial therapy in selected patients, including those who are not critically ill and who are considered unlikely to have a fluconazole-resistant Candida infection. Alternative treatments include voriconazole and amphotericin B formulations. In general, treatment should continue for two weeks after clearance of Candida from the bloodstream and resolution of symptoms attributable to candidiasis. Intravenous catheter removal is recommended for non-neutropenic patients and can be considered for neutropenic patients. For neonatal candidiasis, the recommended primary treatment is amphotericin B deoxycholate or fluconazole for two weeks after clearance of Candida from the bloodstream and resolution of attributable symptoms.

Treatment recommendations vary for other forms of invasive candidiasis. For detailed treatment guidelines, please refer to the Infectious Diseases Society of America’s Clinical Practice Guidelines for the Management of Candidiasis .

Common risk factors for invasive candidiasis include:

• Critical illness with a prolonged intensive care unit stay
• Presence of central venous catheters
• Use of broad-spectrum antibiotics or total parenteral nutrition
• Having hematologic or solid organ malignancy, stem cell transplantation, neutropenia, or recent abdominal surgery (especially in the presence of an anastomotic leak)
• Being a pre-term infant with a very low birth weight
• Having renal failure or hemodialysis
• Injection drug use

In healthcare settings, these measures are important to prevent invasive candidiasis:

• Adhering to hand hygiene recommendations
• Following recommendations for placement and maintenance of central venous catheters
• Practicing antimicrobial stewardship

Some groups of patients may benefit from antifungal prophylaxis:

• Some solid organ transplant recipients
• High-risk ICU patients
• Patients with chemotherapy-induced neutropenia
• Stem cell transplant recipients with neutropenia

CDC performs active population-based surveillance for Candida bloodstream infections in certain areas. Click here for more information about surveillance and statistics .

• Describe the national burden of candidemia
• Identify new and emerging risk factors for invasive candidiasis
• Target areas for intervention and prevention strategies
• Further develop laboratory methods to more rapidly diagnose Candida infections and detect antimicrobial resistance
• Better understand the drivers, mechanisms, and public health burden of antimicrobial-resistant Candida infections to identify the best prevention methods.

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Vulvovaginal Candidosis: Current Concepts, Challenges and Perspectives

Vulvovaginal candidosis (VVC) is a frequently occurring infection of the lower female genital tract, mostly affecting immuno-competent women at childbearing age. Candida albicans is the most prevalent pathogenic yeast—apart from other non- albicans species—related to this fungal infection. Different virulence factors of C. albicans have been identified, which increase the risk of developing VVC. To initiate treatment and positively influence the disease course, fast and reliable diagnosis is crucial. In this narrative review, we cover the existing state of understanding of the epidemiology, pathogenesis and diagnosis of VVC. However, treatment recommendations should follow current guidelines.

1. Background

Vulvovaginal candidosis (VVC) is a disease that affects women of all ethnicities and social classes [ 1 , 2 ]. The exact epidemiology of this disease is based on unreliable data, although based on what is currently known, 70–75% of women experience VVC at least once in their lifetime [ 2 , 3 ]. Numerous risk factors for VVC have been described. However, the pathological mechanism underlying the progression from colonization to infection is not fully understood [ 2 ], partly because most cases do not present a specific trigger [ 4 , 5 ]. The estrogenized vagina of asymptomatic women is often colonized with Candida species, although colonization does not necessarily lead to an infection [ 6 ]. The predominant species in 90–95% of cases is Candida albicans , followed by non- albicans species, such as C. glabrata , C. tropicalis , C. krusei and C. parapsilosis [ 7 ]. If VVC is caused by non- albicans species, it mostly manifests as a mild infection [ 4 ].

VVC causes distress in many affected women, and it is the reason for many consultations in gynecological offices worldwide. Herein, we summarize different aspects of this disease, excluding treatment approaches and concepts, using a non-systematic methodology to search the existing literature.

