Multidrug-resistant Tuberculosis Cases Research Articles

Molecular analysis of bedaquiline resistance and genetic variations in clinical isolates of multidrug and fluoroquinolones-resistant Mycobacterium tuberculosis

BackgroundMycobacterium tuberculosis developing resistance to anti-tubercular therapy leads to pioneering innovative treatment protocols featuring carefully curated combinations of potent medications. The aim of this study was to analyze the frequency and pattern of fluoroquinolone (FQ) resistant mutations among the first-line drug-resistant specimens. By employing an elective sampling strategy, we deliberately focused our investigation on a targeted subset of multidrug resistant (MDR) and FQ resistant (FQR) TB cases. MethodSputum samples from first-line drug-resistant patients were subjected to a GenoType MTBDRsl VER 2.0 assay to determine FQR. To investigate the effect of bedaquiline (BDQ) on these mutation-conferring genes (Rv0678, pepQ, and atpE), sanger sequencing was carried out on the MDR + FQR subset that was obtained. We have also conducted a computational analysis of the gene products of Rv0678 and pepQ with BDQ using molecular docking methods. ResultsEighty-three samples were observed to have FQR, and the majority of these specimens were associated with naïve and treatment failure cases. Among them, 64 isolates exhibited mutations in gyrA gene, while 19 isolates showed mutations in gyrB gene. The predominant occurrence of genetic variations, particularly in D94G and A90V, was observed within the specimens displaying resistance in gyrA gene, and the same has been confirmed by PCR-based detection. And the sequence analysis of BDQ genes among MDR + FQR subset indicated that the majority of the samples did not exhibit mutations in pepQ and atpE genes. However, only 2 samples were found to have the genetic variant G337A, which involves replacing the amino acid glutamic acid (E) at codon position 113 of Rv0678 gene with lysine (K). ConclusionsMost of the mutations were harbored in rpoB + katG + gyrA gene pattern. These findings pave the way for the development of databases and rapid diagnostic probes.

War related disruption of clinical tuberculosis services in Tigray, Ethiopia during the recent regional conflict: a mixed sequential method study

BackgroundMore than 70% of the health facilities in Tigray, northern Ethiopia, have been totally or partially destroyed by the recent war in the region. Diagnosis and management of tuberculosis were among many health services that suffered. In this study we assess the status of tuberculosis care in health facilities of Tigray during the recent war and compare it with the immediate pre-war state.MethodsUsing sequential mixed method, we analyzed and compared the availability of diagnostic services in 69 health facilities and the utilization of tuberculosis care in 50 of them immediately before the war (September-October 2020) and during the war (November-July 2021). TB focal persons in each selected health facility were interviewed to evaluate the status of diagnostic services. Patient service utilization was assessed using health facility registrations. We also compared the average monthly case detection rate of multidrug resistant tuberculosis in the region before and during the war. We computed summary statistics and performed comparisons using t-tests. Finally, existing challenges related to tuberculosis care in the region were explored via in-depth interviews. Two investigators openly coded and analyzed the qualitative data independently via thematic analysis.ResultsAmong the 69 health facilities randomly selected, the registers of 19 facilities were destroyed by the war; data from the remaining 50 facilities were included in the TB service utilization analysis. In the first month of the war (November 2021) the number of tuberculosis patients visiting health facilities fell 34%. Subsequently the visitation rate improved steadily, but not to pre-war rates. This reduction was significant in northwest, central and eastern zones. Tuberculosis care in rural areas was hit hardest. Prior to the war 60% of tuberculosis patients were served in rural clinics; this number dropped to an average of 17% during the war. Health facilities were systematically looted. Of the 69 institutions assessed, over 69% of the microscopes in health centers, 87.5% of the microscopes in primary hospitals, and 68% of the microscopes in general hospitals were stolen or damaged. Two GeneXpert nucleic acid amplification machines were also taken from general hospitals. Regarding drug resistant TB, the average number of multidrug resistant tuberculosis (MDR TB) cases detected per month was reduced by 41% during the war with p-value < 0.001. In-depth interviews with eight health care workers indicated that the main factors affecting tuberculosis care in the area were lack of security, health facility destruction, theft of essential equipment, and drug supply disruption.Conclusion and recommendationMany tuberculosis patients failed to visit health facilities during the war. There was substantial physical damage to health care facilities and systematic looting of diagnostic equipment. Restoring basic public services and revitalizing clinical care for tuberculosis need urgent consideration.

A Case of Multidrug-Resistant Tuberculosis in an Active Duty Military Health Care Worker.

