thesis drug resistance

Assessing the impact of drug resistance and treatment on malaria transmission dynamics

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• Published: 01 February 2024
• Volume 10 , pages 2905–2916, ( 2024 )

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• Akindele Akano Onifade 1 &
• Mayowa Michael Ojo 2  

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Malaria is an ancient parasitic disease of humans caused by a protozoan of the genus Plasmodium and it is transmitted by infected female Anopheles mosquitoes. The model incorporates optimal sequencing (i.e., optimal sequencing of available antimalarial drugs from different classes to achieve the most effective treatment in malaria-endemic regions) and treatment (appropriate proportion of the exposed population that should receive treatment to restrict antimalarial resistance). Optimal sequencing, appropriate use of antimalarial in reducing wide spread of drug resistance, proper preventive measures, and timely medical care are essential in managing and controlling malaria. First, we analyze the state of malaria infection, calculate the baseline reproduction number, and study the local stability of malaria-free equilibrium. Numerical simulations of the malaria model is conducted using MATLAB program to investigate the dynamics of malaria under different scenarios (what if scenarios). The result of our simulations reveal that to effectively control widespread drugs resistance, it is crucial for policymakers to ensure that individuals who become resistant to a particular treatment must be introduced to another form of treatment to confer recovery from infection. This should also be complemented with the WHO-recommended non-pharmaceutical preventive measures.

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Onifade, A.A., Ojo, M.M. Assessing the impact of drug resistance and treatment on malaria transmission dynamics. Model. Earth Syst. Environ. 10 , 2905–2916 (2024). https://doi.org/10.1007/s40808-023-01938-5

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Factors contributing to the high prevalence of multidrug-resistance/Rifampicin-resistance in patients with tuberculosis: an epidemiological cross sectional and qualitative study from Khabarovsk krai region of Russia

• Ilia Bykov 1 , 2 ,
• Olga Dyachenko 3 ,
• Pavel Ratmanov 2 ,
• Huan Liu 1 ,
• Libo Liang 1 &
• Qunhong Wu 1  

BMC Infectious Diseases volume  22 , Article number:  612 ( 2022 ) Cite this article

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Growing prevalence of multidrug-resistant/Rifampicin-resistant tuberculosis (MDR/RR-TB; resistance to Isoniazid and Rifampicin/Isolated resistance to Rifampicin) is putting in jeopardy the WHO End TB strategy. This study aimed to identify factors contributing to the high prevalence of MDR/RR-TB in Khabarovsk krai region of Russia.

A cross-sectional retrospective study was conducted, analyzing clinical, demographic, and drug susceptibility testing data on 1440 patients. As a source of raw data, the national electronic TB surveillance system was used. Anonymous data was collected on every patient diagnosed with TB in all healthcare facilities of the region from January 2018 to December 2019. Only patients with proven excretion of m. tuberculosis were included in the study. Factors associated with MDR/RR-TB were identified through logistic regression analysis, in conjunction with in-depth interviews with eight patients, five healthcare managers and five doctors.

2661 patients were identified with TB, 1440 were incorporated in the study based on inclusion criteria. Of these, 618 (42.9%) were identified with MDR/RR-TB. Patients with a history of imprisonment were 16.53 times (95% CI 5.37 to 50.88,) more likely to have MDR/RR-TB, whereas re-treatment patients were 2.82 times (95% CI 2.16 to 3.66) more likely to have MDR/RR-TB. Other influencing factors included presence of disability (AOR is 2.32, 95% CI 1.38 to 3.89), cavitary disease (AOR is 1.76, 95% CI 1.37 to 2.25), and retirement status (AOR 0.65, 95% CI 0.43 to 0.98, p = 0.042). Poor patient knowledge and understanding of the disease, progressive weariness of prolonged TB treatment, and inability hospitalize infectious patients without their consent were perceived by the interviewees as major influencing factors.

Conclusions

Incarceration and treatment history, regardless of outcome, were identified as major factors influencing MDR/RR-TB prevalence. It is essential for the TB care system to eliminate legal loopholes, which deprive doctors of means to enforce quarantine procedures and epidemiological surveillance on infected patients, former and current inmates. Increasing people’s awareness of TB, early detection and appropriate treatment of patients with TB are needed for successfully combating MDR/RR-TB.

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Introduction

The continuous increase of multidrug-resistant/Rifampicin-resistant tuberculosis (MDR/RR-TB; resistance to Isoniazid and Rifampicin/Isolated resistance to Rifampicin) throughout the globe is a major public health issue. In 2020, the WHO reported that the global treatment success rate for MDR/RR-TB was only 59%. Treatment of MDR/RR-TB is more toxic to the patient, less effective, and it carries a much higher economic burden on the patients and the healthcare system, jeopardizing TB control efforts in developed and developing countries alike [ 1 , 2 , 3 , 4 ].

Russia carries one of the greatest burdens of MDR/RR-TB in the world. In 2018, MDR/RR-TB accounted for 35% of all new TB cases and 71% of all previously treated TB cases, with an MDR/RR-TB incidence of 27 per 100,000 and second highest in the world MDR/RR-TB prevalence rate [ 5 , 6 ].

Such situation develops despite what seems to be a well-designed TB care system, in which all aspects of TB care in Russia are free of charge to the public. The entire system was designed to provide universal, quality, and specialized care that is centralized in TB-designated facilities (TBDF), as depicted in Fig.  1 . All healthcare facilities and schools are participating in detection of asymptomatic TB by performing a mandatory annual chest x-ray in adults and Tuberculin Skin Testing (TST) in children. If TB is suspected, the healthcare facility is legally obliged to transfer such a patient to the TBDF, so the final diagnosis of suspected TB patients and provision of TB treatment are reserved only for TBDF [ 7 ]. The only exception to this system are penitentiary facilities, which screen, diagnose and treat inmates themselves. Such independence has been already proposed by researchers as a main reason for the high incidence of TB in Russian prisons, but little has been done to improve this situation [ 8 ].

Organization of TB care in Russia. PHF primary healthcare facility, HF healthcare facility, TBDF TB designated facility, DOT directly observed treatment, PCR polymerase chain reaction, TST tuberculin skin test, DST drug susceptibility testing, DST Diaskin skin test, CT computed tomography, MTB mycobacterium tuberculosis

High MDR/RR-TB incidence encourages the government of the Russian Federation and the Russian society of Phthisiatricians Footnote 1 have developed specific policies and guidelines to address the issues [ 9 ]. Joint TB control programs with international partners have been initiated, research funds have been extended, a centralized national electronic database of TB patients created, and new diagnostic techniques and policies implemented. However, the progress has been far from satisfactory, as despite the decrease in total TB incidence, the prevalence of MDR/RR-TB is continuing to rise [ 5 , 6 , 7 , 8 ].

It is crucial to identify the underlying reasons for such high MDR/RR-TB prevalence so that more feasible and cost-effective approaches can be developed to control this trend. International reviews, and some country-level studies, have identified that risk factors for MDR/RR-TB vary depending on country, region, or locality. Among the most prevalent are poor adherence to TB treatment on the part of patients, poor monitoring and management of TB treatment adverse events, poverty, overcrowding, HIV co-infection, diabetes, alcoholism, smoking, cavitary disease and young age [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ].

This study was undertaken in Khabarovsk Krai, in the Far East of Russia, where the proportion of MDR-TB among newly diagnosed cases (38%) was estimated to be the third highest in the country, significantly higher than the national average of 29.3% in 2018 [ 19 ]. Unfortunately, there is a notable gap in research into MDR/RR-TB rates between high and low prevalence regions of Russia. Despite some studies carried out in low-prevalence regions, factors influencing MDR/RR-TB in high- prevalence regions have rarely been investigated [ 20 , 21 , 22 ].