2. Epidemiology

Epidemiological data on the incidence of VVC are relatively vague because studies are often imprecise or conducted in unrepresentative populations; the incidence is estimated to range from 12% to 57% in the overall female population [ 2 , 3 ]. An Estonian study that used barcoded pyrosequencing technology found Candida in 67.6% of the asymptomatic women, reporting that the mycobiome that colonizes the healthy vaginal environment is more diverse than what was previously recognized [ 8 ]. Table 1 summarizes the VVC incidence and Candida colonization among symptomatic and asymptomatic women in different countries [ 3 , 9 , 10 , 11 , 12 , 13 ].

Vulvovaginal candidosis (VVC) and Candida colonization in different countries—adapted from Gonçalves et al. [ 3 ].

Apart from asymptomatic fungal colonization, Candida -related infections are the second leading cause of vaginitis, primarily affecting women during their reproductive lifetime, when high estrogen levels increase the glycogen content of the vaginal epithelium, therewith playing a role in the nutrition for the yeast [ 3 , 14 ]. It is of paramount importance to differentiate between colonization and infection because 50% of women with an infection will experience a second episode, and 5–8% will develop recurrent vulvovaginal candidosis (RVVC) [ 2 , 15 ]. RVVC is defined as experiencing four or more episodes of VVC per year [ 2 , 16 ]. Recent data report a worldwide RVVC prevalence of approximately 138 million women per year and an additional 372 million over a lifetime [ 4 , 5 ]. Most episodes of RVVC occur between the ages of 19–35 years, and according to a survey, the prevalence rate is 9% by the age of 50 years [ 5 , 17 ]. Fidel et al. [ 18 , 19 ] suggest that women with RVVC have a dysfunction in the normal protective immune response acquired from a previous Candida infection.

3. Pathogenesis

Recognition of the importance of the innate response in driving inflammatory responses associated with VVC has led to many recent insights regarding the pathogenesis of VVC. It is known that cells of the innate host express receptors that recognize pathogen-associated molecular patterns (PAMPs) [ 20 ]. The major classes of receptors that recognize Candida -associated molecular patterns are those of the Toll-like receptors and lectin-like receptors families [ 21 ]. A mannose-binding lectin (MBL) recognizes and binds to Candida surface mannan, increases complement activation and inhibits Candida growth [ 22 , 23 ]. Similarly, macrophages, dendritic cells and epithelial cells play an important role and exert a protective function. Macrophages and dendritic cells have specific surface receptors that recognize MBL and promote opsonization of MBL-bound microorganisms [ 24 ].

Adaptive immunity—including fungus-specific defense mechanisms—is developed directly or indirectly through cell-mediated immunity (T-cells) [ 25 ]. Decreased T-cell-mediated immunity is associated with increased susceptibility to VVC in women who are immunocompromised (e.g., due to HIV infection, previous organ transplantation, glucocorticoid therapy or antineoplastic chemotherapy) [ 26 , 27 , 28 ]. B-cells and immunoglobulin-secreting plasma cells migrate into the vaginal epithelium [ 18 , 29 ], protecting against pathogenic microorganisms. The exact mechanism by which antibodies protect against Candida is unknown [ 30 , 31 ]. Immunoglobulin A (IgA) and IgG are the predominant immunoglobulin classes found in vaginal secretions [ 32 ].

During the pathogenic process, Candida undergoes reversible yeast-to-hyphae transition, which causes changes in the type of surface carbohydrates, affecting the adhesion and invasion of vaginal epithelial cells ( Figure 1 ). Candida either infects vaginal epithelial cells directly through the invasion of hyphae or indirectly through the contact of PAMPs with pattern recognition receptors (PRRs). In response to this, contact inflammatory immune mediators—chemokines, cytokines, antimicrobial peptides or damage-associated molecular patterns—are secreted, subsequently recruiting innate immune cells, such as macrophages, dendritic cells and neutrophils. These cells also recognize PAMPs through PRRs on their surfaces, bind to the pathogen, and stimulate its removal by phagocytosis.

Pathogenesis of vulvovaginal candidosis.

This mechanism involves the production of reactive oxygen species, which further regulate all stages of inflammation. The phagocytized pathogenic components activate inflammasomes, which induce the release of proinflammatory cytokines, and subsequently promote T-cell activation and neutrophil recruitment. Neutrophils enter through the vaginal epithelium and promote phagocytosis of Candida on the epithelial surfaces of the vagina [ 33 , 34 , 35 ].