Cases of active tuberculosis (TB) in the U.S. Military have fallen over the last century in large part due to improved screening and treatment options. The subset of multidrug-resistant TB (MDR-TB) is almost nonexistent within the U.S. Military. We present a case of MDR-TB in an active duty U.S. Military health care worker and discuss several considerations for treatment that may present challenges for U.S. Military medical practitioners. A 30-year-old active duty Soldier was referred to Army public health services after a bronchoscopy sample was positive for Mycobacterium tuberculosis complex. Sputum smears were negative for acid-fast bacilli, suggesting lower risk for community spread. One month after initiation of the standard 4-drug regimen for active TB, genetic susceptibility testing found the patient's M. tuberculosis isolate to be resistant to rifampin, isoniazid, and pyrazinamide. Contact investigation efforts among co-workers and family members fortunately found no new interferon-gamma release assay conversions. Coordination of public health assets to ensure a successful treatment regimen occurred across varied local, state, and federal agencies. Atypical medications required coordination with the FDA for procurement. An extensive surveillance plan for medication adverse effects was required. Finally, questions of public health authority versus patient autonomy arose requiring multidisciplinary input and ethical discussions.

In vitro and ex vivo activity of the fluoroquinolone DC-159a against mycobacteria.

Antimicrobial resistance is a global health problem. In 2021, it was estimated almost half a million of multidrug-resistant tuberculosis (MDR-TB) cases. Besides, non-tuberculous mycobacteria (NTM) are highly resistant to several drugs and the emergence of fluoroquinolone (FQ) resistant M. tuberculosis (Mtb) is also a global concern making treatments difficult and with variable outcome. The aim of this study was to evaluate the activity of the FQ, DC-159a, against Mtb and NTM and to explore the cross-resistance with the currently used FQs.A total of 12 pre-extensively drug-resistant (XDR) Mtb, 2 XDR, 36 fully drug susceptible strains and 41 NTM isolates were included to estimate the in vitro activity of DC-159a, moxifloxacin (MOX) and levofloxacin (LX), using minimal inhibitory and bactericidal concentration (MIC and MBC). The activity inside the human macrophages and pulmonary epithelial cells were also determined.DC-159a was active in vitro and ex vivo against mycobacteria. Besides, it was more active than MOX/LX. Moreover, no cross-resistance was evidenced between DC-159a and LX/MOX as DC-159a could inhibit Mtb and MAC strains that were already resistant to LX/MOX.DC-159a could be a possible candidate in new therapeutic regimens for MDR/ XDR-TB and mycobacterioses cases.

Trends of Drug-Resistant Tuberculosis in an Urban and a Rural Area in China: A 10-Year Population-Based Molecular Epidemiological Study.

Drug resistance is the critical determinant for appropriate tuberculosis (TB) treatment regimens and an important indicator of the local TB burden. We aimed to investigate and compare trends in TB drug resistance in the urban Songjiang District of Shanghai from 2011 to 2020, and the rural Wusheng County of Sichuan Province from 2009 to 2020, to assess the effectiveness of local TB control and treatment programs. Whole-genome sequencing data of Mycobacterium tuberculosis were used to predict drug-resistance profiles and identify genomic clusters. Clustered, retreated cases of drug-resistant TB with identical resistance mutations, as well as all new resistant cases, were defined as transmitted resistance. The Cochran-Armitage trend test was used to identify trends in the proportions. Differences between groups were tested using the Wilcoxon rank sum or chi-square tests. The annual proportions of rifampicin-resistant (RR), isoniazid-resistant (INH-R) and multidrug-resistant (MDR) TB cases did not change significantly in Songjiang. In Wusheng, however, the percentage of total TB cases that were RR decreased from 13.2% in 2009 to 3.7% in 2020, the INH-R cases decreased from 16.5% to 7.3%, and the MDR cases decreased from 10.7% to 3.7%. In retreated cases, the percentage of drug resistance decreased in both Songjiang and Wusheng, suggesting improved treatment programs. Transmitted resistance accounted for more than two thirds of drug-resistant cases over the entire study periods, and in recent years this proportion has increased significantly in Songjiang. In both urban Songjiang and rural Wusheng, drug-resistant TB is mostly the result of transmission of drug resistant strains and the percentage of transmitted resistance will likely increase with on-going improvements in the TB treatment programs. Reducing the prevalence of drug resistance depends principally upon decreasing transmission through the prompt diagnosis and effective treatment of drug-resistant TB cases.

Spatial Analysis of Drug-Susceptible and Multidrug-Resistant Cases of Tuberculosis, Ho Chi Minh City, Vietnam, 2020-2023.

