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In June 2024, WHO released ‘Key updates to the treatment of drug-resistant tuberculosis: rapid communication’, after the preliminary publication of results from two clinical trials: ‘BEAT-Tuberculosis’ and ‘endTB’. All proposed regimens include clofazimine (Cfz). However, a recent paper has reported a high incidence of QTc prolongation among patients receiving Cfz-based treatment for multidrug-resistant TB in Taiwan. Here, we discuss the cardiac safety of Cfz and the role of active drug safety monitoring at the programme level in collecting information on this issue.

Abstract Background Whole-genome sequencing (WGS)-based prediction of drug resistance in Mycobacterium tuberculosis has the potential to guide clinical decisions in the design of optimal treatment regimens. Methods We utilized WGS to investigate drug resistance mutations in a 32-year-old Tanzanian male admitted to Kibong’oto Infectious Diseases Hospital with a history of interrupted multidrug-resistant tuberculosis treatment for more than three years. Before admission, he received various all-oral bedaquiline-based multidrug-resistant tuberculosis treatment regimens with unfavourable outcomes. Results Drug susceptibility testing of serial M. tuberculosis isolates using Mycobacterium Growth Incubator Tubes culture and WGS revealed resistance to first-line anti-TB drugs, bedaquiline, and fluoroquinolones but susceptibility to linezolid, clofazimine, and delamanid. WGS of serial cultured isolates revealed that the Beijing (Lineage 2.2.2) strain was resistant to bedaquiline, with mutations in the mmpR5 gene (Rv0678. This study also revealed the emergence of two distinct subpopulations of bedaquiline-resistant tuberculosis strains with Asp47f and Glu49fs frameshift mutations in the mmpR5 gene, which might be the underlying cause of prolonged resistance. An individualized regimen comprising bedaquiline, delamanid, pyrazinamide, ethionamide, and para-aminosalicylic acid was designed. The patient was discharged home at month 8 and is currently in the ninth month of treatment. He reported no cough, chest pain, fever, or chest tightness but still experienced numbness in his lower limbs. Conclusion We propose the incorporation of WGS in the diagnostic framework for the optimal management of patients with drug-resistant and extensively drug-resistant tuberculosis.

Background: Whole-genome sequencing (WGS)-based prediction of drug resistance in Mycobacterium tuberculosis has the potential to guide clinical decisions in the design of optimal treatment regimens. Methods: We utilized WGS to investigate drug resistance mutations in a 32-year-old Tanzanian male admitted to Kibong'oto Infectious Diseases Hospital with a history of interrupted multidrug-resistant tuberculosis treatment for more than three years. Before admission, he received various all-oral bedaquiline-based multidrug-resistant tuberculosis treatment regimens with unfavourable outcomes. Results: Drug susceptibility testing of serial M. tuberculosis isolates using Mycobacterium Growth Incubator Tubes culture and WGS revealed resistance to first-line anti-TB drugs, bedaquiline, and fluoroquinolones but susceptibility to linezolid, clofazimine, and delamanid. WGS of serial cultured isolates revealed that the Beijing (Lineage 2.2.2) strain was resistant to bedaquiline, with mutations in the mmpR5 gene (Rv0678. This study also revealed the emergence of two distinct subpopulations of bedaquiline-resistant tuberculosis strains with Asp47f and Glu49fs frameshift mutations in the mmpR5 gene, which might be the underlying cause of prolonged resistance. An individualized regimen comprising bedaquiline, delamanid, pyrazinamide, ethionamide, and para-aminosalicylic acid was designed. The patient was discharged home at month 8 and is currently in the ninth month of treatment. He reported no cough, chest pain, fever, or chest tightness but still experienced numbness in his lower limbs. Conclusion: We propose the incorporation of WGS in the diagnostic framework for the optimal management of patients with drug-resistant and extensively drug-resistant tuberculosis. [ABSTRACT FROM AUTHOR]

Truenat MTB Plus assay was evaluated for diagnosing ocular tuberculosis (OTB) and detecting multi-drug resistant (MDR) and extremely-drug resistant (XDR) OTB. A total of 75 vitreous fluid specimens [five confirmed OTB, 40 clinically suspected OTB and 30 controls] were subjected to Truenat MTB Plus, multiplex PCR, and Xpert Ultra. Chips of Truenat were used for detecting rifampicin, isoniazid, fluoroquinolone and bedaquiline resistance. The performance was compared against culture, composite reference standard, and gene sequencing. The overall sensitivity of TruePlus, MPCR, and Ultra in diagnosing OTB was 66.6%, 73.3%, and 55.5%, respectively. Out of six cases with mutations in rpoB gene, RifR was detected in five by TrueRif and four by Ultra. Three MDR and one XDR-OTB were reported by Truenat. Truenat assay along with its strategic chips is a rapid and reliable tool for diagnosis of OTB and detection of drug resistance, including MDR and XDR-OTB. Abbreviations: OTB: Ocular tuberculosis; XDR: Extremely drug resistant; Ultra: Xpert MTB/RIF Ultra; Xpert: Xpert MTB/RIF; PCR: polymerase chain reaction; NAATs: Nucleic acid amplification tests; MDR: Multi Drug Resistant; NSP: National Strategic plan for elimination of tuberculosis; FqR: Fluoroquinolone resistant; BdqR: bedaquiline resistant; TrueRif: Truenat MTB Rif Dx; TruePlus: Truenat Plus; INH: Isoniazid; DST: Drug susceptibility testing; MGIT: Mycobacterial growth indicator tube; CRF: Composite reference standard; PPV: positive predictive value; NPV: negative predictive value; EPTB: extrapulmonary tuberculosis; VF: vitreous fluid; DNA: deoxyribonucleic acid; ATT: antitubercular therapy; RifR: Rifampicin resistance; RifS: Rifampicin susceptible; RifI: Rifampicin indeterminate. [ABSTRACT FROM AUTHOR]

Abstract Background Engagement of healthcare providers is one of the World Health Organization strategies devised for prevention and provision of patient centered care for multidrug resistant tuberculosis. The need for current research question rose because of the gaps in evidence on health professional’s engagement and its factors in multidrug resistant tuberculosis service delivery as per the protocol in the prevention and management of multidrug resistant tuberculosis. Purpose The purpose of this study was to explore the level of health care providers’ engagement in multidrug resistant tuberculosis prevention and management and influencing factors in Hadiya Zone health facilities, Southern Ethiopia. Methods Descriptive phenomenological qualitative study design was employed between 02 May and 09 May, 2019. We conducted a key informant interview and focus group discussions using purposely selected healthcare experts working as directly observed treatment short course providers in multidrug resistant tuberculosis treatment initiation centers, program managers, and focal persons. Verbatim transcripts were translated to English and exported to open code 4.02 for line-by-line coding and categorization of meanings into same emergent themes. Thematic analysis was conducted based on predefined themes for multidrug resistant tuberculosis prevention and management and core findings under each theme were supported by domain summaries in our final interpretation of the results. To maintain the rigors, Lincoln and Guba’s parallel quality criteria of trustworthiness was used particularly, credibility, dependability, transferability, confirmability and reflexivity. Results Total of 26 service providers, program managers, and focal persons were participated through four focus group discussion and five key informant interviews. The study explored factors for engagement of health care providers in the prevention and management of multidrug resistant tuberculosis in five emergent themes such as patients’ causes, perceived susceptibility, seeking support, professional incompetence and poor linkage of the health care facilities. Our findings also suggest that service providers require additional training, particularly in programmatic management of drug-resistant tuberculosis. Conclusion The study explored five emergent themes: patient’s underlying causes, seeking support, perceived susceptibility, professionals’ incompetence and health facilities poor linkage. Community awareness creation to avoid fear of discrimination through provision of support for those with multidrug resistant tuberculosis is expected from health care providers using social behavioral change communication strategies. Furthermore, program managers need to follow the recommendations of World Health Organization for engaging healthcare professionals in the prevention and management of multidrug resistant tuberculosis and cascade trainings in clinical programmatic management of the disease for healthcare professionals.

Background: Engagement of healthcare providers is one of the World Health Organization strategies devised for prevention and provision of patient centered care for multidrug resistant tuberculosis. The need for current research question rose because of the gaps in evidence on health professional's engagement and its factors in multidrug resistant tuberculosis service delivery as per the protocol in the prevention and management of multidrug resistant tuberculosis. Purpose: The purpose of this study was to explore the level of health care providers' engagement in multidrug resistant tuberculosis prevention and management and influencing factors in Hadiya Zone health facilities, Southern Ethiopia. Methods: Descriptive phenomenological qualitative study design was employed between 02 May and 09 May, 2019. We conducted a key informant interview and focus group discussions using purposely selected healthcare experts working as directly observed treatment short course providers in multidrug resistant tuberculosis treatment initiation centers, program managers, and focal persons. Verbatim transcripts were translated to English and exported to open code 4.02 for line-by-line coding and categorization of meanings into same emergent themes. Thematic analysis was conducted based on predefined themes for multidrug resistant tuberculosis prevention and management and core findings under each theme were supported by domain summaries in our final interpretation of the results. To maintain the rigors, Lincoln and Guba's parallel quality criteria of trustworthiness was used particularly, credibility, dependability, transferability, confirmability and reflexivity. Results: Total of 26 service providers, program managers, and focal persons were participated through four focus group discussion and five key informant interviews. The study explored factors for engagement of health care providers in the prevention and management of multidrug resistant tuberculosis in five emergent themes such as patients' causes, perceived susceptibility, seeking support, professional incompetence and poor linkage of the health care facilities. Our findings also suggest that service providers require additional training, particularly in programmatic management of drug-resistant tuberculosis. Conclusion: The study explored five emergent themes: patient's underlying causes, seeking support, perceived susceptibility, professionals' incompetence and health facilities poor linkage. Community awareness creation to avoid fear of discrimination through provision of support for those with multidrug resistant tuberculosis is expected from health care providers using social behavioral change communication strategies. Furthermore, program managers need to follow the recommendations of World Health Organization for engaging healthcare professionals in the prevention and management of multidrug resistant tuberculosis and cascade trainings in clinical programmatic management of the disease for healthcare professionals. [ABSTRACT FROM AUTHOR]