Data collection

Khabarovsk Krai is a region in the Far East of the Russian Federation, and it considered one of its high-prevalence TB regions. The TB incidence there is 87.7 per 100,000 in 2019 (almost twice the national average) with a population of only 1.2 million. These figures relegate region to ninth place by total TB incidence out of all 85 regions of Russia [ 19 ].

The mixed epidemiological, cross-sectional, retrospective and a qualitative study was conducted in the central “Tuberculosis Hospital” of Khabarovsk Krai. This institution collects and processes information about all patients with tuberculosis in region and functions as a reference laboratory at the regional level.

The Federal Register of TB patients (FRTP) was used as a source of data, which is a subsystem of the digital Unified State Healthcare Information System (USHIS). FRTP stores data of TB patients in form of electronic medical records, which were accessed by the investigator in April 2021. Anonymous demographic and clinical characteristics of every patient that was diagnosed with TB from January 2018 to December 2019 was collected and summarized into single data set for further analysis. The surveillance covered all healthcare institutions in the region and strictly followed the guidelines developed by the WHO and the International Union against Tuberculosis and Lung Disease [ 23 , 24 ].

Diagnostic methods

In all patients with suspected TB in the region, an acid-fast bacilli sputum smear, culture (with both liquid and solid media), real-time PCR, and Drug Susceptibility Testing (DST) are routinely implemented as initial diagnostic tests.

Various DST techniques were employed to detect MDR/RR-TB in patients. A liquid and solid media sputum culture tested MTB resistance to the following agents: Isoniazid, Rifampicin, Ethambutol, Streptomycin, Linezolid, Capreomycin, Amikacin, Ofloxacin, Levofloxacin, Kanamycin, Ethionamide, Para-aminosalicylic acid and Cycloserine. DST in direct PCR was performed with Allele-specific polymerase chain reaction aimed to identify rpoB, katG, inhA, embB and gyrA genes mutations associated with resistance to Isoniazid, Rifampicin, Ethambutol and fluoroquinolones [ 25 ]. All DST strictly followed the procedures and methods set out by WHO and the International Union against Tuberculosis and Lung Disease [ 24 ].

A new patient was defined as a patient with TB who had never been treated for TB previously, or who had received anti-TB drugs treatment for less than 1 month. A re-treatment patient was defined as a patient who had received anti-TB drug treatment for more than 1 month [ 10 ].

Inclusion/Exclusion criteria

A patient whose sample tests positive for mycobacterium tuberculosis (MTB) in at least one of the four initial diagnostic tests was defined as having active pulmonary TB. Patients whose samples are negative for the MTB in all four initial diagnostic tests were defined as having non-active pulmonary TB. Such patients were excluded from the study. Patients with mono-resistance (resistance to one first-line anti-TB drug only), poly-resistance (resistance to more than one first-line anti-TB drug, other than both isoniazid and rifampicin) and extensive drug resistance (resistance to any fluoroquinolone, and at least one second-line injectable TB medication, in addition to multidrug resistance) were excluded from the study. Patients whose electronic medical records contained incomplete set of data were also excluded from the study.

In-depth interviews

The interviewees were purposely selected based on their roles and experience in TB control. A total of 8 re-treatment and newly diagnosed patients completed the interviews, including one with a history of incarceration. 10 healthcare workers involved with their treatment completed interviews, including 5 physicians and 5 health administrative officials. Patients with TB were asked to answer when, where, and why they had received TB services, how they were treated and what problems they faced. The administrative officials were asked to answer questions about the arrangement of treatment regimens and compliance of providers and patients. The physicians were asked to answer questions about their experiences and problems in treating TB patients. The interviews were digitally recorded, transcribed, and thematically coded. The final sample size was determined by a saturation of information when no new categories emerged .

Quantitative data analysis

Quantitative variables of demographic and clinical characteristics of the patients with MDR/RR-TB were compared with those without MDR/RR-TB. Three regression models were constructed for all cases combined—only new cases and only re-treatment cases, respectively. Tested in the regression analysis were the following independent variables: gender, age, social status, place of residence, living conditions, substances abuse, a history of imprisonment, partial or total permanent inability to work (further—disability), HIV status, a history of treatment with Rifampicin and Isoniazid, TB localization, cavitary disease, and circumstances of TB discovery. For the re-treatment patients, additional variables of previous therapy outcome and length of previous treatment with Rifampicin and Isoniazid were added.

Three separate binary logistic regression models were created. Chi square tests were used for testing the statistical significance of the models as a whole. Fitness of the models to the data were tested with the Hosmer & Lemeshow test. Regression coefficient, Odds ratio with 95% confidence interval (95% CI) for each variable category was calculated and Wald statistics method used to determine their statistical significance [ 26 ]. An analysis was performed using SPSS software V24.0.01.

Qualitative data analysis

The interview data was analyzed thematically, with the coding framework developed inductively from the data. The initial coding used open coding and theoretical coding. The initial codes were then refined to produce a smaller set of themes. The coding framework was subject to continuing revision with each iteration during analysis. Main objectives of the analysis were to receive clinical explanation for the results of quantitative data analysis, identify non-apparent factors influencing MDR/RR-TB incidence, determine features of the TB care system organization and limitations of the study. An analysis was performed using Nvivo software V11.0.

Characteristics of the study population

During the study period, in all healthcare institutions of the region, 2661 patients were diagnosed with TB, of which 1544 patients had an active pulmonary tuberculosis, and 101 patients were excluded from the study due to resistance types other then MDR/RR-TB, three patients were excluded due to an incomplete set of variables leaving 1440 patients for further analysis (Fig.  2 ).

Flow chart of patients enrollment. PCR polymerase chain reaction, DST drug susceptibility testing, MDR/RR-TB multidrug-resistant/Rifampicin-resistant tuberculosis

Participants had a median age of 41 years, and 73.5% of them were male. MDR/RR was detected in 618 participants (42.9%, 95% CI 40.3% to 45.5%). The proportion of participants residing in cities was 69.4%, and 989 of them (68.7%) had no record of employment. By residence type, 61.5% were living in separate apartments and 151 (10.5%) were homeless at the time of TB diagnosis. There were 2.01 times more homeless among re-treatment cases than in newly diagnosed cases (16,5% vs 8.2%). Alcoholism was reported in 3.5% of all cases and in 62.5% of TB was discovered actively with an annual chest x-ray in primary healthcare facilities (PHF). More than half of all cases (55.1%) showed signs of cavitary disease. Disabilities were reported in 6% of the entire sample, while 8.3% were tested positive for HIV. 78 patients (5.4%) were in detention or had an official history of incarceration at the time of diagnosis. Overall, incarcerated patients had a much higher prevalence MDR/RR (93.6%, 95% CI 85.6% to 97.8%) compared to the population without a history of imprisonment (40.0%, 95% CI 37.4% to 42.7%) (p < 0.001).

Out of the 1440 patients, 394 were re-treatment patients, totaling 27.4% of the overall sample. The re-treatment patients had greater prevalence of MDR/RR (64.6%, 95% CI 59.8% to 69.4%) than the new patients (34.8%, 95% CI 31.8% to 37.7%) (p < 0.001) (Table 1 ).

Factors associated with MDR/RR-TB

Data of 1440 patients undergone logistic regression analysis. The strongest associative factors for MDR/RR-TB were a history of imprisonment and history of previous treatment. In these cases, the risk of having MDR/RR-TB was 16.53 (95% CI 5.37 to 50.88, p < 0.001) and 2.82 times higher (95% CI 2.16 to 3.66, p < 0.001) respectively.