For Candida colonization on the host surface, adhesion to vaginal epithelial cells is crucial and contributes to infection and persistence [ 36 ]. This process is promoted by cell-surface components (adhesins), which recognize host ligands, such as serum proteins, in the extracellular matrix of host tissues (e.g., laminin, fibronectin, collagen, vitronectin and entactin) [ 37 ]. A major group of adhesins from the agglutinin-like sequence (ALS) gene family is encoded in C. albicans ; this group consists of 8 members (ALS 1–7, ALS 9) [ 38 ]. Cheng et al. [ 39 ] found that ALS 1–3 and ALS 9 occurred more frequently in women with VVC.

3.1. The Role of Enzymes

Candida spp. secrete several hydrolytic enzymes [ 40 ]. Among the most important enzymes are aspartyl proteinases (Saps), which facilitate adhesion [ 36 , 41 ]. In recent years, 10 Sap genes were identified in C. albicans [ 42 ], 3 in C. parapsilosis [ 43 ], and 4 in C. tropicalis [ 44 , 45 ]. Saps only have proteinase activity in acidic environments [ 46 ]; Sap 1–3 show a specific correlation with VVC and the occurrence of C. albicans [ 47 , 48 , 49 ].

Phospholipases similarly play an important role in pathogenicity by damaging host cell membranes and contributing to adhesion. Mohandas and Ballal [ 50 ] observed a greater number of phospholipase-producing strains from vaginal isolates in patients with candidosis than in patients without candidosis. Moreover, different phospholipase genes ( PLA , PLB1–2 , PLC1–3, and PLD1 ) were described in infected women [ 51 ].

3.2. From Colonization to Infection

Vaginal colonization with C. albicans is common, and women with colonization are often asymptomatic [ 8 , 52 ]. However, when colonization progresses to infection, women frequently report vaginal itching, burning, pain, and redness. Typical VVC symptoms are often accompanied by vaginal discharge, consisting of shed epithelium, immune cells, yeast and vaginal fluid [ 53 ]. Candida invasion requires a transition from the yeast to the hyphae form; however, the ability to produce hyphae varies among different species [ 36 ]. In vitro studies showed that C. albicans without hyphae formation has a lower rate of tissue invasion [ 54 ]. In addition, the toxin candidalysin contributes to this transition, as it has a cytotoxic effect on the host cells and promotes invasion, attracting leukocytes [ 34 , 55 ]. Multiple virulence and host-specific factors may play a role in the development from colonization to infection.

4. Virulence Factors

VVC episodes cannot be attributed to a specific trigger [ 4 , 5 ]. The individual infection susceptibility depends on intrinsic and extrinsic factors. Host-specific risk factors, such as local defense mechanisms, age and hormonal status, pregnancy, allergies, psychosocial stress, metabolic issues, immunosuppression and individual genetic susceptibility, are important [ 2 , 56 , 57 , 58 , 59 , 60 ]. Additionally, behavioral risk factors, such as the use of oral contraceptives, antibiotics, glucocorticoids, inhibitors of the sodium glucose co-transporter-2 (SGLT2), intrauterine devices (IUDs), spermicides and condoms, as well as sexual, hygienic and dressing habits, need to be addressed [ 2 , 3 , 61 ].

4.1. Immunologic Factors

Genetic factors contribute to the development of VVC or its relapse. Foxman et al. [ 62 ] reported that women of African ethnicity showed an increased risk for VVC. This might be the result of a reduced occurrence of lactobacilli that happens more frequently in women of African ethnicity [ 63 ]. Moreover, genetic polymorphisms in blood group antigens and MBL have been identified in cases of increased susceptibility to RVVC [ 64 , 65 , 66 , 67 ]. A loss of the last 9 amino-acids in the carbohydrate recognition domain of the Dectin-1 gene has been associated with the occurrence of RVVC [ 68 ]. This mutation leads to insufficient production of cytokines (IL-17, tumor necrosis factor and IL-6) when it comes in contact with Candida (78). Moreover, women with atopic diathesis and type I allergies experience VVC more frequently than healthy individuals [ 69 ]. The typical VVC symptoms, such as itching and redness, may equally be regarded as signs of an allergic phenomenon [ 2 , 70 ].