The emergence of drug-resistant strains of Mycobacterium tuberculosis has become a significant public health problem and has led to a setback in the efforts to end tuberculosis (TB) worldwide. The longer duration, heavier pill load, and higher toxicity profile of drug-resistant TB regimens compared to those for drug susceptible TB lead to reduced adherence and worse treatment results, including mortality. This study was conducted to estimate treatment outcomes and adverse effects in patients with drug resistant TB on a bed aquiline-containing regimen. Patients after the pre-treatment evaluation were enrolled in a bed aquiline-containing regimen. These patients were followed up for 18 months, and the final outcome was assessed along with the adverse effects. It was found that 49 (84.4%) patients achieved culture conversion by 3 months, 54 (93.1%) achieved culture conversion by 6 months, 52 (83.81%) had favorable outcomes (cured, treatment completed), and 10 had unfavorable outcomes (died, lost to follow-up, failed). Coupled with gradually increasing trends in success rates since 2012, lesser failure rates and fewer concerns regarding grave adverse effects are a silver lining in the cloud of increasing burden and widening resistance patterns. More funding has to be directed towards ensuring adherence and finding high-risk individuals to expedite the achievement of sustainable development goals. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is the world's second-deadliest infectious disease. Despite the availability of drugs to cure TB, control of TB is hampered by the emergence of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB). The presence of MDR/XDR-TB is alarming due to the low detection rate, high treatment failure, and high mortality. The increasing cases of MDR/XDR-TB are mainly due to the limitations in the diagnostic tests to detect the drug susceptibility of the pathogen, which contribute to the spread of the disease through close contacts. Moreover, inconsistent drug therapy or unsuitable drug regimens could also lead to the subsequent development of drug resistance. The close contacts of an index MDR/XDR-TB patient are at increased risk of developing MDR/XDR-TB. Also, the BCG vaccine may exhibit varying protective effects due to BCG strain diversification, host immune status, exposure to environmental non-tuberculous mycobacteria (NTM), and differences in Mycobacterium tuberculosis (Mtb) subspecies infection, as in the case of sub-optimal protection in the case of Beijing family genotypes of Mtb. This review provides an overview of the current state of drug-resistant tuberculosis (DR-TB) within the context of the global TB pandemic, with a focus on diagnosis, treatment, and the potential impact of BCG vaccination. It highlights the limitations of current approaches and aims to identify opportunities for improving TB control strategies.

Antibiotics have played a crucial role in the reduction in the incidence of TB globally as evidenced by the fact that before the mid-20th century, the mortality rate within five years of the onset of the disease was 50%. The use of antibiotics has eliminated TB as a devastating disease, but the challenge of resistance to anti-TB drugs, which had already been described at the time of the introduction of streptomycin, has become a major global issue in disease management. Mismanagement of multidrug-resistant tuberculosis (MDR-TB) cases, resulting from intermittent drug use, prescription errors, and non-compliance of patients, has been identified as a critical risk factor for the development of extensively drug-resistant tuberculosis (XDR-TB). Antimicrobial resistance (AMR) in TB is a multi-factorial, complex problem of microbes evolving to escape antibiotics, the gradual decline in antibiotic development, and different economic and social conditions. In this review, we summarize recent advances in our understanding of how Mycobacterium tuberculosis evolves drug resistance. We also highlight the importance of developing shorter regimens that rapidly reach bacteria in diverse host environments, eradicating all mycobacterial populations and preventing the evolution of drug resistance. Lastly, we also emphasize that the current burden of this ancient disease is driven by a combination of complex interactions between mycobacterial and host factors, and that only a holistic approach that effectively addresses all the critical issues associated with drug resistance will limit the further spread of drug-resistant strains throughout the community. [ABSTRACT FROM AUTHOR]

Background: Drug-resistant tuberculosis (DR-TB) is the most exigent and calamitous challenge encountered in treatment of TB. Extra pulmonary (EP) DR-TB poses a complex diagnostic and therapeutic challenge owing to myriad of presentations and paucibacillary nature. Data available on this subset is limited. We studied the prevalence of EPDR-TB cases among the total DR-TB cases visiting our Programmatic management of Drug-Resistant TB (PMDT) site. We also studied the demographic and microbiological profile of these cases and analyzed the prevalence of pre-extensively drug-resistant TB (pre XDR-TB) and extensively drug-resistant TB (XDR-TB) among patients of EPDR-TB in pre Bdq era. Results: Of the 1086 DR-TB patients, 64 (5.89%) were cases of EPDR-TB. Seven out of 64 (10.93%) were primary EPDR-TB. The site wise distribution of cases was 34 (53.125%) lymph node DR-TB, 18 (28.125%) pleural DR-TB, 9 (14.0625%) spinal DR-TB/paraspinal abscess/psoas abscess, 1 case (1.5625%) each of abdominal DR-TB, sternal and gluteal abscess. On the basis of the second-line drug susceptibility testing (DST), patients were grouped into: (1) multidrug-resistant TB (MDR-TB), (2) MDR-TB with fluoroquinolone (FQ) resistance {pre XDR XDR-TB (FQ)}, (3) MDR-TB with second-line injectable (SLI) resistance {pre XDR XDR-TB (SLI)}, (4) XDR-TB. Of the 64 patients, 43 (67.185%) had MDR-TB, 19 (29.687%) had preXDR-TB (FQ), none had preXDR-TB (SLI) and 2 (3.125%) had XDR-TB. Gastro esophageal reflux disease (GERD) was the most common comorbidity seen in 26 (40.6%) patients, followed by anemia in 5 (7.8%), psychiatry problems 5 (7.8%), hypertension in 3 (4.6%), renal disorders in 2 (3.1%) while thyroid disorder, HIV and thalassemia in 1 each (1.5%). Conclusion: EPDR-TB forms a small but significant proportion of total DR-TB. Lymph node DR-TB is its most common subclass. Our study emphasises the momentousness and essentiality of baseline DST to FQ and SLI in patients of DR-TB. This enables an appropriate modification of therapy at baseline itself to better the treatment outcomes. We observed a strikingly high proportion of preXDR-TB (FQ) in our study group.

Multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) make TB difficult to control. Global susceptibility data for six newly recommended anti-TB drugs against M/XDR-TB are still limited. Using publicly available whole-genome sequences, we determined the proportion of 513 phenotypically XDR-TB isolates that carried mutations associated with resistance against these drugs (bedaquiline, clofazimine, linezolid, delamanid, pretomanid and cycloserine). Mutations of Rv0678 and Rv1979c were detected in 69/513 isolates (13.5%) for bedaquiline resistance and 79/513 isolates (15.4%) for clofazimine resistance with additional mmpL5 mutations. Mutations conferring resistance to delamanid were detected in fbiB and ddn genes for 11/513 isolates (2.1%). For pretomanid, a mutation was detected in the ddn gene for 3/513 isolates (0.6%). Nineteen mutations of pykA, cycA, ald, and alr genes, conferring resistance to cycloserine, were found in 153/513 isolates (29.8%). No known mutations associated with linezolid resistance were detected. Cluster analysis showed that 408/513 isolates fell within 99 clusters and that 354 of these isolates were possible primary drug-resistant TB (292 XDR-TB, 57 pre-XDR-TB and 5 MDR-TB). Clonal transmission of primary XDR isolates might contribute significantly to the high prevalence of DR-TB globally.

To describe long-term treatment outcomes in patients with multi-drug-resistant/rifampicin-resistant tuberculosis (MDR/RR-TB) and validate established outcome definitions for MDR/RR-TB treatment. Among patients with MDR/RR-TB admitted to a German MDR/RR-TB referral centre from 1 September 2002 to 29 February 2020, we compared long-term treatment outcomes derived from individual patient follow-up with treatment outcomes defined by WHO-2013, WHO-2021 and the Tuberculosis Network European Trials Group-2016. In a total of 163 patients (mean age, 35 years; standard deviation, 13 years; 14/163 [8.6%] living with HIV; 109/163 [66.9%] men, 149/163 [91.4%] migrating to Germany within 5 years), the treatment of culture-confirmed MDR/RR-TB was initiated. Additional drug resistance to a fluoroquinolone or a second-line injectable agent was present in 15 of the 163 (9.2%) Mycobacterium tuberculosis strains; resistance against both the drug classes was present in 29 of the 163 (17.8%) strains. The median duration of MDR/RR-TB treatment was 20 months (interquartile range, 19.3–21.6 months), with a medium of five active drugs included. The median follow-up time was 4 years (47.7 months; interquartile range, 21.7–65.8 months). Among the 163 patients, cure was achieved in 25 (15.3%), 82 (50.3%) and 95 (58.3%) patients according to the outcome definitions of WHO-2013, WHO-2021, and the Tuberculosis Network European Trials Group-2016, respectively. The lost to follow-up rate was 17 of 163 (10.4%). Death was more likely in patients living with HIV (hazard ratio, 4.28; 95% confidence interval, 1.26–12.86) and older patients (hazard ratio, 1.08; 95% confidence interval, 1.05–1.12; increment of 1 year). Overall, 101/163 (62.0%) patients experienced long-term, relapse-free cure; of those, 101/122 (82.8%) patients with a known status (not lost to-follow-up or transferred out) at follow-up. Under optimal management conditions leveraging individualized treatment regimens, long-term, relapse-free cure from MDR/RR-TB is substantially higher than cure rates defined by current treatment outcome definitions. [ABSTRACT FROM AUTHOR]