Other influencing factors included presence of disability (AOR is 2.32, 95% CI 1.38 to 3.89, p = 0.001), cavitary disease (AOR is 1.76, 95% CI 1.37 to 2.25, p < 0.001), positive HIV status (AOR 1.55, 95% CI 1.01 to 2.39, p = 0.046), age (AOR for being older than 41 years is 1.36, 95% CI 1.06 to 1.76, p = 0.013), place of residence (AOR for residing in the city is 1.44, 95% CI 1.09 to 1.89, p = 0.01). The only variable that showed protective effect against MDR/RR-TB was retirement status (AOR 0.65, 95% CI 0.43 to 0.98, p = 0.042) (Table 2 ).

The multilevel model for the newly diagnosed patients was composed of 1047 cases. Of these, 364 had MDR/RR-TB (34.7%). History of imprisonment was the strongest associative factor, with 11.9 times higher risk of MDR/RR-TB (95% CI 2.94 to 43.78, p < 0.001).

Among remaining factors, three showed association with presence of MDR/RR-TB. Cases with underlying cavitary disease were 1.96 times more likely to have MDR/RR-TB (95% CI 1.46 to 2.63, p < 0.001). Patients living in cities were 1.841 times more likely to have MDR/RR-TB (95% CI 1.25 to 2.44, p = 0.001). Positive HIV status was associated with 1.67 times increase in MDR/RR-TB risk (95% CI 1.01 to 2.77, p = 0.047) (Table 3 ).

393 re-treatment patients were analyzed in the separate multilevel model. Four variables proved to be significant, with a history of incarceration remaining the strongest associative factor. Such patients were 38.5 times more likely to have MDR/RR-TB (95% CI 3.64 to 407.42, p = 0.002). The presence of disability led to a 4.43 times greater likelihood of contracting MDR/RR-TB (95% CI 1.47 to 13.38, p = 0.008). A final two significant variables were official records of employment (AOR 4.32, 95% CI 1.74 to 10.71, p = 0.002) and being discovered actively by PHF (AOR 1.79, 95% CI 1.05 to 3.05, p = 0.03) (Table 3 ).

Interpretation of interviews

Healthcare providers confirmed that former inmates are the most problematic group of TB patients. TB care in penitentiary facilities is provided on site, by the often undertrained medical stuff with insufficient funding and equipment. This medical service is not controlled by the authorities of general TB care system and operates without supervision. Lack of centralized control in tandem with poor nutrition and living conditions, overcrowding, treatment regimen neglect by prisons’ medical staff and inmates, make prisons the clearest breeding ground for drug resistance. After being released, prisoners mostly disappear from epidemiological surveillance and, even if they show up for further treatment, they often fail to adhere to the regimen and follow-up procedures and there are no legal tools for healthcare providers to enforce surveillance on them.

Among interviewees, there was a consensus that the main obstacle toward achieving full patient’s compliance is the length of therapy. Patients become progressively tired as the treatment advances, especially those with drug resistance, whose regimens typically last for 24 months or more.

In these cases, all patients with MDR/RR-TB receive treatment in inpatient conditions for at least twelve months in TBDF. After that period, the patient can be transferred to an outpatient treatment regimen. This option is reserved for patients who have proven themselves trustworthy, showing full compliance during inpatient treatment, and not actively secreting TB mycobacterium so as not to be an ongoing source of infection to others. Patients who do not meet those criteria continue their treatment in inpatient conditions until the end of the course. Such prolonged treatment, combined with insufficient awareness about consequences of intermittent treatment, leads patients to forgo treatment, usually as soon as symptoms disappear.

Outpatients phase of regimens provide many opportunities for the patients to drop out due to various reasons. Local TBDF in collaboration with the Russian Red Cross NGO are trying to address this issue by more thoroughly educating patients about TB treatment, giving out free monthly food packages and reimbursement of travel expenses to fully compliant patients. According to physicians, this has been especially effective in encouraging economically disadvantaged patients to continue their treatment.

Neither patients nor healthcare providers reported adverse effects to be a significant issue in achieving full treatment adherence. During an inpatient stay, patients are closely monitored for occurrence of adverse effects, where they are also given medication for side effects prevention. Physicians stated that they are equipped with all the necessary medications for the effective management of adverse effects.

Monitoring the occurrence of the adverse events among outpatients is carried out through mandatory monthly examination. The only issue here, that during ambulatory phase of the treatment, patients pay out-of-pocket for drugs to combat minor side effects, but in event of adverse effects occurrence during this phase physicians try to hospitalize such patients in TBDF so they could receive free medication and avoid financial burden. Same couldn’t be said about medical service in penitentiary facilities, according to patients, monitoring procedures are next to non-existing and medications for combating adverse events are scarce there. So, it is common for the inmates to discontinue medications as soon as adverse event occurs.

Both physicians and healthcare managers reported that TBDF of the region are sufficiently supplied with quality anti-TB medication and all the necessary diagnostic equipment.

Healthcare providers stated that both outcome and history of previous treatment contributed to the resistance development contrary to our results that mere fact of previous treatment history is increasing risk of resistance presence regardless of its outcome. Same goes for social status and living conditions, which, according to our statistical data, do not influence resistance development, but from a clinical standpoint, socially disadvantaged patients (particularly homeless ones) display a greater tendency to acquire MDR/RR TB. Another substantial problem that was not supported by data but reported by interviewees, is a greater frequency of alcohol and substances abuse. MDR/RR–TB prevalence in those groups is significantly higher than average.

Physicians did not report any association between presence of disability and risk of MDR/RR-TB development but they stated that some patients purposely do not comply with treatment to worsen their condition and acquire disability status for receiving social security benefits.

Besides the TB mycobacterium’s major biological features leading to the prevalence of MDR/RR-TB, such as mutation potential [ 27 ], strains [ 28 ] and draft genome sequences [ 29 ], TB related service patterns, demographics and clinical factors also have a significant impact on the development of MDR/RR-TB. Based on the statistical analysis of 1440 TB patients, we identified several factors influencing incidence of MDR/RR-TB in the Khabarovsk region of Russia. Among them are incarceration and previous anti TB treatment history, cavitary disease, HIV co-infection, age, place of residence, retirement status, presence of disability, circumstance of TB discovery and social status. We also concluded that newly diagnosed patients and retreatment patients tend to have different risk factors for contracting and developing MDR/RR-TB. Qualitative survey showed that organization of the TB care system, features of TB treatment process, healthcare and social security legislation play important role in TB epidemiology and may influence incidence of MDR/RR-TB both directly and indirectly.

Findings of quantitative data analysis were partially supported by interviews with patients, health managers, and physicians. Incarceration history was identified as the strongest risk factor associated with MDR/RR-TB in all studied groups. In this data, a high prevalence of TB and its drug resistant forms can be seen in prisons all around the world, developed and developing countries alike [ 30 , 31 , 32 ].

In 2021, according to Birkbeck University of London, Russia occupied 5th place in the world in terms of total prison population [ 33 ]. Based on literature reports and the interpretation of interviews, we can conclude that persistent unhygienic incarceration conditions and low quality of medical care in penitentiary facilities cause high prevalence of MDR/RR among TB infected inmates [ 7 ]. This creates a substantial pool of hosts, carrying drug resistant TB in the general population. Contrary to all other healthcare facilities in Russia, penitentiary institutions’ medical service operates independently from the general TB care system (Fig.  1 ). Such demarcation deprives inmates of proper care and follow up, which they can receive in TBDF. Either a considerable reduction in the total prison population and/or inclusion of penitentiary facilities in the TB care system may address the problem.