Apart from common immunologic factors, pregnancy increases the likelihood of experiencing VVC; its incidence increases from 9% to 54% between the first and the third trimesters of pregnancy [ 71 , 72 , 73 ]. This rise may be partly attributed to immunologic factors, but also to the increase in sex hormones [ 56 , 57 ]. The occurrence of VVC during pregnancy is generally not considered dangerous with regard to preterm birth [ 57 ]. Recurrent candidosis showed an association with preterm birth in a large retrospective trial [ 72 ]. However, preterm birth is a multifactorial event, and it is likely that chronic inflammation but not VVC itself contributes to this event [ 72 ]. Of important note, almost all infants born from mothers with VVC during pregnancy show “diaper rash” or oral thrush due to the vertical mother-to-infant transmission [ 74 ].

4.2. Hormonal Factors

Glycogen serves as a nutrient substrate for fungi in the vaginal epithelium. There is a relationship between the respective hormonal cycle phase and the occurrence of VVC influenced by estrogen. Therefore, most women experience VVC cyclically or during the luteal phase. When estrogen levels drop during menstruation, symptoms often disappear [ 75 ]. Women who are on oral contraceptives and postmenopausal women who receive hormone replacement therapy are more likely to develop VVC than others [ 76 ]. Several studies report a higher incidence of colonization with Candida and VVC in women who use oral contraceptive pills [ 3 , 26 , 77 ]. The intake of contraceptives increases the level of vaginal glycogen, providing a better condition for Candida growth [ 78 ]. Miller et al. [ 79 ] demonstrated that IUDs compromise the vaginal defense against infections. Donders et al. [ 80 ] reported that the risk of developing VVC increased during the first 5 years after placement of levonorgestrel intrauterine systems, with the risk particularly high during the first year of placement [ 80 ]. Progesterone, however, reduces the ability of C. albicans to develop hyphae forms.

4.3. Metabolic Factors

Women with diabetes mellitus have an increased risk of experiencing VVC. This risk is exacerbated when their serum glucose levels are not within the normal range. Hyperglycemia leads to increased fungal adhesion and growth, and a glycemic index of 10–11 mmol/L can impair the host’s defense mechanisms [ 81 ]. Similarly, C. albicans shows a high ability to bind to vaginal epithelial cells in in vitro studies [ 82 , 83 ]. The yeast exhibits a glucose-inducible surface protein that promotes its adhesion to vaginal epithelial cells [ 81 ], and an increase in this protein impairs the recognition of neutrophil phagocytes [ 84 ]. Therefore, the migration of neutrophils is reduced and their functions, including phagocytosis, adhesion, chemotaxis, and intracellular killing, are impaired, increasing the sensitivity to VVC [ 3 , 5 , 59 , 80 ].

From a clinical perspective, women with diabetes are often unresponsive to standard antifungal treatment [ 58 , 59 ]. Compared with non-diabetic women, diabetic women are frequently colonized with non- albicans species, such as C. glabrata [ 85 , 86 , 87 ], impacting their treatment concept [ 85 ]. In diabetic women with RVVC, discontinuation of the antidiabetic agent should be considered [ 34 ]. The undesirable side effect of hyperglycemia caused by glucocorticoids has a similar effect to that of non-drug-induced hyperglycemia [ 88 ] because the steroid hormones suppress the immune response, increasing the susceptibility to VVC [ 89 ]. In pregnant women with gestational diabetes, their diabetic state impairs metabolic control and leukocyte function [ 5 , 80 ].

4.4. Lifestyle Factors

Various lifestyle factors can have a significant influence on the development of VVC. There is weak evidence for the impact of nutrition on Candida growth, although some studies have reported that the consumption of food rich in sugar and carbohydrates, as well as dairy products, can lead to increased fungal growth [ 90 , 91 ]. In contrast, others have reported that yogurt, oat bran and flaxseed might have positive effects in preventing fungal growth [ 7 ]. Despite their theoretical basis, these findings are not well substantiated.