The emergence of drug-resistant strains of Mycobacterium tuberculosis has become a significant public health problem and has led to a setback in efforts to end tuberculosis (TB) worldwide. The longer duration, heavier pill load, and higher toxicity profile of DR-TB regimens compared to those for drug-susceptible TB (DS-TB) lead to reduced adherence and worse treatment results, including mortality. This study was conducted to estimate treatment outcomes and adverse effects in patients with drug-resistant TB patients on bedaquiline-containing regimen. Patients after the pre-treatment evaluation were enrolled for bedaquiline-containing regimen. These patients were followed up for 18 months and the final outcome was assessed along with the adverse effects. It was found that 49 (84.4%) patients achieved culture conversion by three months and 54 (93.1%) achieved culture conversion by six months, 52 (83.81%) patients had favourable outcomes (cured, treatment completed) and 10 patients had unfavourable outcomes (died, lost to follow-up, failed). Coupled with gradually increasing trends of success rates from 2012, lesser failure rates and lesser concerns regarding grave adverse effects are a silver lining along the cloud of increasing burden and widening resistance patterns. More funding has to be directed towards ensuring adherence and finding high-risk individuals in order to expedite the achievement of sustainable development (SDG) goals.

Objectives: Previous diversity studies on local Mycobacterium tuberculosis (MTB) isolates, with or without antibiotic resistance, showed predominance of Indo-Oceanic East African-Indian (EAI) strains. This study focused specifically on a drug-resistant MTB population from Central Malaysia and aimed to investigate the genotypes and resistance patterns involved. Methods: Whole-genome sequencing was performed on 56 local MTB isolates with known rifampicin resistance or multidrug resistance towards 13 anti-TB agents. Analysis of each genome sequence was performed using the widely recognized online MTB genotyping platforms, TBProfiler and Mykrobe, to determine lineage and genotypic drug resistance profiles. Results: Forty (71.4%) isolates were identified as East-Asian Beijing strains. Phenotypic to genotypic antibiotic resistance patterns differed in 33 isolates (58.9%), with one isolate showing extensive drug-resistance (XDR) previously not detected by conventional drug-susceptibility testing. Conclusion: This drug resistance population study demonstrated predominance of the East-Asian Beijing strains and a newly detected extensively drug-resistant MTB (XDR-TB) isolate in Malaysia. Information regarding the association between lineage and drug-resistant TB in Malaysia is scarce, and more studies are needed to determine the significance of such association, if any, in our local settings.

In the present study genotypic resistance of bacterial strain to first- and second-line anti-tuberculosis drugs was determined by Line probe assay. Toxic effect of tellurite on the growth of Mycobacterium tuberculosis (MTB) was determined by growing cells in different concentrations of tellurite (1 to 5 mM). Morphological effects of tellurite and uptake of metal in bacterial cells were confirmed by Scanning electron microscope (SEM) and energy dispersive X-ray (EDX) analysis. Change in fold expression of the efflux pump gene was measured by RT-PCR. Mycobacterial strain was characterized as XDR-TB based on the genotypic resistance to rifampicin and isoniazid, along with resistance to fluoroquinolones and second line injectable. XDR-TB showed black colonies in tellurite presence and growth was delayed (2–3 weeks) when compared with the control. The reduced cell size, metal accumulation and the characteristic tellurite peaks appeared in metal-treated cells. MTB showed MIC value of 1 mM and had high susceptibility for higher concentrations (2–5 mM). However, no significant metal inhibitory effect on the mmpL7 efflux system was determined. Tellurite shows significant growth reduction potential against XDR-TB strain. However, the exact mechanism of action needs to be elucidated with further research.

Background and Aim: Emergence of drug resistance, especially to second‐line drugs, hampers tuberculosis elimination efforts. The present study aimed to evaluate MTBDRplus and MTBDRsl assays for detecting first‐line and second‐line drug resistance, respectively, in gastrointestinal tuberculosis (GITB). Methods: Thirty ileocecal biopsy specimens, processed in the Department of Microbiology between 2012 and 2022, that showed growth of Mycobacterium tuberculosis on culture were included in the study. DNA, extracted from culture, was subjected to MTBDRplus and MTBDRsl (Hain Lifescience GmbH, Nehren, Germany), following manufacturer's instructions. Their performance was compared against phenotypic drug susceptibility testing (pDST) and gene sequencing. Results: Out of the 30 specimens, 4 (13.33%) were mono‐isoniazid resistant, 4 (13.33%) were multidrug resistant (MDR), 2 (6.67%) were pre‐extensively drug resistant (pre‐XDR), and 2 (6.67%) were mono‐fluoroquinolone resistant. The results were 100% concordant with pDST and gene sequencing. Conclusions: In the wake of growing drug resistance in all forms of extrapulmonary tuberculosis, including GITB, MTBDRplus and MTBDRsl are reliable tools for screening of resistance to both first‐line and second‐line drugs. [ABSTRACT FROM AUTHOR]

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Background: Extensively drug resistant tuberculosis (XDR-TB) is considered as a major threat to global health. This study aimed to analyse the treatment outcomes and identify the factors significantly associated with unfavourable treatment outcomes among XDR-TB patients. Methods: We conducted a retrospective observational study at 10 Programmatic Management Units of the National Tuberculosis Control Program of Pakistan. The Electronic Nominal Recording Reporting System records were used to collect data of all eligible XDR-TB patients registered at the study sites between March 2012 and August 2018. Treatment outcomes were analysed as per the standard criteria. Factors associated with unfavourable treatment outcomes were analysed by using multivariate binary logistic regression analysis. Results: Out of the total 184 patients, 59 (32.1%) completed their treatment successfully. Whereby, 83 patients (45.1%) died, 24 (13%) had treatment failure, and 11 (6%) were lost to follow-up. Treatment outcomes were not evaluated in 7 (3.8%) patients. Factors significantly associated with unfavourable treatment outcomes included; conventional therapy with bedaquiline, unfavourable interim treatment outcomes and occurrence of adverse drug events (negative association). Conclusion: Treatment success rate in the study cohort was sub-optimal (i.e.,

Multidrug-resistant tuberculosis (MDR-TB) is caused by an organism that is resistant to both rifampicin and isoniazid. Extensively drug-resistant TB, a rare type of MDR-TB, is caused by an organism that is resistant to quinolone and one of group A TB drugs (i.e., linezolid and bedaquiline). In 2018, the World Health Organization revised the groupings of TB medicines and reclassified linezolid as a group A drug for the treatment of MDR-TB. Linezolid is a synthetic antimicrobial agent in the oxazolidinone class. Although linezolid has a good efficacy, it can cause substantial adverse events, especially hematologic toxicity. In both TB infection and linezolid mechanism of action, mitochondrial dysfunction plays an important role. In this concise review, characteristics of linezolid as an anti-TB drug are summarized, including its efficacy, pathogenesis of hematologic toxicity highlighting mitochondrial dysfunction, and the monitoring and management of hematologic toxicity.

Abstract Background There was a lack of information about prognostic accuracy of time to sputum culture conversion (SCC) in forecasting cure among extensively drug-resistant tuberculosis (XDR-TB) patients. Therefore, this study evaluated the prognostic accuracy of SCC at various time points in forecasting cure among XDR-TB patients. Methods This retrospective observational study included 355 eligible pulmonary XDR-TB patients treated at 27 centers in Pakistan between 01-05-2010 and 30-06-2017. The baseline and follow-up information of patients from treatment initiation until the end of treatment were retrieved from electronic nominal recording and reporting system. Time to SCC was analyzed by Kaplan–Meier method, and differences between groups were compared through log-rank test. Predictors of time to SCC and cure were respectively evaluated by multivariate Cox proportional hazards and binary logistic regression analyses. A p-value 40 years (hazards ratio [HR] = 0.632, p-value = 0.004), baseline sputum grading of scanty, + 1 (HR = 0.511, p-value = 0.002), + 2, + 3 (HR = 0.523, p-value = 0.001) and use of high dose isoniazid (HR = 0.463, p-value = 0.004) were significantly associated with early SCC. Only SCC at 6 month of treatment had statistically significant association with cure (odds ratio = 15.603, p-value