We characterized the spatial distribution of drug-susceptible (DS) and multidrug-resistant (MDR) tuberculosis (TB) cases in Ho Chi Minh City, Vietnam, a major metropolis in southeastern Asia, and explored demographic and socioeconomic factors associated with local TB burden. Hot spots of DS and MDR TB incidence were observed in the central parts of Ho Chi Minh City, and substantial heterogeneity was observed across wards. Positive spatial autocorrelation was observed for both DS TB and MDR TB. Ward-level TB incidence was associated with HIV prevalence and the male proportion of the population. No ward-level demographic and socioeconomic indicators were associated with MDR TB case count relative to total TB case count. Our findings might inform spatially targeted TB control strategies and provide insights for generating hypotheses about the nature of the relationship between DS and MDR TB in Ho Chi Minh City and the wider southeastern region of Asia.

Empowering care: Unleashing pharmaceutical care to confront MDR-TB transmission risks-A prospective interventional study

IntroductionAccording to recent NTEP report it was estimated that in India the MDR-TB cases were 9.1/lakh population. Patients undergoing the pulmonary TB are known to cause MDR-TB due to multi drug resistance. Early identification of risk elements in Multidrug resistant-TB patients is crucial to managing and preventing the disease. ObjectiveTo evaluate risk variables that contribute to cause Multidrug resistant tuberculosis and to providing patient counselling to TB patients regarding risk factors. Methodology: A Prospective interventional study to assess the various Risk factors involved in cause of Multi drug resistance tuberculosis. This study was conducted for period of 09 months. The study is conducted with standard validated questionnaires which are prepared to assess the risk factors among Multidrug resistant-TB patients. Study site includes the tertiary care hospitals in Belagavi. ResultOverall, 120 Multidrug resistant tuberculosis patients were recruited from the district tuberculosis centre, Belagavi District, Karnataka. India. Most patients (47.50%) were aged 25–44 years. Of the 120 MDR-TB patients, 67.50% are male and 32.5% are female. Of 120 MDR-TB patients, 7.50% are HIV positive. As part of the study, smoking (26.67%), chewing tobacco (50%), and alcohol consumption (33.33%) were found to be other major risk factors. 24.17% of patients had a family history of tuberculosis, of which 5% had contact with an infected person as a source of infection. ConclusionThis study documented various risk variables involved in the emergence of Multidrug resistant TB. This research also highlighted the significance of pharmaceutical care in the effective management of multidrug-resistant tuberculosis (MDR-TB). This study identified risk variables that contribute to MDR-TB and helped educate tuberculosis patients about these risk factors.

Risk factors for diagnosis and treatment delay among patients with multidrug-resistant tuberculosis in Hunan Province, China.

Multidrug-resistant tuberculosis (MDR-TB) is a global health threat associated with high morbidity and mortality rates. Diagnosis and treatment delays are associated with poor treatment outcomes in patients with MDR-TB. However, the risk factors associated with these delays are not robustly investigated, particularly in high TB burden countries such as China. Therefore, this study aimed to measure the length of diagnosis and treatment delays and identify their risk factors among patients with MDR-TB in Hunan province. A retrospective cohort study was conducted using MDR-TB data from Hunan province between 2013 and 2018. The main outcomes of the study were diagnosis and treatment delay, defined as more than 14days from the date of symptom to diagnosis confirmation (i.e., diagnosis delay) and from diagnosis to treatment commencement (i.e., treatment delay). A multivariable logistic regression model was fitted, and an adjusted odds ratio (AOR) with a 95% confidence interval (CI) was used to identify factors associated with diagnosis and treatment delay. In total, 1,248 MDR-TB patients were included in this study. The median length of diagnosis delays was 27days, and treatment delays were one day. The proportion of MDR-TB patients who experienced diagnosis and treatment delay was 62.82% (95% CI: 60.09-65.46) and 30.77% (95% CI: 28.27-33.39), respectively. The odds of experiencing MDR-TB diagnosis delay among patients coming through referral and tracing was reduced by 41% (AOR = 0.59, 95% CI: 0.45-0.76) relative to patients identified through consultations due to symptoms. The odds of experiencing diagnosis delay among ≥ 65years were 65% (AOR = 0.35, 0.14-0.91) lower than under-15 children. The odds of developing treatment delay among foreign nationalities and people from other provinces were double(AOR = 2.00, 95% CI: 1.31-3.06)compared to the local populations. Similarly, the odds of experiencing treatment delay among severely ill patients were nearly 2.5 timeshigher (AOR = 2.49, 95% CI: 1.41-4.42)compared to patients who were not severely ill.On the other hand, previously treated TB cases had nearly 40% (AOR = 0.59, 95% CI: 0.42-0.85) lower odds of developing treatment delay compared with new MDR-TB cases. Similarly, other ethnic minority groups had nearly 40% (AOR = 0.57, 95% CI: 0.34-0.96) lower odds of experiencing treatment delay than the Han majority. Many MDR-TB patients experience long diagnosis and treatment delays in Hunan province. Strengthening active case detection can significantly reduce diagnosis delays among MDR-TB patients. Moreover, giving attention to patients who are new to MDR-TB treatment, are severely ill, or are from areas outside Hunan province will potentially reduce the burden of treatment delay among MDR-TB patients.