This predicament of prisons is explained by a contradiction of Russian laws in the field of healthcare. No medical procedures can be instituted without a patient's consent, including hospitalization, so some patients simply leave TBDF at will. To ensure epidemiological surveillance, healthcare providers have to file a claim for forced hospitalization to the court, but there are no legal mechanisms to execute positive court decisions without a patient's written consent. Thereby, infectious TB patients can leave TBDF even with a court decision of forced hospitalization. In 2011 it was that 3500 out of 6000 lawsuits were satisfied in favor of forced hospitalization, and it took an average of 3 months to obtain a court decision and up to 30% of patients left TBDF after forced hospitalization [ 34 ].

To ensure proper TB surveillance, measures should be taken to eliminate such a loophole in the legal framework. For reducing the pool of former inmates with MDR/RR-TB, better treatment conditions and epidemiological surveillance in penitentiary facilities must be established. Such intervention of providing TB care for inmates in civil clinics has been implemented in the Tomsk oblast region of Russia from 2000 to 2002 [ 7 ], which consisted of two phases of DOTS-plus individualized MDR-TB treatment regimens. In first “intensive” inpatient phase, patients received a high calories and protein rich diet, a separate and better accommodation, and were closely monitored for occurrence of treatment’s side effects. In the second “continuation” ambulatory phase, a community-based approach was used to provide directly observed therapy in outpatient clinics. For avoiding treatment discontinuation, adverse effects were managed aggressively, alongside with provision of monthly food packages to fully compliant patients and reimbursement of travel expenses.

The results showed significant increase in compliance, reduction in adverse effects, decrease in mortality rate, and increased treatment efficiency among incarcerated patients. Listed interventions, contrary to penitentiary facilities, are common practice in civil TB designated clinics therefore success of this study supports the necessity of centralized TB care for all TB patients [ 8 ].

As it was reported by numerous studies, poor adherence to drug susceptible TB treatment and poor screening for MDR/RR-TB are the major threats to MDR/RR-TB spread. According to the WHO, in 2020 DST underwent 92% and 94% of all newly diagnosed and retreatment TB cases respectively [ 4 ]. Such large-scale testing combined with routine usage of direct PCR DST and culture-based DST methods in all TB suspected patients provide a reliable and effective system of monitoring and detection of MDR/RR-TB. This conclusion is supported by the results of healthcare providers’ interviews.

A much larger concern is the problem of the poor adherence to the TB treatment. Implementation of DOT and DOTS plus were beneficial but didn’t fully address this problem in Russia [ 7 , 34 ]. As was reported, the length of therapy seems to be a major factor affecting a patient’s drop-out rate. Because of Russian legislation, it is challenging to keep patients in hospitals against their will but attempts to overcome this obstacle are present. For example, a special mobile medical team may visit some infected patients daily in their homes to deliver DOT. Those patients are typically not from economically disadvantaged groups, and their living conditions are much better than those of inpatient TB designated facilities, so their compliance is much higher when they stay in conditions that can be compared to home confinement but not in inpatient facility. Another instance is that pediatric TBDF provides compulsory school education to children, so they don’t disrupt their studies during a hospital stay.

A study from Belarus performed in 2009 identified positive association between disability and MDR/RR-TB prevalence [ 35 ]. Concerning another type of social security policies, influence of retirement social status on the risk of MDR/RR-TB development is uncertain as both positive and negative relationships were reported in the literature [ 13 , 36 ]. A study conducted in Ethiopia revealed a tenfold increase in risk of MDR-TB for the military pensioners, explaining it as pensioners receive much fewer social benefits compared to the active military servicemen [ 13 ]. At the same time, researchers from Belarus describe a protective effect similar to results received in our study with a reported AOR of 0.6 [ 36 ]. Such consistency in results may be due to that Russia and Belarus, both being part former Soviet Union members, have similar social security policies regarding retirement benefits and benefits for people with permanent inability to work. There is a need for further investigation of that phenomenon in countries with and without such policies. Such studies may support disability status as a risk factor or reveal its connection to social security policies. It should be mentioned as limitation, that we had no data on whether disability was TB-related or determined by another disease, thus the full statistical meaning of this variable remains uncertain.

Our results concerning association between MDR/RR-TB with younger age, cavitary disease, and positive HIV status correspond with previous studies [ 28 , 37 , 38 ].

Regarding place of residency, city dwellers have better access to healthcare in general and have a far greater capacity to complete annual chest X-rays. Therefore, cities tend to see greater number of people diagnosed with TB than in rural areas. Likewise, the increased population density in cities provides more chances to contract MDR/RR–TB. This can explain an emerging trend observed by physicians—the increase in the prevalence of MDR / RR-TB among newly diagnosed patients.

Our study has several limitations. We failed to explain the significance of official employment status as a risk factor among re-treatment patients and insignificance of social status and living conditions, as these results contradict with previous studies [ 12 , 38 , 39 , 40 ]. Also, our data indicates that outcome of previous treatment does not influence risk of MDR/RR-TB development which contradicts with previous studies and healthcare providers’ interviews [ 38 ]. During patients selection process, gyrB mutation of m.tuberculosis in DST was not tested due to usage of premanufactured reagent in allele-specific PCR [ 25 ], but because of simultaneous use of cultural DST methods we are confident that no patient with fluoroquinolones resistance was enrolled in the study.

It should be stated that data on narcotics and alcohol use disorders was based on official records of seeking medical attention for such conditions. Because significantly few patients in Russia seek medical attention for addiction-related problems [ 41 ] based on this and interviewee reports of high prevalence of these conditions in TB patients and corresponding literature [ 19 ], we acknowledge that our data may not fully represent the overall prevalence of substance abuse in the studied population.

It is worth mentioning that, even so according to the healthcare professionals’ interviews, TBDF is sufficiently supplied with medications of proper quality, our quantitative data didn’t contain information about supply and quality of anti-TB drugs. Another piece of valuable information that has not been represented in the quantitative data set was the occurrence of adverse effects. But based on the in-depth interview results, we can conclude that adverse events don’t affect compliance of patients receiving TB care in TBDF. Contrary to the penitentiary institutions where treatment drop-out due to adverse events occurrence is a major problem [ 31 ].

Incarceration and treatment history, regardless of outcome, seems to be a major factor influencing MDR/RR-TB prevalence in Russia. It is essential for the TB care system to eliminate legal loopholes, which deprive doctors of means to enforce quarantine procedures and epidemiological surveillance on infected patients, former and current inmates, who seem to be the main source of MDR/RR-TB hosts in the general population. The last can be addressed by treating inmates in the facilities of the general TB care system. In the end, we want to say that further attempts to better patients’ education and public awareness about TB, with continuing coordinated and centralized care for patients with TB, in tandem with greater compliance by patients with TB treatment guidelines, are the keys to success in the battle against MDR/RR-TB globally.

Availability of data and materials

The datasets analyzed during the current study are under jurisdiction of corresponding authority body and are not publicly available but are available from the corresponding author on reasonable request due to need of corresponding authority body notification of data sharing with the third party.

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Acknowledgements

The authors thank the staff of central “Tuberculosis Hospital” of Khabarovsk Krai for their support, access to the data and help with this study as well as Kremer M. for the proofreading and editing of the paper.

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Ilia Bykov, Huan Liu, Libo Liang & Qunhong Wu

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IB, QW, PR, LL, LH designed and planned this study; IB undertook data collection, performed statistical analysis, conducted interviews and wrote the manuscript draft; OD provided access to the data, follow up the study on data collection and interviews conduction as well as guidance and expert opinion on TB matters; IB, QW, PR, OD, LL, LH revised, proofread and edited the paper. All authors read and approved the final manuscript.