Background: Drug-resistant tuberculosis (DR-TB) is the most exigent and calamitous challenge encountered in treatment of TB. Extra pulmonary (EP) DR-TB poses a complex diagnostic and therapeutic challenge owing to myriad of presentations and paucibacillary nature. Data available on this subset is limited. We studied the prevalence of EPDR-TB cases among the total DR-TB cases visiting our Programmatic management of Drug-Resistant TB (PMDT) site. We also studied the demographic and microbiological profile of these cases and analyzed the prevalence of pre-extensively drug-resistant TB (pre XDR-TB) and extensively drug-resistant TB (XDR-TB) among patients of EPDR-TB in pre Bdq era. Results: Of the 1086 DR-TB patients, 64 (5.89%) were cases of EPDR-TB. Seven out of 64 (10.93%) were primary EPDR-TB. The site wise distribution of cases was 34 (53.125%) lymph node DR-TB, 18 (28.125%) pleural DR-TB, 9 (14.0625%) spinal DR-TB/paraspinal abscess/psoas abscess, 1 case (1.5625%) each of abdominal DR-TB, sternal and gluteal abscess. On the basis of the second-line drug susceptibility testing (DST), patients were grouped into: (1) multidrug-resistant TB (MDR-TB), (2) MDR-TB with fluoroquinolone (FQ) resistance {pre XDR XDR-TB (FQ)}, (3) MDR-TB with second-line injectable (SLI) resistance {pre XDR XDR-TB (SLI)}, (4) XDR-TB. Of the 64 patients, 43 (67.185%) had MDR-TB, 19 (29.687%) had preXDR-TB (FQ), none had preXDR-TB (SLI) and 2 (3.125%) had XDR-TB. Gastro esophageal reflux disease (GERD) was the most common comorbidity seen in 26 (40.6%) patients, followed by anemia in 5 (7.8%), psychiatry problems 5 (7.8%), hypertension in 3 (4.6%), renal disorders in 2 (3.1%) while thyroid disorder, HIV and thalassemia in 1 each (1.5%). Conclusion: EPDR-TB forms a small but significant proportion of total DR-TB. Lymph node DR-TB is its most common subclass. Our study emphasises the momentousness and essentiality of baseline DST to FQ and SLI in patients of DR-TB. This enables an appropriate modification of therapy at baseline itself to better the treatment outcomes. We observed a strikingly high proportion of preXDR-TB (FQ) in our study group. [ABSTRACT FROM AUTHOR]

Background: The emergence of multidrug resistance and extensively drug-resistant tuberculosis is a serious public health crisis. Using rapid and inexpensive molecular methods such as HRM assay in the detection of second-line drugs resistance in M. tuberculosis would be helpful in the treatment and control of XDR tuberculosis cases. Methods: MDR-TB isolates were collected from Iranian tuberculosis laboratories. Drug susceptibility test performed via the indirect proportion method utilizing LJ Medium. Susceptibility to ciprofloxacin, ofloxacin, amikacin, kanamycin, and capreomycin, as second-line anti-tuberculosis agents were assessed. Single point mutations in gyrA, rrs and eis genes were detected via HRM assay and DNA sequencing. Results: A DST test was performed for 56 MDR isolates and at least 27 (48.2%) isolates were resistant to CIP or OFL. Also, 14 (25%), 12 (21.4%), and 15 (26.7%) isolates were resistant to capreomycin, amikacin, and kanamycin, respectively. D94G, A90V, and G88C mutations were the most frequent mutations in gyrA gene. Also, A1401G mutation was detected more than the other mutations in rrs gene. Conclusions: The frequency of CIP/OFL and AMK/CAP/KAN-resistant TB is considerable among Iranian tuberculosis cases. HRM assay is a rapid and inexpensive test and can detect important mutation-based drug resistance in MDR-TB and XDR-TB isolates. [ABSTRACT FROM AUTHOR]

Karan Varshney, Beverly Anaele, Matthew Molaei, Rosemary Frasso, Vittorio Maio College of Population Health, Thomas Jefferson University, Philadelphia, PA, USACorrespondence: Karan VarshneyCollege of Population Health, Thomas Jefferson University, 901 Walnut Street, 10th Floor, Philadelphia, PA, 19107, USATel +1 604-359-6721Email karan.varshney@students.jefferson.eduAbstract: In recent years, there has been an upsurge in cases of drug-resistant TB, and strains of TB resistant to all forms of treatment have begun to emerge; the highest level of resistance is classified as extensively drug-resistant tuberculosis (XDR-TB). There is an urgent need to prevent poor outcomes (death/default/failed treatment) of XDR-TB, and knowing the risk factors can inform such efforts. The objective of this scoping review was to therefore identify risk factors for poor outcomes among XDR-TB patients. We searched three scientific databases, PubMed, Scopus, and ProQuest, and identified 25 articles that examined relevant risk factors. Across the included studies, the proportion of patients with poor outcomes ranged from 8.6 to 88.7%. We found that the most commonly reported risk factor for patients with XDR-TB developing poor outcomes was having a history of TB. Other risk factors were human immunodeficiency virus (HIV), a history of incarceration, low body mass, being a smoker, alcohol use, unemployment, being male, and being middle-aged. Knowledge and understanding of the risk factors associated with poor outcomes of XDR-TB can help policy makers and organizations in the process of designing and implementing effective programs.Keywords: drug-resistant, tuberculosis, risk factors, compliance, adherence, XDR-TB

BACKGROUND: Spinal tuberculosis (STB), or Pott’s disease, is a relatively frequent form of extrapulmonary involvement representing 50% of bone tuberculosis. Its diagnosis continues to be challenging due to the insidious presentation of the condition and is essential because it can cause disability due to late diagnosis or inadequate management. CASE REPORT: The objective of this study is to report a case of Pott’s disease due to multidrug-resistant bacilli in a pediatric patient who required surgical management with pharmacological support in a tertiary care pediatric hospital. The management of these deformities is surgical; however, with new technologies and techniques in spinal surgery, the best approach for this type of patient has been discussed, whether it should be anterior, posterior, or mixed. In our case, a 360° approach was necessary due to the magnitude of the deformity with a favorable postoperative period with good tolerance to antituberculosis drugs without additional neurological deficit. CONCLUSIONS: Pott’s disease due to multidrug-resistant bacilli continues to be a challenge thanks to the insidious presentation of the condition. However, there is no consensus regarding the best surgical approach for patients with the presented characteristics.

Antibiotics have played a crucial role in the reduction in the incidence of TB globally as evidenced by the fact that before the mid-20th century, the mortality rate within five years of the onset of the disease was 50%. The use of antibiotics has eliminated TB as a devastating disease, but the challenge of resistance to anti-TB drugs, which had already been described at the time of the introduction of streptomycin, has become a major global issue in disease management. Mismanagement of multidrug-resistant tuberculosis (MDR-TB) cases, resulting from intermittent drug use, prescription errors, and non-compliance of patients, has been identified as a critical risk factor for the development of extensively drug-resistant tuberculosis (XDR-TB). Antimicrobial resistance (AMR) in TB is a multi-factorial, complex problem of microbes evolving to escape antibiotics, the gradual decline in antibiotic development, and different economic and social conditions. In this review, we summarize recent advances in our understanding of how Mycobacterium tuberculosis evolves drug resistance. We also highlight the importance of developing shorter regimens that rapidly reach bacteria in diverse host environments, eradicating all mycobacterial populations and preventing the evolution of drug resistance. Lastly, we also emphasize that the current burden of this ancient disease is driven by a combination of complex interactions between mycobacterial and host factors, and that only a holistic approach that effectively addresses all the critical issues associated with drug resistance will limit the further spread of drug-resistant strains throughout the community.

Abstract Background According to World Health Organization (WHO), drug-resistant tuberculosis (DR-TB) is a major contributor to antimicrobial resistance globally and continues to be a public health threat. Annually, about half a million people fall ill with DR-TB globally. The gradual increase in resistance to fluoroquinolones (FQs) and second-line injectable drugs (SLIDs), poses a serious threat to effective TB control and adequate patient management. Therefore, WHO suggests the use of GenoType MTBDRsl v.2.0 assay for detection of multiple mutations associated with FQs and SLIDs. Hence, the study was conducted to determine the prevalence of resistance to FQs and SLIDs by comparing direct GenoType MTBDRsl v.2.0 assay with phenotypic drug susceptibility testing (DST). Methods The study was conducted on 1320 smear positive sputum samples from a total of 2536 RR-TB, confirmed by GeneXpert MTB/RIF. The smear positive specimens were decontaminated, and DNA extraction was performed. Furthermore, the extracted DNA was used for GenoType MTBDRsl v.2.0 assay. While 20% of the decontaminated specimens were inoculated in Mycobacterium growth indicator tube (MGIT) for drug susceptibility testing (DST). Results Out of 1320 smear positive sputum samples, 1178 were identified as Mycobacterium tuberculosis complex (MTBC) and remaining were negative by GenoType MTBDRsl v.2.0 assay. Of the 1178 MTBC positive, 26.6% were sensitive to both FQs and SLIDs, whereas 57.3% were only FQs resistant and 15.9% were resistant to both FQs and SLIDs. Further DST of 225 isolates by liquid culture showed that 17% were sensitive to both FQs and SLIDs, 61.3% were only FQs resistant and 21.3% were resistant to both. The specificity for FQs and SLIDs was 92.31% and 100% whereas sensitivity was 100% respectively by GenoType MTBDRsl v.2.0 assay in direct sputum samples. Conclusions Our study clearly suggests that GenoType MTBDRsl v.2.0 assay is a reliable test for the rapid detection of resistance to second-line drugs after confirmation by GeneXpert MTB/RIF assay for RR-TB. Though, high rate FQ (ofloxacin) resistance was seen in our setting, moxifloxacin could be used as treatment option owing to very low resistance.