Evaluation of the multiple doses thiozonide’s pharmacokinetics in patients diagnosed with pulmonary tuberculosis with multidrug-resistant or extensively drug-resistant &lt;i&gt;Mycobacterium tuberculosis&lt;/i&gt;

Relevance. The increase in the number of cases of multidrug-resistant tuberculosis (MDR-TB) determines the relevance of the development of new anti-TB drugs (ATDs). Determining the pharmacokinetics of a drug in the context of MDR-TB therapy is an integral part of the study of the original drug. Objective. Evaluation of the pharmacokinetic properties of a new original drug, thiozonide, in patients with MDR-TB with multiple doses of the drug. Methods. Thiozonide was used in patients with a verified diagnosis of MDR-TB as part of a clinical trial according to protocol No. THIO22 "Multicenter 12-week doubleblind, randomized, placebo-controlled clinical trial on the selection of optimal dosages of the drug thiozonide, capsules (CJSC Pharm-Sintez") for against the background of standard anti-tuberculosis chemotherapy in patients diagnosed with pulmonary tuberculosis with multidrug-resistant or extensively drugresistant Mycobacterium tuberculosis” (permission of the Ministry of Health of the Russian Federation No. 661 dated 11/24/2014). Results. The pharmacokinetic characteristics of thiozonide were determined during its repeated use in patients diagnosed with pulmonary tuberculosis with multidrug-resistant or extensively drug-resistant mycobacterium tuberculosis, receiving standard anti-tuberculosis chemotherapy, by HPLC with mass spectrometric detection. The time to reach the maximum concentration T max of thiozonide with repeated administration at a dose of 200 mg, 400 mg and 600 mg was 4.21 ± 1.23 hours, 4.9 ± 1.08 and 5.29 ± 0.91, respectively; the half-life T1/2 for the same dosages of the drug was 7.84 ± 1.86, 7.56 ± 1.92 and 6.3 ± 2.12 hours, respectively. The maximum concentration of thiozonide after taking the drug thiozoinide by volunteers was Cmax was observed at the level of 1386.89 ± 533.68 ng / ml in the group taking 200 mg of thiozonide per day, 2684.48 ± 712.40 when taking the drug at a dosage of 400 mg and 5558, 99 ± 2143.81 – at a dosage of 600 mg. Conclusion. A linear dependence of the maximum concentration and the area under the pharmacokinetic curve on the dose taken and also the average concentration of thiozonide in the blood plasma of patients with pulmonary tuberculosis with multidrug resistance of the causative agent of the disease was revealed.

Drug-resistant pulmonary tuberculosis at Maradi Regional Hospital Center, Niger (2014-2018)