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Bykov, I., Dyachenko, O., Ratmanov, P. et al. Factors contributing to the high prevalence of multidrug-resistance/Rifampicin-resistance in patients with tuberculosis: an epidemiological cross sectional and qualitative study from Khabarovsk krai region of Russia. BMC Infect Dis 22 , 612 (2022). https://doi.org/10.1186/s12879-022-07598-7

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Drug resistance pattern and associated risk factors of tuberculosis patients in the central province of Iran

Aliasghar farazi.

1 Department of Infectious Diseases, Arak University of Medical Sciences, Arak, Iran.

Masoomeh Sofian

Nader zarrinfar, fatemeh katebi.

2 Arak University of Medical Sciences, Arak, Iran.

Seyed Davood Hoseini

3 Razi Vaccine and Serum Research Institute, Central Province Branch, Arak, Iran.

Roohollah Keshavarz

Background: One of the fundamental issues of infectious disease treatment is drug resistance. The aim of the present study was to investigate the first-line anti-tuberculosis drug resistance rates and determine the risk factors related to multidrug resistant mycobacterium tuberculosis.

Methods: From March 2011 to September 2012, mycobacterial strains were collected from one hundred fifteen diagnosed smear positive patients in the central province of Iran and tested for drug susceptible against ethambutol, rifampicin, isoniazid and streptomycin and the risk factors influencing the development of drug resistance were determined.

Results: The mean age of patients was 52.23±19.75 years. The rate of multi-drug resistant tuberculosis (MDR-TB) was 7.8%. Our study revealed that there were significant associations between prior treatment, age < 45 years, positive smear result at the end of the second month and positive smear result at the end of the third month. However, there was no association found between gender, inhabitant, nationality, close contact with TB patient, HIV infection and size of mantoux test.

Conclusion: The results show that about 8% of TB cases in Arak are MDR TB. The age under 45 years, previous TB treatment and positive smear at the end of the second and third months of treatment were the main factors in the development of MDR-TB.

Tuberculosis (TB) is one of the important leading causes of death in humans and it remains a serious public health obstacle in the developing countries ( 1 ). Early detection and correct treatment of MDR strains of mycobacteria are the most effective measures for the management of multidrug-resistant (MDR) TB ( 2 ). Drug resistance is the capability of organisms to stay viable or to multiply within the presence of the concentration of the drug that may ordinarily destroy or inhibit cell growth ( 3 ). With the introduction of the first anti-tuberculosis in the world in 1943, drug resistance began to rise and became a major problem and threat for TB control programs in many countries ( 4 ). Multi-drug resistant TB is one of the major types of resistance that microorganisms are resistant to at least two drugs of isoniazid and rifampin. Drug-resistant TB is a result of poor management of treatment or transmission from patients with drug-resistant TB ( 5 ). The treatment of such cases is expensive and lengthy with higher morbidity and mortality ( 6 ). Currently, there are many challenges in the treatment of resistant TB notably for the first detection and effective treatment. Studies indicated that drug resistance is increasing and the native information of the drug resistance pattern of clinical isolates is important mostly used to take suitable treatment for preventing treatment failures and reducing the quantity of secondary cases of multi-drug resistant TB ( 7 ).

The purpose of this study was to evaluate the drug resistance patterns of MTB and determine the risk factors for multi-drug resistant TB so as to supply policy-makers with recommendations for proper management of these patients.

From March 2011 to Sepember 2012, all patients with suspected tuberculosis sputum samples were collected. The Ziehl-Neelsen staining technique was used to identify mycobacteria. Then the positive smears were submitted for culture and drug sensitivity test (DST). Sputum smear exam was performed in the health center laboratory, whereas culture was done at the provincial research laboratory. After getting informed consent, a designed questionnaire for demographic information, the history of previous TB treatment, result of sputum smear, tuberculin skin test and HIV status was completed for every patient. The sputum samples were decontaminated with sodium hydroxide (NaOH) then centrifuged and refined on Lowenstein-Jensen (LJ) culture media. The LJ culture media was incubated at 37°C and determined on days three and seven to identify contaminations or quick growth of atypical mycobacteria. The identity of MTB was recognized by the p-nitrobenzoic acid (PNB) and thiophene carboxylic acid hydrazine (TCH) resistance. Species other than MTB were excluded from the present analysis. For DST, the LJ medium was impregnated with ethambutol (EMB), rifampicin (RIF), isoniazid (INH) and streptomycin (SM), in conforming with the proportional technique as suggested by World Health Organization and Clinical and Laboratory Standards Institute(CLSI) ( 8 , 9 ).

The concentrations were 2 µg/ml for EMB, 40 µg/ml for RIF, 4 µg/ml for SM, and 0.2 µg/ml for INH. If the microorganism grew on the medium, the particular drug was ≥1% compared to the control culture, the strain was detected as resistant and sensitive if growth rate was < 1% compared to control culture. For external quality control, microscopic smear exam and sputum culture were conducted by the Provincial Research Laboratory and for the internal quality control, a standard laboratory strain (H37Rv) was enclosed for every culture. This project has been approved by Institutional Review Board and Ethics Committee of Arak University of Medical Sciences. The prevalence of mono and multi- drug resistance among the new and antecedently treated cases was determined. The results were analyzed by SPSS statistics Version 19.0. Categorical information (MDR-TB and non-MDR-TB) was compared by chi-square and Fisher's exact tests. Multiple logistic regression analysis was performed to identify the risk factors for MDR-TB and the strength of association was measured by odds ratio (OR) with 95% confidence interval (95% CI) and a two-tailed p-value of <0.05 was considered significant.

Among the one hundred- twenty smear positive TB patients entered into the study, five cases were excluded (two cases infected with nontuberculosis mycobacteria and cultures of three cases were contaminated). One hundred fifteen cases determined as MTB were finally analyzed. Most of them (91.3%) were Iranian, the mean age was 52.23±19.75 years and fifty six (48.7%) patients were men and fifty nine (51.3%) were women. Among them, 103 (89.6%) were new cases and twelve (10.4%) were those previously treated. Sixteen (13.9%) patients had close contact with tuberculosis patients, three (2.7%) were HIV+ and 65 (56.6%) cases were urban.

The smear of 18 (15.6%) patients were paucibacillary, 37 (32.2%) were 1+, 31 (27%) were 2+ and 29 (25.2%) were 3+ in microscopic examination. The DST results showed that seventy eight (67.8%) strains were sensitive to all first-line antibiotics tested in our study and thirty seven (32.2%) were resistant to at least one drug. The proportions of mono-drug resistance were 7% for EMB, 2.6% for INH, 1.7% for RIF and 2.6% for SM ( table 1 ). Among all isolates, 9 (7.8%) strains were MDR-TB and 2 (1.7%) strains were resistant to all four first-line drugs. There was the association of initial smear grading of 2+ and 3+ with drug resistant tuberculosis (p=0.0284, OR=2.56) however, its association with MDR-TB was not important (p=0.6867, OR=0.52) ( table 2 ). Multivariate analysis of risk factors associated with MDR-TB showed that in previously treated cases, were considerably more than the new cases (p=0.0174). The frequency of MDR-TB was higher in age under forty-five years old (p=0.0428) and in patient with positive smear at the end of second (p=0.0390) or third (p=0.0339) months of treatment.