Abstract Background BPaL, a 6 month oral regimen composed of bedaquiline, pretomanid, and linezolid for treating extensively drug-resistant tuberculosis (XDR-TB) is a potential alternative for at least 20 months of individualized treatment regimens (ITR). The ITR has low tolerability, treatment adherence, and success rates, and hence to limit patient burden, loss to follow-up and the emergence of resistance it is essential to implement new DR-TB regimens. The objective of this study was to assess the acceptability, feasibility, and likelihood of implementing BPaL in Indonesia, Kyrgyzstan, and Nigeria. Methods We conducted a concurrent mixed-methods study among a cross-section of health care workers, programmatic and laboratory stakeholders between May 2018 and May 2019. We conducted semi-structured interviews and focus group discussions to assess perceptions on acceptability and feasibility of implementing BPaL. We determined the proportions of a recoded 3-point Likert scale (acceptable; neutral; unacceptable), as well as the overall likelihood of implementing BPaL (likely; neutral; unlikely) that participants graded per regimen, pre-defined aspect and country. We analysed the qualitative results using a deductive framework analysis. Results In total 188 stakeholders participated in this study: 63 from Kyrgyzstan, 51 from Indonesia, and 74 from Nigeria The majority were health care workers (110). Overall, 88% (146/166) of the stakeholders would likely implement BPaL once available. Overall acceptability for BPaL was high, especially patient friendliness was often rated as acceptable (93%, 124/133). In contrast, patient friendliness of the ITR was rated as acceptable by 45%. Stakeholders appreciated that BPaL would reduce workload and financial burden on the health care system. However, several stakeholders expressed concerns regarding BPaL safety (monitoring), long-term efficacy, and national regulatory requirements regarding introduction of the regimen. Stakeholders stressed the importance of addressing current health systems constraints as well, especially in treatment and safety monitoring systems. Conclusions Acceptability and feasibility of the BPaL regimen is high among TB stakeholders in Indonesia, Kyrgyzstan, and Nigeria. The majority is willing to start using BPaL as the standard of care for eligible patients despite country-specific health system constraints.

Multidrug-resistant/rifampicin-resistant tuberculosis is a major obstacle to successful tuberculosis control. The recommendation by the WHO to use bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaL(M)) for 6 months, based on results of two trials with high efficacy and low toxicity, has revolutionized treatment options. In this study, representatives of the Tuberculosis Network European Trials group in 44 of 54 countries of the WHO Europe region documented the availability of the medicines and drug susceptibility testing (DST) of the BPaL(M) regimen through a structured questionnaire between September and November 2023. In total, 24 of 44 (54.5%), 42 of 44 (95.5%), 43 of 44 (97.7%), and 43 of 44 (97.7%) countries had access to pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, 23 of 44 (52.3%) countries had access to all the drugs composing the BPaL(M) regimen. In total, 21 of 44 (47.7%), 37 of 44 (84.1%), 40 of 44 (90.9%), and 41 of 44 (93.2%) countries had access to DST for pretomanid, bedaquiline, linezolid, and moxifloxacin, respectively. Overall, DST was available for all medicines composing the BPaL(M) regimen in 21 of 44 (47.7%) countries, including countries where pretomanid DST was available at specialized laboratories. The availability of DST for the drugs the countries had access to, varied from 87.5% to 95.3% (pretomanid 21 of 24 (87.5%), bedaquiline 37 of 42 (88.1%), linezolid 40 of 43 (93.1%) and moxifloxacin 41 of 43 (95.3%)). In only about half of the countries participating in the survey, clinicians had access to all the BPaL(M) regimen drugs. A complete DST for the BPaL(M) medicines was possible in less than half of the countries, because of the low accessibility of DST for pretomanid. Equal access to new regimens is urgently needed in Europe and a rapid scale up of DST, especially for pretomanid, is important to prevent unnoticed spread of drug resistance. [ABSTRACT FROM AUTHOR]

The optimal treatment for osteoarticular infection due to multidrug-resistant tuberculosis strains (MDR-OATB) remains unclear. This study aims to evaluate the diagnosis, management and outcome of MDR-OATB in France. We present a case series of MDR-OATB patients reviewed at the French National Reference Center for Mycobacteria between 2007 and 2018. Medical history and clinical, microbiological, treatment and outcome data were collected. Twenty-three MDR-OATB cases were reported, representing 3% of all concurrent MDR-TB cases in France. Overall, 17 were male, and the median age was 32 years. Six patients were previously treated for TB, including four with first-line drugs. The most frequently affected site was the spine (n = 16). Bone and joint surgery were required in 12 patients. Twenty-one patients (91%) successfully completed the treatment with a regimen containing a mean of four drugs (range, 2–6) for a mean duration of 20 months (range, 13–27). Overall, high rates of treatment success were achieved following WHO MDR-TB treatment guidelines and individualized patient management recommendations by the French National TB Consilium. However, the optimal combination of drugs, duration of treatment and role of surgery in the management of MDR-OATB remains to be determined. [ABSTRACT FROM AUTHOR]

Background: In 2019, new therapeutic recommendations for multidrug-resistant (MDR-) and extensively drug-resistant (XDR) tuberculosis (TB) were published by the WHO, advocating the use of oral drugs and stepwise composition of antibiotic regimens. To date, the economic consequences of those recommendations in low incidence settings have not been evaluated. Objective: To assess the costs of applying the new recommendations against a set of 86 MDR-TB/XDR-TB strains, each with individual phenotypic drug resistance patterns, identified in 2018/2019 by the German National Reference Center for Mycobacteria. Methods: Hospitalization costs as covered by German statutory health insurance and the loss of productivity due to illness were calculated using the most recent 2018 statistical data. Costs due to combining five agents in the intensive phase and costs of outpatient monitoring were determined by Monte-Carlo simulation covering all treatment options over an 18-month period. Drug costs were compared to those arising under the approach recommended by the WHO in 2016. Results: Hospitalization costs per MDR-TB patient were €30,152 and the mean costs of antimicrobials over a period of 18 months were €66,854 (range €20,671 to €187,444). Total treatment costs, including outpatient monitoring, were €73,551.56 per patient (range €30,114 to €145.878). In addition, we determined an average cost of €11,410.20 due to productivity loss over a period of 6 months sick leave. Despite a shortened minimum recommended treatment duration (18 versus 20 months), the estimated costs were 24.5% higher based on the 2019 recommendations as compared to the 2016 guideline version. Conclusion: Higher costs for treating MDR-TB/XDR-TB in Germany are to be expected under the new WHO regimens. However, it must be determined whether treatment duration and costs associated with sick leave may be further reduced in the future through shorter hospital stays and earlier culture conversion.

Extensively drug resistant tuberculosis (XDR-TB) is considered as a major threat to global health. This study aimed to analyse the treatment outcomes and identify the factors significantly associated with unfavourable treatment outcomes among XDR-TB patients. We conducted a retrospective observational study at 10 Programmatic Management Units of the National Tuberculosis Control Program of Pakistan. The Electronic Nominal Recording Reporting System records were used to collect data of all eligible XDR-TB patients registered at the study sites between March 2012 and August 2018. Treatment outcomes were analysed as per the standard criteria. Factors associated with unfavourable treatment outcomes were analysed by using multivariate binary logistic regression analysis. Out of the total 184 patients, 59 (32.1%) completed their treatment successfully. Whereby, 83 patients (45.1%) died, 24 (13%) had treatment failure, and 11 (6%) were lost to follow-up. Treatment outcomes were not evaluated in 7 (3.8%) patients. Factors significantly associated with unfavourable treatment outcomes included; conventional therapy with bedaquiline, unfavourable interim treatment outcomes and occurrence of adverse drug events (negative association). Treatment success rate in the study cohort was sub-optimal (i.e., <75%). The poor success rate and high mortality are concerning, and requires immediate attention of the program managers and clinicians. [ABSTRACT FROM AUTHOR]

Background: There was a lack of information about prognostic accuracy of time to sputum culture conversion (SCC) in forecasting cure among extensively drug-resistant tuberculosis (XDR-TB) patients. Therefore, this study evaluated the prognostic accuracy of SCC at various time points in forecasting cure among XDR-TB patients.Methods: This retrospective observational study included 355 eligible pulmonary XDR-TB patients treated at 27 centers in Pakistan between 01-05-2010 and 30-06-2017. The baseline and follow-up information of patients from treatment initiation until the end of treatment were retrieved from electronic nominal recording and reporting system. Time to SCC was analyzed by Kaplan-Meier method, and differences between groups were compared through log-rank test. Predictors of time to SCC and cure were respectively evaluated by multivariate Cox proportional hazards and binary logistic regression analyses. A p-value < 0.05 was considered statistically significant.Results: A total of 226 (63.6%) and 146 (41.1%) patients respectively achieved SCC and cure. Median time to SCC was significantly shorter in patients who achieved cure, 3 months (95% confidence interval [CI]: 2.47-3.53), than those who did not (median: 10 months, 95% CI: 5.24-14.76) (p-value < 0.001, Log-rank test). Patient's age > 40 years (hazards ratio [HR] = 0.632, p-value = 0.004), baseline sputum grading of scanty, + 1 (HR = 0.511, p-value = 0.002), + 2, + 3 (HR = 0.523, p-value = 0.001) and use of high dose isoniazid (HR = 0.463, p-value = 0.004) were significantly associated with early SCC. Only SCC at 6 month of treatment had statistically significant association with cure (odds ratio = 15.603, p-value < 0.001). In predicting cure, the sensitivities of SCC at 2, 4 and 6 months were respectively 41.8% (95%CI: 33.7-50.2), 69.9% (95%CI: 61.7-77.2) and 84.9% (95%CI: 78.1-90.3), specificities were respectively, 82.8% (95%CI: 76.9-87.6), 74.6% (95%CI: 68.2-80.4) and 69.4% (95%CI: 62.6-75.5) and prognostic accuracies were respectively 65.9% (95%CI: 60.7-70.8), 72.7% (95%CI: 67.7-77.2) and 75.8% (95%CI: 71.0-80.1).Conclusion: In forecasting cure, SCC at month 6 of treatment performed better than SCC at 2 and 4 months. However, it would be too long for clinicians to wait for 6 months to decide about the regimen efficacy. Therefore, with somewhat comparable prognostic accuracy to that SCC at 6 month, using SCC at 4 month of treatment as a prognostic marker in predicting cure among XDR-TB patients can decrease the clinicians waiting time to decide about the regimen efficacy. [ABSTRACT FROM AUTHOR]