To describe the clinical, therapeutic and evolutionary profile of patients followed for rifampicin-resistant pulmonary tuberculosis (RR-TB) at the Regional Hospital Centre (RHC) of Maradi (Niger) from 2014 to 2018. We conducted a retrospective and descriptive study based on the records of patients followed for Multidrug-resistant tuberculosis (MDR-TB) between January 1, 2014 and June 30, 2018 at the resistant tuberculosis management unit in Maradi (Niger). This unit is located within the RHC of Maradi and has a capacity of 20 beds in 4 wards. It receives patients with tuberculosis resistant to first-line anti-tuberculosis drugs. In this study, patients diagnosed with RR-TB by genotypic (GeneXpert MTB/RIF) or phenotypic (culture) testing were included. We excluded from this study: patients previously treated for more than 1 month with second-line anti-TB drugs; patients with resistance to second-line injectables (SLI) and/or fluoroquinolones (FQ); patients with an electrocardiogram QTc greater than 500 ms (the corrected QT (QTc) estimates the QT interval at a rate of 60 beats per second); cases of atypical mycobacteriosis detected by phenotypic testing.Patients were previously on 2RHZE/4RH prior to the discovery of resistance. The treatment protocol for resistant TB was as follows: 4KmMfxPtoCfzHZE/5MfxCfzZE (The second-line injectable was replaced by Lzd in case of initial or treatment-emergent deafness). HIV co-infected patients received, in addition to anti-tuberculosis drugs, antiretrovirals and cotrimoxazole in preventive doses. A total of 80 patients were included in the present study (70 males and 10 females, mean age 34.4 years with extremes ranging from 18 to 71 years). Patients aged 18-35 years accounted for more than half. Patients with primary treatment failure were the most frequent type (36%) followed by patients with retreatment failure (24%) and patients with retreatment relapse (17%). It should be noted that 77 patients (96%) were previously treated for TB and only 3 patients (4%) were new cases. The majority of patients (70%) had a Body mass index of less than 18 kg/m2. 7.5% of patients were HIV positive, one was diabetic, 52% of the patients had grade 2 radiological lesions. Grade 1 deafness was noted at the beginning of treatment in 3%. A third of patients (36%) were primary treatment failures. The treatment protocol was as follows: 4KmMfxPtoCfzHZE/5MfxCfzZE. Only 1 patient had a positive culture at the end of the 4th month of treatment. Most of the patients had experienced adverse events, mainly digestive, with vomiting being the most common. The therapeutic success rate was 88%. We noted 10% of deaths, 1% of therapeutic failure and 1% of lost to follow-up.Six months after treatment, 48 patients (60%) were smear negative and 43 (54%) were culture negative. In 32 patients (40%), the smear was not performed and culture was not performed in 37. The short treatment regime gives satisfactory results in the absence of resistance to fluoroquinolones, with rare adverse effects. In Niger, further efforts should be made to minimize the delay in diagnosis which is responsible for most deaths during treatment. A centre could usefully be designated to organize "TB consiliums" allowing any practitioner to submit difficult cases of MDR-TB.

Multidrug Resistant Tuberculosis (MDR-TB) Factors: Literature Review

Background: Multidrug-resistant tuberculosis (MDRTB) is the biggest problem in preventing and eradicating TB in the world. MDR-TB occurs if the tuberculosis germs are resistant to various first-line OAT, at least two drugs, namely isoniazid and rifampicin. The emergence of MDR-TB cases presents new obstacles and challenges to the effectiveness of TB control programs due to difficult diagnosis, high rates of therapy failure, and death. This literature review aims to determine the factors that cause multidrug-resistant tuberculosis (MDR-TB). Methods: The method used in this article is a literature review using journal databases from Pubmed and Google Scholar in the 2020-2023 time period with the keywords "drug MDR TB," "multi-drug TB MDR factors," "TB MDR," and " resistant TB medicine" found in 1,990 articles, 304 from Pubmed, and 1,960 from Google Scholar). Articles were selected according to the criteria, and the result was 20 articles ready to be reviewed Results: The results of this study show that risk factors have been proven to show that there is a significant relationship between history of diabetes mellitus, history of TB treatment, patient motivation, adherence to taking medication, duration of TB treatment, status of drug side effects, employment, marital status, economic level, history of contact with patients. MDR TB, stress level, and family support are related to the incidence of MDR TB Conclusion: The conclusion of the 20 articles reviewed shows that age, gender, compliance with taking medication, diabetes mellitus, and a history of contact with MDR TB patients are the factors that most influence the occurrence of MDR TB

Socio-Demographic Profile of Patients with Pulmonary Tuberculosis, Including Multi-Drug Resistant Cases, at Chest Diseases Hospital, Rajshahi

Tuberculosis (TB) remains a significant global public health concern, with Pulmonary Tuberculosis (PTB) constituting a substantial burden. This study aimed to assess the socio-demographic profile of PTB patients, with a focus on Multi-Drug Resistant Tuberculosis (MDR-TB) cases, at Chest Diseases Hospital in Rajshahi, Bangladesh. Data from 299 patients were analyzed, considering variables such as age, gender, education, income, and urban or rural residence. The study revealed that the majority of patients were aged 30-44 years, with a mean age of 38.06 years. Gender distribution showed 54.18% males and 45.82% females. Most patients had primary education, and a significant portion were illiterate. Housewives were the largest occupational group, and the majority had a monthly family income of less than Taka 10,000. Furthermore, the study found a significant relationship between MDR-TB and the type of family and monthly family income, with higher MDR-TB prevalence in nuclear families and among those with lower income. This study provides critical insights into the socio-demographic characteristics of PTB patients, especially those with MDR-TB, in Rajshahi, contributing to tailored TB control strategies.

Tuberculosis in Ukrainian War Refugees and Migrants in the Czech Republic and Slovakia: A Molecular Epidemiological Study.