Sexual behavior, especially oral sex, plays a role particularly for re-infections [ 92 , 93 , 94 ]. Reed et al. demonstrated that oral microorganisms could be transmitted from the oral cavity to the vagina [ 93 , 95 , 96 ]. Genital hygiene can also become a risk factor for VVC, when poor personal hygiene and a high frequency of sexual intercourse increase the likelihood for colonization [ 92 ], VVC [ 97 ] and RVVC [ 98 , 99 ]. Women should be advised to avoid excessive washing of the genital area and the use of potential irritants such as perfumed soaps, bubble baths, powders or vaginal sprays [ 100 ].

The use of tight clothing and synthetic underwear might also promote fungal growth due to the increased perineal moisture and temperature [ 61 , 97 ].

4.5. Other Exogenous Factors

Women who are colonized with Candida have a 33% higher risk of developing VVC after antibiotic treatment than non-colonized women [ 92 , 101 , 102 , 103 ]. However, the routine use of antimycotic treatment after antibiotic therapy should be avoided because it fosters drug-resistant fungi [ 104 ]. There are different theories about why VVC occurs more frequently after antibiotic treatment. One of the theories involves the reduction or eradication of vaginal and intestinal lactobacilli caused by antibiotics. As a result, affected patients lack protection from pathogenic microorganisms because lactobacilli have the ability to adhere to vaginal epithelial cells and inhibit pathogenic fungal growth [ 105 , 106 ].

Some lactobacilli have antagonistic effects on Candida [ 107 , 108 ]; their vaginal administration may lead to an adequate colonization and reduction in fungal load [ 34 , 109 ]. In vitro, lactobacilli have also shown direct fungicidal and immuno-stimulatory effects [ 110 ]. The interactions are manifold: lactobacilli can block the passage of pathogenic microbes from the gastrointestinal tract into the vagina, modulate the host’s immune response, influence epithelial defense and thus affect the expression of VVC-induced inflammatory genes. Probiotics take advantage of these effects [ 111 ].

5. Biofilm Formation

Microbes can form biofilms in response to various factors, including cellular recognition of specific or non-specific attachment sites on a surface, nutritional cues or exposure of planktonic cells to sub-inhibitory concentrations of antibiotics. A cell that switches to a biofilm growth mode undergoes a phenotypic shift in behavior wherein large suites of genes are differentially regulated [ 112 ]. The demonstration of a vaginal biofilm in bacterial vaginosis and its postulated importance in the pathogenesis of recurrent infections have led to the hypothesis that biofilms might be crucial for the development of VVC. However, fungal biofilms have been identified in vitro, although histological lesions in vivo are primarily polymicrobial and do not contain biofilms [ 106 ].

The shift from colonization to infection involves adherence to the vaginal epithelium, invasion, infection and inflammation through virulence factors. Most importantly, the formation of pseudo-hyphae leads to the formation of fungal components that stimulate the chemotaxis of granulocytes, causing inflammation. Changes in or overexpression of the target molecules, active extrusion of antimycotics by efflux pumps, limited diffusion of antimycotics in the matrix, stress tolerance, cell density and the presence of persistent cells may be involved in this drug-resistance phenomenon [ 113 ].

Candida is well known for forming biofilms on the acrylics of dentures, implantable devices in the bloodstream, urinary catheters and mucosal surfaces, such as the oral cavity [ 114 , 115 ]. The ability of C. albicans , C. glabrata , C. parapsilosis , C. tropicalis and C. guilliermondii , isolated from patients with VVC, to form biofilms, has also been investigated in vitro [ 116 ]. However, 20–34% of patients with RVVC show mixed biofilms. Streptococcus agalactiae and Gardnerella vaginalis were the bacterial microbes identified in these cases [ 117 , 118 ]. It remains unclear if the presence of a fungal biofilm determines whether Candida behaves as a pathogen or as a colonizer on the vaginal mucosa, leading to a switch from commensalism to a pathogenic state. From what is known, it can be assumed that biofilm formation causes a certain resistance to antimycotics, despite the unknown mechanisms [ 119 ].