Abstract Background Interest in carbapenems has been rising in the last few years due to the emergence of drug resistant tuberculosis. Ertapenem (ETP), given once a day parenteral, and faropenem (FAR), oral, have a better administration profile than meropenem (MEM), imipenem (IPM) and doripenem (DOR). The addition of amoxicillin-clavulanate (AMC) inhibits the hydrolysis by the carbapenemase present in Mycobacterium tuberculosis (MTB). The aim of this study was to determine the in vitro activity of ETP and FAR against susceptible and resistant clinical MTB strains by two widely use methodologies, the BACTEC960 MGIT and microdilution. Results 19 clinical isolates with different susceptibility profiles and H37Rv were included. Minimal inhibitory concentration (MIC) testing was performed using two methods of different concentrations of ETP and FAR with and without AMC. MIC50 was 2 and 8 for FAR with and without AMC by both methods. MIC90 was > 16 and > 8 by microdilution and MGIT respectively and did not change after AMC addition. 18/20 samples were resistant to the highest concentration of ETP, with and without AMC. Half of the samples had some susceptibility to FAR; addition of AMC further reduced the MIC level in seven isolates. 10/20 isolates showed susceptibility to FAR and the addition of AMC further reduced the MIC in 7 isolates. However, most of the MICs were near the limit of effectiveness (8 μg/mL). Resistance to FAR was associated with resistance to MEM (p = 0.04) but not to resistance profiles of other drugs, including M/XDR status. Conclusions The lack of ETP activity may be associated with its degradation, independent of carbapenemase, during incubation. No susceptibility pattern to traditional drugs can predict susceptibility to FAR and susceptibility testing is not routinely available. PK/PD studies are needed as reaching the concentrations tested in these experiments may be challenging. This work highlighted some of the limitations of carbapenem use. More evidence is needed to clarify their true impact in TB treatment and outcome, considering the financial burden, complications and microbiota changes associated with their use.

Abstract Background Fluoroquinolones are broad-spectrum antibiotics that are recommended, and increasingly important, for the treatment of multidrug-resistant tuberculosis (MDR-TB). Resistance to fluoroquinolones is caused by mutations in the Quinolone Resistance Determining Region (QRDR) of gyrA and gyrB genes of Mycobacterium tuberculosis. In this study, we characterized the phenotypic and genotypic resistance to fluoroquinolones for the first time in northeast Iran. Methods A total of 123 Mycobacterium tuberculosis isolates, including 111 clinical and 12 collected multidrug-resistant isolates were studied. Also, 19 WHO quality control strains were included in the study. The phenotypic susceptibility was determined by the proportion method on Löwenstein-Jensen medium. The molecular cause of resistance to the fluoroquinolone drugs ofloxacin and levofloxacin was investigated by sequencing of the QRDR region of the gyrA and gyrB genes. Results Among 123 isolates, six (4.8%) were fluoroquinolone-resistant according to phenotypic methods, and genotypically three of them had a mutation at codon 94 of the gyrA gene (Asp→ Gly) which was earlier reported to cause resistance. All three remaining phenotypically resistant isolates had a nucleotide change in codon 95. No mutations were found in the gyrB gene. Five of the 19 WHO quality control strains, were phenotypically fluoroquinolone-resistant, four of them were genotypically resistant with mutations at codon 90, 91 of the gyrA gene and one resistant strain had no detected mutation. Conclusions Mutation at codon 94 of the gyrA gene, was the main cause of fluoroquinolone resistance among M. tuberculosis isolates in our region. In 3/6 fluoroquinolone-resistant isolates, no mutations were found in either gyrA or gyrB. Therefore, it can be concluded that various other factors may lead to fluoroquinolone resistance, such as active efflux pumps, decreased cell wall permeability, and drug inactivation.

Coronavirus disease (COVID-19) pandemic determined a 10 years-set back in tuberculosis (TB) control programs. Recent advances in available therapies may help recover the time lost. While Linezolid (LZD) and Bedaquiline (BDQ), previously Group D second line drugs (SLDs) for TB, have been relocated to Group A, other drugs are currently being studied in regimens for drug resistant TB (DR-TB). Among these, Pretomanid (PA), a recently introduced antimycobacterial drug derived from nitroimidazole with both solid bactericidal and bacteriostatic effect, and with an excellent effectiveness and tolerability profile, is in the spotlight. Following promising data obtained from recently published and ongoing randomized controlled trials (RCTs), the World Health Organization (WHO) determined to include PA in its guidelines for the treatment of rifampicin-resistant (RR), multi drug resistant (MDR) and pre-extensively drug resistant TB (pre-XDR-TB) with BDQ, LZD and Moxifloxacine (MFX) in a 6-month regimen. Although further studies on the subject are needed, PA may also represent a treatment option for drug-susceptible TB (DS-TB), latent TB infection (LTBI) and non tuberculous mycobacteria (NTM). This narrative review aims to examine current implementation options and future possibilities for PA in the never-ending fight against TB.

Background The Médecins Sans Frontières Clinic in Mumbai, India, has been providing concomitant bedaquiline (BDQ) and delamanid (DLM) in treatment regimen for patients with drug-resistant tuberculosis (DR-TB) and limited therapeutic options, referred from other healthcare institutions, since 2016. The study documents the end-of-treatment outcomes, culture-conversion rates, and serious adverse events (SAEs) during treatment. Methods This was a retrospective cohort study based on routinely collected program data. In clinic, treatment regimens are designed based on culture drug sensitivity test patterns and previous drug exposures, and are provided for 20–22 months. BDQ and DLM are extended beyond 24 weeks as off-label use. Patients who initiated DR-TB treatment including BDQ and DLM (concomitantly for at least 4 weeks) during February 2016–February 2018 were included. Results Of the 70 patients included, the median age was 25 (interquartile range [IQR], 22–32) years and 56% were females. All except 1 were fluoroquinolone resistant. The median duration of exposure to BDQ and DLM was 77 (IQR, 43–96) weeks. Thirty-nine episodes of SAEs were reported among 30 (43%) patients, including 5 instances of QTc prolongation, assessed as possibly related to BDQ and/or DLM. The majority (69%) had culture conversion before 24 weeks of treatment. In 61 (87%), use of BDQ and DLM was extended beyond 24 weeks. Successful end-of-treatment outcomes were reported in 49 (70%) patients. Conclusions The successful treatment outcomes of this cohort show that regimens including concomitant BDQ and DLM for longer than 24 weeks are effective and can be safely administered on an ambulatory basis. National TB programs globally should scale up access to life-saving DR-TB regimens with new drugs. [ABSTRACT FROM AUTHOR]

ABSTRACT Extensive drug-resistant tuberculosis (XDR-TB) is highly life threatening and its diagnosis is usually difficult and time-consuming. Here we present the first two cases of XDR and pre-XDR-TB diagnosed in 2018 on the Thailand-Myanmar border, more specifically in Tak province. Rapid detection of XDR-TB was performed by loop-mediated isothermal amplification (LAMP), Xpert MTB/RIF, and line probe assays. Mutation analyses targeting rpoB, katG, inhA, gyrA and rrs genes showed an association with drug-resistant phenotypes, except for rifampicin resistance. Spoligotyping revealed uncommon Beijing and T2 genotypes and the analysis of M. tuberculosis interspersed repetitive unit-variable number tandem repeat (MIRU-VNTR) showed the presence of more polymorphisms. This report highlights the importance of the early detection of drug-resistant tuberculosis by molecular tests followed by phenotyping assays. Based on the up-to-date definition of XDR- and pre-XDR-TB, the susceptibility testing for bedaquiline and linezolid is required and the two reported cases may correspond to putative XDR-TB.

Background: Multidrug-resistant Mycobacterium tuberculosis (Mtb) is a significant global public health threat. Genotypic resistance prediction from Mtb DNA sequences offers an alternative to laboratory-based drug-susceptibility testing. User-friendly and accurate resistance prediction tools are needed to enable public health and clinical practitioners to rapidly diagnose resistance and inform treatment regimens. Results: We present Translational Genomics platform for Tuberculosis (GenTB), a free and open web-based application to predict antibiotic resistance from next-generation sequence data. The user can choose between two potential predictors, a Random Forest (RF) classifier and a Wide and Deep Neural Network (WDNN) to predict phenotypic resistance to 13 and 10 anti-tuberculosis drugs, respectively. We benchmark GenTB's predictive performance along with leading TB resistance prediction tools (Mykrobe and TB-Profiler) using a ground truth dataset of 20,408 isolates with laboratory-based drug susceptibility data. All four tools reliably predicted resistance to first-line tuberculosis drugs but had varying performance for second-line drugs. The mean sensitivities for GenTB-RF and GenTB-WDNN across the nine shared drugs were 77.6% (95% CI 76.6–78.5%) and 75.4% (95% CI 74.5–76.4%), respectively, and marginally higher than the sensitivities of TB-Profiler at 74.4% (95% CI 73.4–75.3%) and Mykrobe at 71.9% (95% CI 70.9–72.9%). The higher sensitivities were at an expense of ≤ 1.5% lower specificity: Mykrobe 97.6% (95% CI 97.5–97.7%), TB-Profiler 96.9% (95% CI 96.7 to 97.0%), GenTB-WDNN 96.2% (95% CI 96.0 to 96.4%), and GenTB-RF 96.1% (95% CI 96.0 to 96.3%). Averaged across the four tools, genotypic resistance sensitivity was 11% and 9% lower for isoniazid and rifampicin respectively, on isolates sequenced at low depth (< 10× across 95% of the genome) emphasizing the need to quality control input sequence data before prediction. We discuss differences between tools in reporting results to the user including variants underlying the resistance calls and any novel or indeterminate variants Conclusions: GenTB is an easy-to-use online tool to rapidly and accurately predict resistance to anti-tuberculosis drugs. GenTB can be accessed online at https://gentb.hms.harvard.edu, and the source code is available at https://github.com/farhat-lab/gentb-site. [ABSTRACT FROM AUTHOR]