The war in Ukraine has led to significant migration to neighboring countries, raising public health concerns. Notable tuberculosis (TB) incidence rates in Ukraine emphasize the immediate requirement to prioritize approaches that interrupt the spread and prevent new infections. We conducted a prospective genomic surveillance study to assess migration's impact on TB epidemiology in the Czech Republic and Slovakia. Mycobacterium tuberculosis isolates from Ukrainian war refugees and migrants, collected from September 2021 to December 2022 were analyzed alongside 1574 isolates obtained from Ukraine, the Czech Republic, and Slovakia. Our study revealed alarming results, with historically the highest number of Ukrainian tuberculosis patients detected in the host countries. The increasing number of cases of multidrug-resistant TB, significantly linked with Beijing lineage 2.2.1 (p < 0.0001), also presents substantial obstacles to control endeavors. The genomic analysis identified the three highly related genomic clusters, indicating the recent TB transmission among migrant populations. The largest clusters comprised war refugees diagnosed in the Czech Republic, TB patients from various regions of Ukraine, and incarcerated individuals diagnosed with pulmonary TB specialized facility in the Kharkiv region, Ukraine, pointing to a national transmission sequence that has persisted for over 14years. The data showed that most infections were likely the result of reactivation of latent disease or exposure to TB before migration rather than recent transmission occurring within the host country. However, close monitoring, appropriate treatment, careful surveillance, and social support are crucial in mitigating future risks, though there is currently no evidence of local transmission in EU countries.

Direct Detection of Fluoroquinolone Resistance in Sputum Samples from Tuberculosis Patients by High Resolution Melt Curve Analysis.

Multidrug-resistant tuberculosis (MDR-TB) requires treatment with fluoroquinolone (FLQ) drugs, however, the excessive use of FLQ has led to the rise of extensively drug-resistant TB. In 2019, ~ 20% of total MDR-TB cases were estimated to be resistant to FLQ drugs. In the present study, we developed and evaluated the utility of high-resolution melt curve analysis (HRM) for the rapid detection of FLQ-resistant Mycobacterium tuberculosis for the first time directly from sputum samples. A reference plasmid library was generated for the most frequently observed mutations of gyrA gene and was used to discriminate between mutant and wild-type samples in the FLQ-HRM assay. The developed assay was evaluated on n = 25 MDR M. tuberculosis clinical isolates followed by validation on archived sputum DNA (n = 88) using DNA sequencing as a gold standard. The FLQ-HRM assay showed a 100% sensitivity [95% Confidence Interval (CI): 71.5 to 100] and specificity (95% CI: 39.7 to 100) in smear-positive category, and a sensitivity of 88.9% (95% CI: 77.3 to 95.8) with 84.2% (95% CI: 60.4 to 96.6) specificity in smear-negative category. The assay showed a high level of concordance of ~ 90% (κ = 0.74) with DNA sequencing, however, we were limited by the absence of phenotypic drug susceptibility testing data. In conclusion, HRM is a rapid, cost-effective (INR150/USD1.83) and closed-tube method for direct detection of FLQ resistance in sputum samples including direct smear-negative samples.

Tuberculosis multirresistente en Colombia, 2013-2018: estudio de casos y controles

Multidrug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) is difficult to control, has high morbidity and mortality, and demands priority public health intervention. In Colombia, MDR/RR-TB has been becoming more widespread annually. Before the COVID-19 pandemic, over an 8-year period, the number of cases of multidrug-resistant tuberculosis in Colombia was close to a thousand cases. Timely identification of the different risk factors for MDR/RR-TB will contribute fundamentally to the systematic management. To determine which risk factors were associated with the presentation of MDR in Colombia between 2013 and 2018. A retrospective case-control study was carried out, for which the data from the routine surveillance of MDR/events in the country were used. The cases of multidrug-resistant tuberculosis were mainly in young people, Afrodescendants, and males. Of the clinical conditions, comorbidities such as malnutrition, diabetes, and HIV, presence of at least one factor, such as drug dependence, taking immunosuppressive medications, belonging to the black race, afro, and living in an area of high disease burden were risk factors. In addition to the diagnosis and timely provision of MDR-TB treatment, it is necessary that public health programs at the local level pay special attention to patients with the identified risk factors.