First line anti-tuberculosis drugs resistance in M. tuberculosis strains (new vs previously treated cases)

Univariate analysis of association of risk factors with MDR-TB

Currently, the emergence of MDR and XDR (extensively drug-resistant) tuberculosis in the world is becoming a major health problem ( 4 , 10 ). World Health Organization has enforced a worldwide stewardship program, whereas, findings showed regional variations in trends of drug-resistance ( 11 ). MDR-TB patients were seemingly younger than sixty five years ( 12 , 13 ). In this study, we found that the frequency of MDR-TB was higher in patients younger than forty five year old, which was the same as the findings from thirteen countries of Europe ( 14 ).

A systematic review analysis in Europe implied that the danger of MDR-TB for patients younger than forty five years was more than among the older patients and the risk of MDR was up to ten times higher in antecedently treated cases than in untreated ones ( 12 ). In several studies, it was found that the history of anti-tuberculosis treatment had been related to MDR-TB ( 15 ). Our study is consistent to the previous reports that showed the importance of previous treatment history as a risk factor of drug resistance ( table 3 ) ( 16 - 20 ). Identification of patterns of transmission is considerable in TB management because acquired resistance and primary resistance need different management methods ( 21 ). The DST results showed that 32.2% in which almost one third of all TB cases were resistant to at least one drug and the proportion of MDR-TB among all 115 TB cases were 7.8% which means that in every thirteen cases of TB might have MDR-TB. In this study, univariate and multivariate analysis showed four relevant risk factors of MDR-TB. Age under 45 years, previous TB treatment, positive smear result at the end of the second and third months. Preventing the development of drug resistant, TB should continue to be the top priority for all countries, however, managing the MDR-TB cases that emerge is a part of the Stop TB strategy and should be a component of all TB programs and developing rapid detection and management of drug resistant cases is of great urgency.

Significant risk factors associated with MDR-TB reported in current and previous studies in Iran

In this study, we found the association between conversion at the end of intensive phase of treatment and the risk of MDR-TB. Drug susceptibility test should be strengthened and the patients infected with sensitive strains will get DOTS, those with mono-drug resistance will get intensive DOTS to prevent multidrug resistance, and the patients with MDR-TB will get the treatment for rescue of life ( 22 ). The limitation of this study is the potential recall bias while responding to a history of prior anti-TB treatment and it cannot empirically be determined whether MDR-TB cases in this study had had primary drug resistance or were acquired through inadequate and/or incomplete prior TB treatment. In conclusion, the results show that about 8% of TB cases in Arak are MDR TB. The age under 45 years, previous TB treatment and positive smear at the end of the second and third months of treatment were the main factors in the development of MDR-TB.

Acknowledgments

The authors thank the Arak School of Medicine for the approved thesis as well as the patients who took part in the study.

Funding: The Arak School of Medicine supported financially this research. This study was a thesis conducted at the Arak University of Medical Sciences with the collaboration of the Central Province Branch of Razi Vaccine and Serum Research Institute.

Conflict of interest: The authors declare no competing interests.

Drug Resistance Patterns and Trends in Patients with Suspected Drug-Resistant Tuberculosis in Dalian, China: A Retrospective Study

Affiliation.

• 1 School of Public Health, Dalian Medical University, Dalian, 116000, People's Republic of China.
• PMID: 35937782
• PMCID: PMC9348136
• DOI: 10.2147/IDR.S373125

Purpose: The emergence of drug-resistant tuberculosis (DR-TB) represents a threat to the control of tuberculosis. This study aimed to estimate the patterns and trends of DR-TB in patients with suspected DR-TB. In addition, risk factors for multidrug-resistant tuberculosis (MDR-TB) were identified among suspected DR-TB patients in Dalian, China.

Patients and methods: A total of 5661 patients with suspected DR-TB from Jan 1, 2013 to Dec 31, 2020 were included in the final analysis. The resistance pattern of all resistant strains was determined by drug susceptibility testing (DST) using the conventional Lowenstein-Jensen Proportion Method (LJ). DR-TB trends were estimated from 2013 to 2020. During the research period, the chi-square test was employed to analyze the significance of linear drug-resistance trends across time. Bivariate and multivariate logistic regression were performed to assess factors associated with MDR-TB.

Results: From 2013 to 2020, the resistance rates of rifampicin (RFP) and isoniazid (INH) decreased significantly, whereas the resistance rates of ethambutol (EMB) and streptomycin (SM) increased in patients with suspected DR-TB. From 2013 to 2020, the prevalence of DR-TB decreased in all patients from 34.71% to 28.01% with an average annual decrease of 3.02%. Among new cases, from 2013 to 2020, the prevalence of DR-TB (from 26.67% to 24.75%), RFP-resistant TB (RR-TB) (from 15.09% to 3.00%) and MDR-TB (from 6.08% to 2.62%) showed a significant downward trend. Among patients with a previous treatment history, DR-TB (from 54.70% to 37.50%), RR-TB (from 44.16% to 11.49%) and MDR-TB (from 26.90% to 10.34%) showed a significant downward trend from 2013 to 2020. Males (AOR 1.28, 95% CI 1.035-1.585), patients 45 to 64 years of age (AOR 1.75, 95% CI 1.342-2.284), patients 65 years and older (AOR 1.65, 95% CI 1.293-2.104), rural residents (AOR 1.24, 95% CI 1.014-1.519) and a previous treatment history (AOR 3.94, 95% CI 3.275-4.741) were risk factors for MDR-TB.

Conclusion: The prevalence of DR-TB, RR-TB and MDR-TB was significantly reduced from 2013 to 2020. Considerable progress has been made in the prevention and treatment of DR-TB during this period. However, the increasing rate of drug resistance in EMB and SM should be taken seriously. Suspected DR-TB patients who are male, older than 45 years of age, live in rural areas, and have a history of TB treatment should be given priority by health care providers.

Keywords: DR-TB; Mycobacterium tuberculosis; RR-/MDR-TB; associated factors; prevalence.

© 2022 Pan et al.

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• Review Article
• Published: 11 February 2020

Drug resistance and tolerance in fungi

• Judith Berman   ORCID: orcid.org/0000-0002-8577-0084 1 &
• Damian J. Krysan 2  

Nature Reviews Microbiology volume  18 ,  pages 319–331 ( 2020 ) Cite this article

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• Antifungal agents
• Antimicrobials
• Fungal biology
• Fungal pathogenesis

An Author Correction to this article was published on 29 June 2020

Systemic fungal infections pose a serious clinical problem. Treatment options are limited, and antifungal drug resistance is increasing. In addition, a substantial proportion of patients do not respond to therapy despite being infected with fungi that are susceptible to the drug. The discordance between overall treatment outcome and low levels of clinical resistance may be attributable to antifungal drug tolerance. In this Review, we define and distinguish resistance and tolerance and discuss the current understanding of the molecular, genetic and physiological mechanisms that contribute to those phenomena. Distinguishing tolerance from resistance might provide important insights into the reasons for treatment failure in some settings.

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Acknowledgements

The authors thank M. Ralser, D. Jarosz and members of the Berman laboratory for helpful comments, and S. Everson, Iuliana Ene, Brown University, Anton Levitan, Tel-Aviv University, Aleeza C. Gerstein, University of Manitoba and M. Hajooj for help with illustrations. Work in the authors’ laboratories was supported by the European Research Council (RAPLODAPT 340087) and the Israel Science Foundation (grant number 997/18) (J.B.), and by the National Institutes of Health (1R01AI125094) (D.J.K.).

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Supplementary information

Candidaemia is a candidal infection of the blood stream.

Sensitivity to a drug, arresting growth (static drugs) and/or killing cells (cidal drugs).