Background: According to World Health Organization (WHO), drug-resistant tuberculosis (DR-TB) is a major contributor to antimicrobial resistance globally and continues to be a public health threat. Annually, about half a million people fall ill with DR-TB globally. The gradual increase in resistance to fluoroquinolones (FQs) and second-line injectable drugs (SLIDs), poses a serious threat to effective TB control and adequate patient management. Therefore, WHO suggests the use of GenoType MTBDRsl v.2.0 assay for detection of multiple mutations associated with FQs and SLIDs. Hence, the study was conducted to determine the prevalence of resistance to FQs and SLIDs by comparing direct GenoType MTBDRsl v.2.0 assay with phenotypic drug susceptibility testing (DST). Methods: The study was conducted on 1320 smear positive sputum samples from a total of 2536 RR-TB, confirmed by GeneXpert MTB/RIF. The smear positive specimens were decontaminated, and DNA extraction was performed. Furthermore, the extracted DNA was used for GenoType MTBDRsl v.2.0 assay. While 20% of the decontaminated specimens were inoculated in Mycobacterium growth indicator tube (MGIT) for drug susceptibility testing (DST). Results: Out of 1320 smear positive sputum samples, 1178 were identified as Mycobacterium tuberculosis complex (MTBC) and remaining were negative by GenoType MTBDRsl v.2.0 assay. Of the 1178 MTBC positive, 26.6% were sensitive to both FQs and SLIDs, whereas 57.3% were only FQs resistant and 15.9% were resistant to both FQs and SLIDs. Further DST of 225 isolates by liquid culture showed that 17% were sensitive to both FQs and SLIDs, 61.3% were only FQs resistant and 21.3% were resistant to both. The specificity for FQs and SLIDs was 92.31% and 100% whereas sensitivity was 100% respectively by GenoType MTBDRsl v.2.0 assay in direct sputum samples. Conclusions: Our study clearly suggests that GenoType MTBDRsl v.2.0 assay is a reliable test for the rapid detection of resistance to second-line drugs after confirmation by GeneXpert MTB/RIF assay for RR-TB. Though, high rate FQ (ofloxacin) resistance was seen in our setting, moxifloxacin could be used as treatment option owing to very low resistance. [ABSTRACT FROM AUTHOR]

Mohsen Heidary,1,2 Saeed Zaker Bostanabad,3,4 Seyed Mohammad Amini,5 Alireza Jafari,6 Mostafa Ghalami Nobar,4,7 Arash Ghodousi,8 Morteza Kamalzadeh,9 Davood Darban-Sarokhalil1 1Department of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; 2Student Research Committee, School of Medicine, Iran University of Medical Sciences, Tehran, Iran; 3Microbiology Department, Islamic Azad University-Parand Branch, Tehran, Iran; 4Mycobacteriology Department, Massoud Laboratory, Tehran, Iran; 5Radiation Biology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran; 6Inflammatory Lung Diseases Research Center, Department of Internal Medicine, Razi Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran; 7Reference Health Laboratory of Iran (RHL), Ministry of Health and Medical Education, Tehran, Iran; 8Emerging Bacterial Pathogens Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS San Raffaele Scientific Institute, Milano, Italy; 9Quality Control, Department, Razi Vaccine and Research Institute, Agricultural Research Education and Extension Organization, Karaj, IranCorrespondence: Davood Darban-SarokhalilDepartment of Microbiology, School of Medicine, Iran University of Medical Sciences, Tehran, IranEmail davood_darban@yahoo.comBackground: Nowadays, tuberculosis (TB) is one of the top ten leading causes of mortality worldwide. The emergence of multidrug-resistant (MDR) – and extensively drug-resistant (XDR) – Mycobacterium tuberculosis (M. tuberculosis) is identified as one of the most challenging threats to TB control. Thus, new and safe nano-drugs are urgently required for the elimination of TB. The aim of this study was to investigate the anti-bacterial effects of Ag, ZnO, and Ag-ZnO nanoparticles (NPs) on MDR- and XDR-M. tuberculosis.Materials and methods: In this study, Ag, ZnO, and Ag-ZnO NPs were synthesized by the chemical reduction and chemical deposition methods. NPs were characterized using ultraviolet–visible spectroscopy, dynamic light scattering, and transmission electron microscopy. Then, various dilutions of NPs were prepared and their minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) were determined against M. tuberculosis strains using the broth microdilution and agar microdilution methods. Finally, MTT test and cell culture assay were performed.Results: The effects of concentrations of 1–128 μg/mL Ag NPs, ZnO NPs, 2Ag: 8ZnO, 8Ag:2ZnO, 3Ag: 7ZnO, 7Ag:3ZnO, and 5Ag:5ZnO on M. tuberculosis strains were investigated. MIC results showed the inhibitory effect of 1 μg/mL of all NPs against XDR-M. tuberculosis. In addition, the concentrations of 4 μg/mL Ag, 8 μg/mL 5Ag:5ZnO, 8 μg/mL 7Ag:3ZnO, 32 μg/mL 3Ag:7ZnO, 16 μg/mL 8Ag:2ZnO, and 64 μg/mL 2Ag:8ZnO inhibited MDR-M. tuberculosis growth. However, MBC results indicated the inability of Ag, ZnO and Ag-ZnO NPs, either in combination or alone, to kill MDR- or XDR-M. tuberculosis.Conclusion: To the best of our knowledge, this is the first study to evaluate the effects of Ag and ZnO NPs against MDR and XDR strains of M. tuberculosis. According to the results, Ag and ZnO NPs showed bacteriostatic effects against drug-resistant strains of M. tuberculosis. Therefore, these NPs may be considered as promising anti-mycobacterial nano-drugs. However, further studies are required to affirm the bactericidal effects of these NPs against TB.Keywords: Mycobacterium tuberculosis, silver, zinc oxide, nanoparticle, MDR-TB, XDR-TB

Abstract Background Mycobacterium tuberculosis resistance to anti-tuberculosis drugs is a major threat to global public health. Whole genome sequencing (WGS) is rapidly gaining traction as a diagnostic tool for clinical tuberculosis settings. To support this informatically, previous work led to the development of the widely used TBProfiler webtool, which predicts resistance to 14 drugs from WGS data. However, for accurate and rapid high throughput of samples in clinical or epidemiological settings, there is a need for a stand-alone tool and the ability to analyse data across multiple WGS platforms, including Oxford Nanopore MinION. Results We present a new command line version of the TBProfiler webserver, which includes hetero-resistance calling and will facilitate the batch processing of samples. The TBProfiler database has been expanded to incorporate 178 new markers across 16 anti-tuberculosis drugs. The predictive performance of the mutation library has been assessed using > 17,000 clinical isolates with WGS and laboratory-based drug susceptibility testing (DST) data. An integrated MinION analysis pipeline was assessed by performing WGS on 34 replicates across 3 multi-drug resistant isolates with known resistance mutations. TBProfiler accuracy varied by individual drug. Assuming DST as the gold standard, sensitivities for detecting multi-drug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) were 94% (95%CI 93–95%) and 83% (95%CI 79–87%) with specificities of 98% (95%CI 98–99%) and 96% (95%CI 95–97%) respectively. Using MinION data, only one resistance mutation was missed by TBProfiler, involving an insertion in the tlyA gene coding for capreomycin resistance. When compared to alternative platforms (e.g. Mykrobe predictor TB, the CRyPTIC library), TBProfiler demonstrated superior predictive performance across first- and second-line drugs. Conclusions The new version of TBProfiler can rapidly and accurately predict anti-TB drug resistance profiles across large numbers of samples with WGS data. The computing architecture allows for the ability to modify the core bioinformatic pipelines and outputs, including the analysis of WGS data sourced from portable technologies. TBProfiler has the potential to be integrated into the point of care and WGS diagnostic environments, including in resource-poor settings.

Abstract Background Kazakhstan remains a high-burden TB prevalence country with a concomitent high-burden of multi-drug resistant tuberculosis. For this reason, we performed an in depth genetic diversity and population structure characterization of Mycobacterium tuberculosis complex (MTC) genetic diversity in Kazakhstan with both patient and community benefit. Methods A convenience sample of 700 MTC DNA cultures extracts from 630 tuberculosis patients recruited from 12 out of 14 regions in Kazakhstan, between 2010 and 2015, was independently studied by high-throughput hybridization-based methods, TB-SPRINT (59-Plex, n = 700), TB-SNPID (50-Plex, n = 543). DNA from 391 clinical isolates was successfully typed by two methods. To resolve the population structure of drug-resistant clades in more detail two complementary assays were run on the L2 isolates: an IS6110-NTF insertion site typing assay and a SigE SNP polymorphism assay. Results Strains belonged to L2/Beijing and L4/Euro-American sublineages; L2/Beijing prevalence totaled almost 80%. 50% of all samples were resistant to RIF and to INH., Subtyping showed that: (1) all L2/Beijing were “modern” Beijing and (2) most of these belonged to the previously described 94–32 sublineage (Central Asian/Russian), (3) at least two populations of the Central Asian/Russian sublineages are circulating in Kazakhstan, with different evolutionary dynamics. Conclusions For the first time, the global genetic diversity and population structure of M. tuberculosis genotypes circulating in Kazakhstan was obtained and compared to previous local studies. Results suggest a region-specific spread of a very limited number of L2/Beijing clonal complexes in Kazakhstan many strongly associated with an MDR phenotype.