Trends and Progress on Antibiotic-Resistant Mycobacterium tuberculosis and Genes in relation to Human Immunodeficiency Virus

Human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and tuberculosis (TB) are among the infectious diseases that cause high rates of mortality worldwide. The epidemiology of antibiotic resistance in correlation to people that live with TB and HIV has not been thoroughly investigated particularly in South Africa. Numerous cases of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) have been announced immensely worldwide. The spread and control of the MDR-TB pandemic due to unsuccessful treatment is one of the most serious public issues of concern, and this challenge is of international interest. Despite all measures that have been executed to overcome the challenge of MDR-TB in recent decades, the global MDR-TB trends have kept on accelerating with more and more people becoming victims. This is attributed to the abuse, misuse, and overuse of different antibacterial agents in human medicine, animal farms, and agricultural activities which serve as a wellspring for the evolution of antimicrobial resistance within the population. Over and above, the impetuous evolution, mutation, and the transfer of resistant genes via horizontal gene transfer are well-known contributive factors towards the antimicrobial resistance problem. Among the public health concerns in the world currently is the ever-increasing problem of antibiotic resistance which outpaces the progress of newly developed antimicrobials. The propagation of antimicrobial resistance (AMR) is even more amplified in areas where the pressure of antimicrobial resistant pathogens is elevated, and hence the population with ubiquitous HIV and AIDS is considered the hotspot. This review therefore aims to give in-depth coverage on the trends and the progress on the development of TB and HIV-resistant strains, highlight strategies to solve the problem, and accentuate the repercussions of the COVID-19 epidemic on the AMR.

Predictors of multidrug-resistant tuberculosis in a teaching hospital in Ghana: A case-control study.

Multidrug-resistant Tuberculosis (MDR-TB) remains a global health concern. The disease results in a prolonged treatment and hence, poses a financial burden to affected individuals and their families. The Ghana National TB Control Programme (NTP) has made extensive efforts to control the menace, however, it remains a concern. This study, therefore, aimed to determine the predictors of multidrug-resistant TB in the Cape Coast Teaching Hospital of Ghana. An unmatched case-control study involving 37 cases and 111 controls was conducted using data of TB cases registered for treatment between January 2018 and December 2020 at the Cape Coast Teaching Hospital. Socio-demographic, individual level and social characteristics information were collected from respondents through telephone surveys, face-to-face interviews and review of records using a structured questionnaire built in the Kobo Collect Toolbox. The data was exported to Stata version 16.0 for analysis. Chi-square test and multiple logistic regression were used to determine the predictors of MDR-TB. Associations were considered statistically significant at a 95% confidence interval with a p-value of less than 0.05. The results revealed that the majority (25 [67.6%]) of MDR-TB cases and controls (76 [68.5%]) were aged 30 years and above with a median age of 36.5 (IQR: 28-50) years for all respondents, while 20 (54.1%) of MDR-TB cases and 33 (29.7%) of controls lived in households with one room residences for their families. The following predictors for MDR-TB were identified: BCG vaccination status (AOR = 0.17,95% CI:0.07-0.45), long distance to health facility (AOR = 4.11, 95% CI: 1.55-10.87), number of rooms in residence (AOR = 0.37,95% CI: 0.14-0.99) and first place of visit upon noticing TB symptom (AOR = 4.22,95% CI:1.31-13.64). Predictors of MDR-TB in the current study were multi-faceted. Measures to control MDR-TB should target socio-demographic, health-seeking behaviour and social-related concerns.

Detection and management of tuberculosis in Tunisia: challenges and outcomes

Abstract Introduction Tuberculosis (TB) is a major cause of morbidity and mortality worldwide. In Tunisia, where TB remains endemic, the national control program ensures free vaccination, free outpatient TB treatment in addition to early detection of cases and directly observed treatment short course. However, available data on these activities and outcomes are limited. The objective of this study was to describe the evolution of TB detection and management indicators and outcomes from 2018 to 2021. Methods We analyzed data collected part of the epidemiological investigations of notified cases and active search for cases over a period of 4 years (2018-2021). In each governorate, dedicated teams collect samples from cases’ contacts for microscopic sputum examination for screening and ensure patients’ follow-up. All data related to contact tracing, treatment and outcomes were collected, entered and analyzed using SPSS-21. Results The number of screened cases decreased from 30337 in 2018 to 16045 in 2021. The number of investigations of reported cases also decreased; from 2408 in 2018 to 1295 in 2021 (proportion of 74.6% to 48.9% respectively). However, the percentage of positives increased from 1.4% to 2.1%. In 2021, therapeutic success was recorded among 81% of cases (compared to 86% in 2018). From 2018 to 2021, there was an increase in three indicators: fatality rate (1.55 to 2.53%), discontinuation of treatment (from 2.5% to 3.2%) and the proportion of multidrug-resistant TB cases (0.45 to 0.69%). Conclusions Despite free care and treatment, our study showed challenges in the prevention and management of TB. Several activities of the national tuberculosis program have decreased, probably due to the pandemic, as noted in general preventive and care activities worldwide. More education and awareness efforts should be made, not only for patients and their contacts, but also for health care professionals, to be more vigilant in early case detection and continued treatment. Key messages • Several activities of the national tuberculosis program have decreased from 2018 to 2021, probably due to the pandemic. • From 2018 to 2021, there was an increase in the fatality rate, discontinuation of treatment and multidrug-resistant TB cases.