A measure of tolerance based on assays performed on a solid medium. Measured at 48 h, the growth within the zone of inhibition (and thus above the minimum inhibitory concentration) is estimated as a proportion of total growth possible outside the zone of inhibition.

(SMG). A measure of tolerance based on assays performed in a liquid medium. Growth at concentrations above the minimum inhibitory concentration is estimated as a proportion of the total growth without a drug. SMG provides a quantitative measure of growth similar to some measures of trailing growth.

The expression of different phenotypes in different cells within an isogenic population of cells. For example, some fungal cells grow whereas other sister cells do not grow (or grow too slowly to be detected) in the presence of an antifungal drug.

Drugs that inhibit growth but do not necessarily kill a majority of the cell population at concentrations at or above the minimum inhibitory concentration.

A clinical term for isolates that contain small subpopulations of cells (generally <1%) that have the ability to grow at drug concentrations that are at least 8× the minimum inhibitory concentration for the vast majority of susceptible cells in the population.

Generally defined as reduced but persistent visible growth of Candida spp. at fluconazole concentrations above the minimum inhibitory concentration (MIC). Trailing has also been described as an increase in the MIC during growth beyond 24 h (the standard end point for MIC measurements for Candida spp.) and can be measured as the residual growth in the presence of fluconazole concentrations above the MIC. Trailing was quantified in a recent study as the percentage of residual yeast growth at fluconazole concentrations above the MIC in each well and mean trailing as the geometric mean of trailing observed in all of the wells above the MIC.

Also referred to as the Eagle effect. The ability of a fungal isolate to reconstitute growth in the presence of high drug concentrations, but being fully susceptible at lower concentrations. Paradoxical growth appears with a delay of one to several days, but resembles growth in the absence of the drug. Paradoxical growth has been reported primarily for echinocandins.

A drug that potentiates the effect of an anti-infective, but is not an anti-infective on its own.

Drugs with fungicidal activity reduce a population of cells by >99.9% or 3 log 10 units at a concentration equal to or greater than the minimum inhibitory concentration.

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Berman, J., Krysan, D.J. Drug resistance and tolerance in fungi. Nat Rev Microbiol 18 , 319–331 (2020). https://doi.org/10.1038/s41579-019-0322-2

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A peptide-based ph-sensitive antibacterial hydrogel for healing drug-resistant biofilm-infected diabetic wounds †.

* Corresponding authors

a Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, P. R. China E-mail: [email protected] , [email protected]

b Hunan Key Laboratory of Diagnostic and Therapeutic Drug Research for Chronic Diseases, Central South University, Changsha, P. R. China

c Xiangya Hospital of Central South University, Changsha, P. R. China

Diabetic foot ulcers are a significant complication affecting roughly 15% of diabetic patients. These chronic wounds can be incredibly burdensome, leading to high treatment costs, potential amputations, and additional health complications. Microbiological studies reveal that bacterial infections are the primary culprit behind delayed wound healing. To solve the problem of infection at the wound site, the most fundamental thing is to kill the pathogenic bacteria. Herein, a neoteric strategy to construct novel antibacterial hydrogel COA-T3 that combined photosensitizers (PSs) and antimicrobial peptides (AMPs) via covalent coupling was proposed. Hydrogel COA-T3 composed of quaternized chitosan (QCS) and oxidized dextran (OD) was constructed for co-delivery of the photosensitizer TPI-PN and the antimicrobial peptide HHC10 . In vitro and in vivo experiments demonstrated remarkable effectiveness of COA-T3 against drug-resistant bacteria. Furthermore, the hydrogel significantly promoted healing of diabetic infected wounds. This enhanced antibacterial activity is attributed to the pH-sensitive release of both PSs and AMPs within the hydrogel. Additionally, COA-T3 exhibits excellent biocompatibility, making it a promising candidate for wound dressing materials. These findings indicated that the COA-T3 hydrogel is a promising wound dressing material for promoting the healing of diabetic foot ulcers by providing an environment conducive to improved wound healing in diabetic patients.

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A peptide-based pH-sensitive antibacterial hydrogel for healing drug-resistant biofilm-infected diabetic wounds

D. Fan, R. Xie, X. Liu, H. Li, Z. Luo, Y. Li, F. Chen and W. Zeng, J. Mater. Chem. B , 2024, Advance Article , DOI: 10.1039/D4TB00594E

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Inequality is driving antimicrobial resistance. Here's how to curb it

The effects of antimicrobial resistance are not spread equally across society. Image:  Unsplash/Towfiqu barbhuiya

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• Antimicrobial resistance is one of the biggest global challenges of our time. It threatens public health and requires urgent action.
• The driving forces of antimicrobial resistance are unequally distributed across society, with vulnerable populations at the sharp end of associated health and economic risks and burdens.
• International and national antimicrobial resistance policies must consider social and economic factors to maximize their effectiveness and minimize health inequalities.

Antimicrobial resistance (also known as AMR) is estimated to be directly responsible for 1.27 million deaths in 2019 alone , equivalent to approximately 3,500 people each day. This number is estimated to reach 10 million per annum by 2050 without substantial action.

The economic consequences of antimicrobial resistance for individuals, health systems and society are also considerable. Individuals who contract antimicrobial-resistant infections are at risk of mortality, treatment delays, long-term disability, lost income and debt or poverty from high health costs, with suffering and socio-economic impacts for families and communities.

Antimicrobial resistance increases financial pressure on health systems as it leads to more hospitalizations, longer stays, more expensive diagnosis and treatment and reduced ability to provide treatments such as chemotherapy and surgical care safely.

It can also negatively impact national economies, which may have fewer and less productive workers and populations spending more on health care. If infections cannot be prevented and treated, trade and agriculture can also be negatively affected, with increased death and illness among farmed animals.

However, the consequences of antimicrobial resistance are not equally distributed across society.

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Antimicrobial resistance: avoiding antibiotic overconsumption with the right data, it's a bigger killer than hiv/aids and malaria. here's what we can do to beat antimicrobial resistance, who does antimicrobial resistance affect.

Social, cultural and biological factors mean that women are more likely than men to experience occupational exposure to antimicrobial resistance and to be prescribed antimicrobials for several infections.

The risk of its development is heightened in populations living in urban and overcrowded environments with limited access to clean water, sanitation, and hygiene (WASH) infrastructure, as is the case in many low- and middle-income countries. Populations with limited access to formal healthcare can experience increased inappropriate antibiotic use due to poorly regulated access. Many countries also experience persistent shortages of essential antimicrobials, leaving them infected for longer periods and given less targeted antimicrobials.

Conditions in conflict-affected areas make infections easier to spread, with populations who are forcibly displaced also facing fragile healthcare systems, supply of essential antimicrobials and access to WASH infrastructure. Implementing effective policies to combat antimicrobial resistance is also challenging in contexts with political instability, limited rule of law and higher levels of corruption .

How environmental factors impact resistant infections

Climate change is a significant driver of antimicrobial resistance as rising ambient temperatures increase the proliferation of bacteria while also contributing to extreme weather events that can disrupt healthcare services, displace communities and reduce access to sanitation.

The use of antimicrobials on animals, together with poor measures to prevent and control infections, can further drive antimicrobial resistance. Drug-resistant pathogens can be passed between animals and humans in occupational settings and through food contamination.

Pollution is also a major driver of antimicrobial resistance in the environment – for example, through waste from the pharmaceutical and healthcare industries, heavy metals from industrial and agricultural processes, particle pollution in the air and plastic waste in our water systems.