To investigate transmission of drug-resistant strains of Mycobacterium tuberculosis in Tunisia, we performed whole-genome sequencing on 46 multidrug-resistant strains isolated during 2012–2016. Core-genome multilocus sequence typing grouped 30 strains (65.2%) into 3 clusters, indicating extensive recent transmission and Haarlem clone predominance. Whole-genome sequencing might help public health services undertake appropriate control actions.

Background: BPaL, a 6 month oral regimen composed of bedaquiline, pretomanid, and linezolid for treating extensively drug-resistant tuberculosis (XDR-TB) is a potential alternative for at least 20 months of individualized treatment regimens (ITR). The ITR has low tolerability, treatment adherence, and success rates, and hence to limit patient burden, loss to follow-up and the emergence of resistance it is essential to implement new DR-TB regimens. The objective of this study was to assess the acceptability, feasibility, and likelihood of implementing BPaL in Indonesia, Kyrgyzstan, and Nigeria.Methods: We conducted a concurrent mixed-methods study among a cross-section of health care workers, programmatic and laboratory stakeholders between May 2018 and May 2019. We conducted semi-structured interviews and focus group discussions to assess perceptions on acceptability and feasibility of implementing BPaL. We determined the proportions of a recoded 3-point Likert scale (acceptable; neutral; unacceptable), as well as the overall likelihood of implementing BPaL (likely; neutral; unlikely) that participants graded per regimen, pre-defined aspect and country. We analysed the qualitative results using a deductive framework analysis.Results: In total 188 stakeholders participated in this study: 63 from Kyrgyzstan, 51 from Indonesia, and 74 from Nigeria The majority were health care workers (110). Overall, 88% (146/166) of the stakeholders would likely implement BPaL once available. Overall acceptability for BPaL was high, especially patient friendliness was often rated as acceptable (93%, 124/133). In contrast, patient friendliness of the ITR was rated as acceptable by 45%. Stakeholders appreciated that BPaL would reduce workload and financial burden on the health care system. However, several stakeholders expressed concerns regarding BPaL safety (monitoring), long-term efficacy, and national regulatory requirements regarding introduction of the regimen. Stakeholders stressed the importance of addressing current health systems constraints as well, especially in treatment and safety monitoring systems.Conclusions: Acceptability and feasibility of the BPaL regimen is high among TB stakeholders in Indonesia, Kyrgyzstan, and Nigeria. The majority is willing to start using BPaL as the standard of care for eligible patients despite country-specific health system constraints. [ABSTRACT FROM AUTHOR]

Background: The current study is conducted with the aim to the fill the gap of information regarding treatment outcomes and variables associated with unsuccessful outcome among XDR-TB patients from Pakistan.Methods: A total of 404 culture confirmed XDR-TB patients who received treatment between 1st May 2010 and June 30, 2017 at 27 treatment centers all over Pakistan were retrospectively followed until their treatment outcomes were reported. A p-value 60 years (OR = 4.69, 95%CI:1.57–15.57) and receiving high dose isoniazid (OR = 2.36, 95%CI:1.14–4.85) had statistically significant positive association with death, whereas baseline body weight >40 kg (OR = 0.43, 95%CI:0.25–0.73) and sputum culture conversion in the initial two months of treatment (OR = 0.33, 95%CI:0.19–0.58) had statistically significant negative association with death. Moreover, male gender had statistically significant positive association (OR = 1.92, 95%CI:1.04–3.54) with LTFU.Conclusion: The treatment success rate (40.6%) of XDR-TB patients in Pakistan was poor. Providing special attention and enhanced clinical management to patients with identified risk factors for death and LTFU in the current cohort may improve the treatment outcomes.

ABSTRACT The emergence and spread of extensively drug-resistant tuberculosis (XDR-TB) is a serious threat to global health. Therefore, its rapid diagnosis is crucial. The present study aimed to characterize mutations conferring resistance to second line drugs (SLDs) within multidrug Mycobacterium tuberculosis (MDR-MTB) isolates and to estimate the occurrence of XDR-TB in Casablanca, Morocco. A panel of 200 MDR-TB isolates was collected at the Pasteur Institute between 2015-2018. Samples were subjected to drug susceptibility testing to Ofloxacin (OFX), Kanamycin (KAN) and Amikacin (AMK). The mutational status of gyrA, gyrB, rrs, tlyA and eis was assessed by sequencing these target genes. Drug susceptibility testing for SLDs showed that among the 200 MDR strains, 20% were resistant to OFX, 2.5% to KAN and 1.5% to AMK. Overall, 14.5% of MDR strains harbored mutations in gyrA, gyrB, rrs and tlyA genes. From the 40 OFXR isolates, 67.5% had mutations in QRDR of gyrA and gyrB genes, the most frequent one being Ala90Val in gyrA gene. Of note, none of the isolates harbored simultaneously mutations in gyrA and gyrB genes. In eight out of the 200 MDR-TB isolates resistant either to KAN or AMK, only 25% had A1401G or Lys89Glu change in rrs and tlyA genes respectively. This study is very informative and provides data on the alarming rate of fluoroquinolone resistance which warrants the need to implement appropriate drug regimens to prevent the emergence and spread of more severe forms of Mycobacterium tuberculosis drug resistance.

The optimal treatment for osteoarticular infection due to multidrug-resistant tuberculosis strains (MDR-OATB) remains unclear. This study aims to evaluate the diagnosis, management and outcome of MDR-OATB in France. We present a case series of MDR-OATB patients reviewed at the French National Reference Center for Mycobacteria between 2007 and 2018. Medical history and clinical, microbiological, treatment and outcome data were collected. Twenty-three MDR-OATB cases were reported, representing 3% of all concurrent MDR-TB cases in France. Overall, 17 were male, and the median age was 32 years. Six patients were previously treated for TB, including four with first-line drugs. The most frequently affected site was the spine (n = 16). Bone and joint surgery were required in 12 patients. Twenty-one patients (91%) successfully completed the treatment with a regimen containing a mean of four drugs (range, 2–6) for a mean duration of 20 months (range, 13–27). Overall, high rates of treatment success were achieved following WHO MDR-TB treatment guidelines and individualized patient management recommendations by the French National TB Consilium. However, the optimal combination of drugs, duration of treatment and role of surgery in the management of MDR-OATB remains to be determined.

DprE1 is a potential target of resistant tuberculosis (TB), especially multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB. 2-benzoxazolinone is a closely related bioisostere of some scaffolds such as benzoxazoles, benzimidazole, benzothiazolinone, and benzothiazoles that have been previously explored against DprE1. Thus, a ligand-based quantitative pharmacophore model (AHRR.8) of DprE1 was developed and this pharmacophore model was utilized in activity profiling of some 2-benzoxazolinones from an in-house database using virtual screening. Obtained hits were subject to molecular docking, molecular dynamics (MD), and MM/GBSA calculations, which resulted in benzoyl-substituted derivatives of 2-benzoxazolinone showing strong interactions with the key amino acid residues in the active site of DprE1. Based on in silico results, the top five hits were duly synthesized and evaluated against the XDR-TB strain. This study is an initial effort to explore 2-benzoxazolinones against XDR-TB, which can be submitted further to lead optimization for refining the results. [ABSTRACT FROM AUTHOR]

Due to the great resistance to first-line drugs, XDR-TB and MDR-TB are often difficult to cure completely. Pretomanid, PA-824 is one of the preferred drugs evaluated in clinical trials for the treatment of drug-resistant Mycobacterium tuberculosis. By inhibiting cell wall formation and respiratory toxicity, Pretomanid shows significant bactericidal activity against both replicative and stationary Mycobacterium tuberculosis. This article explores the effects of PA-824 on releasing active nitrogen substances and producing strong oxidative and cytotoxicity to Mycobacterium tuberculosis, prolonging early bactericidal activity, reducing the speed of Mycobacterium tuberculosis load in patients' sputum, and causing controllable adverse reactions, and comprehensively understand the anti-tuberculosis mechanism of pretomanid, including inhibiting the development of drug resistance of Mycobacterium tuberculosis strains, shortening the duration of tuberculosis treatment, and so on. The combination of pretomanid PA-824, bedaquinoline and linezolid, which has synergistic or additive potential in killing bacteria and inhibiting drug resistance, is also described, and is expected to further improve current TB treatment outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis, and the number of new cases of multidrug resistant TB (MDR-TB), pre extensively drug-resistant TB (pre-XDR-TB) and extensively drug-resistant TB (XDR-TB) has increased considerably worldwide. OBJECTIVES Herein, using 156 M. tuberculosis isolates from 106 patients previously classified as MDR or pre-XDR or XDR isolates, we investigated the genetic mutation profiles associated with phenotypic resistances in patients with MDR-TB, pre-XDR-TB and XDR-TB, treatment outcomes and resistance evolution. METHODS Molecular analyses were performed by partial sequencing of the rpoB, katG, gyrA, gyrB, rrs genes and analysis of the fabG-inhA promoter region. Clinical, epidemiologic and demographic data were obtained from the TB Notification database system of São Paulo (TB-WEB) and the Information System for Special Tuberculosis Treatments (SITE-TB). FINDINGS Drug resistance was attributed to previously known mutations and a novel Asp449Val mutation in gyrB was observed in four isolates from the same patient. Ten patients had more than one isolate evaluated and eight of these patients displayed resistance progression. MAIN CONCLUSIONS The present study is the first to report the frequency of mutations related to second-line drug resistance in MDR-TB, pre-XDR-TB and XDR-TB isolates. The results could lead to the improvement of available technologies for the rapid detection of drug resistant TB.