6. Diagnostic Work-Up

VVC can cause psychosocial stress and may negatively affect the work and social lives of patients [ 60 , 120 ]. The decrease in quality of life through VVC is comparable with that of patients with bronchial asthma or chronic obstructive bronchitis [ 121 ]. In 90% of the affected women, the predominant symptom of VVC is itching. Anamnesis and proper diagnostic work-up is crucial for VVC, considering the rising number of women with similar symptoms who practice self-medication. Although many people use over-the-counter therapies, studies have shown that only 28% of self-treated women actually experienced VVC [ 122 ]. Premenopausal women experience candidosis that is mostly limited to the vestibule and vulva and symptoms that occur prior to the menstrual period, whereas postmenopausal women experience candidosis of the groin and vulvar areas. In addition, edematous labia minora and burning rhagades can occur in cases of RVVC. However, physicians should consider that only 35–40% of all women with itching complaints actually have VVC [ 123 , 124 , 125 ]. For a better differential diagnosis, it should be considered that VVC has no unpleasant odor and that the vaginal discharge of affected women is mostly of whitish color and lumpy consistency [ 5 ].

Apart from clinical presentation characteristics, the diagnosis should involve laboratory methods. Following anamnesis and gynecological examination of the patient, phase contrast microscopy should be used to examine the vaginal discharge using saline solution (or alternatively 10% KOH solution) at 400-fold magnification [ 126 ]. The clear presence of hyphae upon microscopic examination is a major criterion for appropriate diagnosis; however, it can only be observed in 50–80% of positive cases [ 2 , 126 ]. Microscopy is essential since the formation of hyphae plays an important role in tissue invasion [ 36 ]. Accordingly, in vitro studies have shown that C. albicans has a lower rate of tissue invasion in the absence of hyphae in microscopic examination [ 54 ].

In some cases, low germ load hinders microscopic detection. In particular, RVVC cases require culture tests; however, these methods should not routinely involve the determination of minimal inhibitory concentration [ 2 , 92 , 127 , 128 ]. The typical culture medium for detecting Candida spp. is Sabouraud 2% glucose agar. Chromogenic media may be superior because they are more sensitive to Candida and, in case of mixed cultures, certain Candida spp. may be immediately identified by these means. Other diagnostic methods for the detection of Candida are DNA hybridization tests, which have a reported sensitivity and specificity of 84.2% and 96.3% [ 129 ], or qualitative detection tests of Candida antigens with a sensitivity and specificity approximately 93% and 95%, respectively [ 130 ].

To date, the serological tests that determine the antibody levels of Candida still lack evidence and specificity. These tests may detect fungi colonization in other body parts, such as the oral cavity, in mild or superficial VVC cases.

7. Future Perspectives

In the future, it will be increasingly important to avoid the emergence of drug-resistant Candida strains, prevent cases of RVVC and consider multiple drug interactions. One of the greatest challenges will be the prevention of antimycotic drug resistances in fungal infections. Consequently, alternative treatment strategies to conventional antimycotic treatment will be increasingly important [ 131 ]. Despite the desire of many women to self-treat instead of seeking professional help [ 132 ], they should be adequately informed that over-the-counter treatment without proper diagnosis is often inaccurate and ineffective [ 122 , 133 ]. Moreover, decreasing the occurrence of self-treatment would assist in reducing the risk of developing drug resistance.

Because VVC constitutes a “neglected disease” in scientific research, which contributes to its relatively high prevalence, it is increasingly important to focus on its virulence factors [ 134 ]. Research on Candida is potentially promising as it offers various opportunities for clinical and translational studies. As an example, Candida vaccination could potentially become a realization [ 135 , 136 , 137 ]. Studies in animal models are ongoing, and their results are also promising [ 57 , 138 ].

To summarize, progress is being made in Candida research, but there is still more effort needed—despite the light on the horizon.

Acknowledgments

The figure was created with BioRender.com.

Author Contributions

Conceptualization, V.S. and A.F.; validation, A.F.; investigation, V.S.; resources, A.F. and P.F.; writing—original draft preparation, V.S.; writing—review and editing, A.F., P.F. and H.K.; visualization, P.F.; supervision, A.F. and H.K.; project administration, A.F. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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