Discovery, Synthesis, and Optimization of 1,2,4-Triazolyl Pyridines Targeting Mycobacterium tuberculosis.

The rise in multidrug resistant tuberculosis cases underscores the urgent need to develop new treatment strategies for tuberculosis. Herein, we report the discovery and synthesis of a new series of compounds containing a 3-thio-1,2,4-triazole moiety that show inhibition of Mycobacterium tuberculosis (Mtb) growth and survival. Structure-activity relationship studies led us to identify several potent analogs displaying low micromolar to nanomolar inhibitory activity, specifically against Mtb. The potent analogs demonstrated no cytotoxicity in mammalian cells at over 100 times the effective concentration required in Mtb and were bactericidal against Mtb during infection of macrophages. In the exploratory ADME investigations, we observed suboptimal ADME characteristics, which prompted us to identify potential metabolic liabilities for further optimization. Our preliminary investigations into the mechanism of action suggest that this series is not engaging the promiscuous targets that arise from many phenotypic screens. We selected for resistant mutants with the nanomolar potent nitro-containing compound 20 and identified resistant isolates with mutations in genes required for coenzyme F420 biosynthesis and the nitroreductase Ddn. This suggests that the aromatic nitro-1,2,4-triazolyl pyridines are activated by F420-dependent Ddn activity, similar to the nitro-containing TB drug pretomanid. We were able to circumvent the requirement for F420-dependent Ddn activity using compounds that contained non-nitro groups, identifying a key feature to be modified to avoid this predominant resistance mechanism. These studies provide the foundation for the development of a new class of 1,2,4-triazole compounds for the treatment of tuberculosis.

Genotypic and phenotypic comparison of drug resistance profiles of clinical multidrug-resistant Mycobacterium tuberculosis isolates using whole genome sequencing in Latvia

BackgroundMultidrug-resistant tuberculosis (MDR–TB) remains a major public health problem in many high tuberculosis (TB) burden countries. Phenotypic drug susceptibility testing (DST) take several weeks or months to result, but line probe assays and Xpert/Rif Ultra assay detect a limited number of resistance conferring gene mutations. Whole genome sequencing (WGS) is an advanced molecular testing method which theoretically can predict the resistance of M. tuberculosis (Mtb) isolates to all anti-TB agents through a single analysis.MethodsHere, we aimed to identify the level of concordance between the phenotypic and WGS-based genotypic drug susceptibility (DS) patterns of MDR–TB isolates. Overall, data for 12 anti-TB medications were analyzed.ResultsIn total, 63 MDR–TB Mtb isolates were included in the analysis, representing 27.4% of the total number of MDR–TB cases in Latvia in 2012–2014. Among them, five different sublineages were detected, and 2.2.1 (Beijing group) and 4.3.3 (Latin American-Mediterranean group) were the most abundant. There were 100% agreement between phenotypic and genotypic DS pattern for isoniazid, rifampicin, and linezolid. High concordance rate (> 90%) between phenotypic and genotypic DST results was detected for ofloxacin (93.7%), pyrazinamide (93.7%) and streptomycin (95.4%). Phenotypic and genotypic DS patterns were poorly correlated for ethionamide (agreement 56.4%), ethambutol (85.7%), amikacin (82.5%), capreomycin (81.0%), kanamycin (85.4%), and moxifloxacin (77.8%). For capreomycin, resistance conferring mutations were not identified in several phenotypically resistant isolates, and, in contrary, for ethionamide, ethambutol, amikacin, kanamycin, and moxifloxacin the resistance-related mutations were identified in several phenotypically sensitive isolates.ConclusionsWGS is a valuable tool for rapid genotypic DST for all anti-TB agents. For isoniazid and rifampicin phenotypic DST potentially can be replaced by genotypic DST based on 100% agreement between the tests. However, discrepant results for other anti-TB agents limit their prescription based solely on WGS data. For clinical decision, at the current level of knowledge, there is a need for combination of genotypic DST with modern, validated phenotypic DST methodologies for those medications which did not showed 100% agreement between the methods.