Policies must go beyond ‘drugs and bugs’

Until recently, policymakers and academics have primarily focused on the medical and microbiological factors that drive antimicrobial resistance. There has been insufficient focus on the relationship between the social and economic factors described here and the emergence of antimicrobial-resistant infections.

A new report published by the European Observatory on Health Systems and Policies, distilling findings from research supported by the World Economic Forum and the Novo Nordisk Foundation, sheds light on key socio-economic drivers and impacts of antimicrobial resistance and what this will mean for policy and research.

It helps explain how these factors can impact our health and economies and the effectiveness of measures to tackle antimicrobial resistance at the individual, health system and societal levels.

The policy report argues that four socio-economic elements must be built into the design of antimicrobial resistance policy and policy implementation, monitoring and evaluation (Figure 1):

• Governance and leadership that are mindful of the socio-economic drivers and impacts of antimicrobial resistance are central to co-ordinate action across different sectors.
• Action focused on people and that fosters equity and encourages policies responsive to individuals’ needs.
• Multi-sectorality recognizes antimicrobial resistance policy as a cross-cutting issue with involvement from various government departments and levels.
• Best evidence-informed policies help ensure that they look beyond the biomedical and value research from different disciplines and approaches to tackle the socio-economic drivers and impacts of antimicrobial resistance.

The report describes how these overarching principles can be incorporated into four core antimicrobial resistance policy areas.

• Stewardship relates to the responsible use of pre-existing and new antimicrobials, in humans and animals. However, many people, especially in low- and middle-income countries still die from a lack of or delayed access to antimicrobials. A balanced approach is therefore needed to promote rational use of antimicrobials while not inadvertently creating barriers for populations in situations of vulnerability.
• Prevention highlights the need for more investment in programmes that prevent and control infections in community and healthcare settings and biosecurity measures in animal health settings. Policymakers must also not neglect the global need for equitable access to WASH infrastructure.
• Access relates to ensuring equitable access to essential health services, antimicrobials, and diagnostics. This requires reducing barriers to accessing healthcare, changing procurement policy and strengthening the supply of antimicrobials in poorer and richer countries.
• Innovation in antimicrobial resistance health technologies seeks to improve prevention, diagnosis and treatment of infections. Stimulating research and development requires investment and incentivization but in ways that match the needs and operational contexts of lower resource settings, including access and affordability.

Many policymakers are currently revisiting their policy priorities related to antimicrobial resistance. At the international level, the UN General Assembly is holding a high-level meeting , which is expected to result in a political declaration on global antimicrobial resistance priorities and commitments. Simultaneously, many countries are revising their national action plans on antimicrobial resistance.

Policymakers and other stakeholders must leverage this critical window of opportunity to move beyond a “drugs and bugs” approach to antimicrobial resistance towards a more holistic, people-centred, equity-oriented approach that tackles key social and economic drivers and impacts of antimicrobial resistance.

Learn more by registering for the European Observatory webinar series “From evidence to practice in AMR prevention and control” on 21 May and 23 May 2024.

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Cancer is a leading cause of death globally. One of the primary reasons why cancer is such a deadly disease is the ability of cancer cells to become drug-resistant. After decades of medical research, scientists came to understand that malignant tumors often harbor a special population of cells called cancer stem cells (CSCs). Much like normal stem cells, CSCs can self-renew and differentiate into various cell types within a tumor, playing important roles not only in tumor growth and metastasis but also in the development of drug resistance.

Unfortunately, developing therapies targeting CSCs directly has proven quite challenging, given their ability to adapt and repopulate. Thus, some researchers have directed their attention to the blood vessels within the tumor tissue. Over the past few years, researchers have found that certain subpopulations of endothelial cells (cells lining the blood vessels) secrete angiocrine factors, which regulate the proliferation and maturation of stem cells. Understanding which cells produce these factors and their functions in the tumor microenvironment can, in turn, lead to novel cancer therapies.

Against this backdrop, a research team from Japan, including Professor Hiroyasu Kidoya and Dr. Yumiko Hayashi from the Department of Integrative Vascular Biology at the Faculty of Medical Science at the University of Fukui, conducted a study on secreted frizzled-related protein 1 (Sfrp1) -- an angiocrine factor -- to clarify its role in tumor tissues. Their findings were published online in the journal In Vitro Cellular & Developmental Biology -- Animal on April 16, 2024.

"While blood vessels are usually considered merely a supply route for oxygen and nutrients, our research focused on a completely different function of blood vessels, namely the production of angiocrine factors. We conducted this research with the idea that angiocrine factors might also be involved in tumor progression and aimed to elucidate whether Sfrp1 affects CSC maintenance and that of the tumor tissue as a whole," explains Prof. Kidoya.

To shed light on these issues, the researchers bred Sfrp1-knockout (KO) mice using CRISPR-Cas9 genome editing. Then, they transplanted lung carcinoma tumors into Sfrp1-KO and wild-type mice and observed the effects of Sfrp1 (or the lack thereof) using standard techniques, such as immunostaining, flow cytometry, and quantitative genetic expression analysis.

Initial experiments revealed that Sfrp1 is produced in a small subset of vascular endothelial cells in tumor tissue and that its presence is important for tumor growth. Not only was the tumor growth suppressed in Sfrp1-KO mice, but transplanted tumor cells overexpressing Sfrp1 gave rise to faster growing tumors.

Interestingly, researchers found that Sfrp1-deficient tumors could not maintain substantial CSC populations during the late stages of tumor growth, even though these tumors had a higher initial percentage of CSCs. This finding is particularly important as it hints at one of the biological roles of Sfpr1 in the tumor microenvironment and its involvement in cancer pathology. "Some CSCs in tumor tissues exist in a state of arrested cell proliferation, and their presence contributes to tumor growth and resistance to anticancer drugs," explains Prof. Kidoya. "Our results indicate that Sfrp1 may regulate CSC self-renewal and transient malignant growth, and act to maintain a dormant state."

Further cementing these results, the researchers noted that Sfrp1 did not affect the structure of blood vessels within the tumor, implying that the observed effects on tumor growth were unrelated to vasculature. Instead, genetic expression analyses revealed that Sfrp1 contributes to CSC maintenance by modulating the well-preserved Wnt signaling pathway (an evolutionarily conserved pathway that regulates crucial aspects of cell fate determination, cell migration, and organogenesis during embryonic development).

Overall, the newfound knowledge provided by this work could pave the way for the development of new cancer therapies targeting mechanisms that help maintain CSCs. "Targeting specialized vascular endothelial cells involved in producing angiocrine factors could help destroy the CSC niche, serving as a potential approach for inhibiting tumor growth with minimal side effects," concludes Prof. Kidoya. "I believe this could lead to the development of treatments for intractable cancer patients whose tumors exhibit resistance to anticancer drugs as well as therapeutic agents to suppress cancer recurrence and metastasis."

Further research building on these findings will serve as a stepping stone to effective therapies for drug-resistant cancer.

• Brain Tumor
• Lung Cancer
• Colon Cancer
• Ovarian Cancer
• Prostate Cancer
• Brain tumor
• Monoclonal antibody therapy
• Pernicious anemia
• Adult stem cell

Story Source:

Materials provided by University of Fukui . Note: Content may be edited for style and length.

Journal Reference :

• Yumiko Hayashi, Masakazu Hashimoto, Katsuyoshi Takaoka, Tatsuya Takemoto, Nobuyuki Takakura, Hiroyasu Kidoya. Tumor endothelial cell-derived Sfrp1 supports the maintenance of cancer stem cells via Wnt signaling . In Vitro Cellular & Developmental Biology - Animal , 2024; DOI: 10.1007/s11626-024-00899-y

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