Burden and Patterns of Multidrug-Resistant Tuberculosis in Pediatric and Adolescent Patients at a Tertiary Care Hospital in Pakistan.

Background Multidrug-resistant tuberculosis (MDR-TB) presents a significant global health challenge, particularly in developing countries. This study focuses on the burden and pattern of pediatric and adolescent MDR-TB in a tertiary care hospital setting. Aims/objectives The main objective is to evaluate MDR-TB's prevalence and resistance patterns among pediatric and adolescent patients, highlighting critical demographic factors and resistance trends. Materials and methods The study utilized a prospective analytical design in two tertiary care facilities, focusing on children aged four months to 18 years diagnosed with extra-pulmonary tuberculosis. Data on demographic profiles, clinical outcomes, and drug resistance patterns were collected and analyzed using the Statistical Package for the Social Sciences (IBM SPSS Statistics for Windows, IBM Corp., Version 27.0, Armonk, NY). Results Out of 99 enrolled participants, 63 (63.64%) met the inclusion criteria. The mean age was 70.22±48.90 months. A significant proportion, 60 (95.2%) of the cases, originated from Punjab. Notably, 10 (15.9%) of the cultures demonstrated MDR, with specific resistance observed to isoniazid (INH) in 10 (15.9%) cases, rifampicin (RIF) in 11 (17.5%) cases, and pyrazinamide (PZA) in seven (11.1%) cases. The study also recorded a high prevalence of tuberculous meningitis, affecting 52 (82.5%) participants, and malnutrition, affecting 49 (77.8%). Conclusions MDR-TB in 10 (15.9%) of the study children and adolescents presenting in Pakistan's specialized health centres is a notable burden. This points to a need for better diagnostic methods and treatment plans for pediatric patients. Implementing advanced diagnostics and personalized therapies is crucial for managing MDR-TB in susceptible demographics. Our findings emphasize the importance of updating treatment protocols to tackle the impacts of MDR-TB and its evolving resistance.

Screening of bioactive compounds from selected mushroom species against putative drug targets in Mycobacterium tuberculosis: a multi-target approach.

Mycobacterium tuberculosis (Mtb) is a notorious pathogen that causes one of the highest mortalities globally. Due to a pressing demand to identify novel therapeutic alternatives, the present study aims to focus on screening the putative drug targets and prioritizing their role in antibacterial drug development. The most vital proteins involved in the Biotin biosynthesis pathway and the Lipoarabinomannan (LAM) pathway such as biotin synthase (bioB) and alpha-(1->6)-mannopyranosyltransferase A (mptA) respectively, along with other essential virulence proteins of Mtb were selected as drug targets. Among these, the ones without native structures were modelled and validated using standard bioinformatics tools. Further, the interactions were performed with naturally available lead molecules present in selected mushroom species such as Agaricus bisporus, Pleurotus djamor, Hypsizygus ulmarius. Through Gas Chromatography-Mass Spectrometry (GC-MS), 15 bioactive compounds from the methanolic extract of mushrooms were identified. Further, 4 were selected based on drug-likeness and pharmacokinetic screening for molecular docking analysis against our prioritized targets wherein Benz[e]azulene from Pleurotus djamor illustrated a good binding affinity with a LF rank score of -9.036 kcal mol -1 against nuoM (NADH quinone oxidoreductase subunit M) and could be used as a prospective candidate in order to combat Tuberculosis (TB). Furthermore, the stability of the complex are validated using MD Simulations and subsequently, the binding free energy was calculated using MM-GBSA analysis. Thus, the current in silico analysis suggests a promising role of compounds extracted from mushrooms in tackling the TB burden.Communicated by Ramaswamy H. Sarma.

Confronting Tuberculosis: A Synthetic Quinoline-Isonicotinic Acid Hydrazide Hybrid Compound as a Potent Lead Molecule Against Mycobacterium tuberculosis.

The current tuberculosis (TB) treatment is challenged by a complex first-line treatment for drug-sensitive (DS) TB. Additionally, the prevalence of multidrug (MDR)- and extensively drug (XDR)-resistant TB necessitates the search for new drug prototypes. We synthesized and screened 30 hybrid compounds containing aminopyridine and 2-chloro-3-formyl quinoline to arrive at a compound with potent antimycobacterial activity, UH-NIP-16. Subsequently, antimycobacterial activity against DS and MDR Mycobacterium tuberculosis (M.tb) strains were performed. It demonstrated an MIC50 value of 1.86 ± 0.21 µM for laboratory pathogenic M.tb strain H37Rv and 3.045 ± 0.813 µM for a clinical M.tb strain CDC1551. UH-NIP-16 also decreased the MIC50 values of streptomycin, isoniazid, ethambutol, and bedaquiline to about 45, 55, 68, and 76%, respectively, when used in combination, potentiating their activities. The molecule was active against a clinical MDR M.tb strain. Cytotoxicity on PBMCs from healthy donors and on human cell lines was found to be negligible. Further, blind docking of UH-NIP-16 using Auto Dock Vina and MGL tools onto diverse M.tb proteins showed high binding affinities with multiple M.tb proteins, the top five targets being metabolically critical proteins CelA1, DevS, MmaA4, lysine acetyltransferase, and immunity factor for tuberculosis necrotizing toxin. These bindings were confirmed by fluorescence spectroscopy using a representative protein, MmaA4. Envisaging that a pathogen will have a lower probability of developing resistance to a hybrid molecule with multiple targets, we propose that UH-NIP-16 can be further developed as a lead molecule with the bacteriostatic potential against M.tb, both alone and in combination with first-line drugs.

Drug-Resistant Bone, Joint and Spine Tuberculosis: Evolution of Diagnosis and Treatment.

Background: Drug resistant (DR) osteoarticular TB (OATB) is a challenge in view of it being deep seated lesion and paucibacillary disease. Case definition, investigation protocol, treatment of proven DR and those cases where DR could not be demonstrated lacks clarity and evidence. Hence, a series of studies were conducted to develop an algorithm to investigate and treat therapeutically refractory disease (TRD) or presumptive drug resistance (PDR) cases of OATB. Patients and methods: 6 studies were conducted. Study one and two evaluated criteria to label TRD/PDR. Three subsequent studies were conducted where TDR/PDR or fresh cases of OATB cases were investigated by AFB smear, Bactec/liquid culture, histology and genotypic DST by CBNAAT & LPA. Sixth study was a retrospective evaluation of all DR cases treated for proven or clinical drug resistance (CDR). Results: Patient of bone/spine TB on ATT for 5 months or more show poor clinico-radiological treatment response as worsening of lesion, increased spinal deformity, persistent discharging sinus/ulcer, appearance of fresh lesion, recurrence of previous lesion, wound dehiscence of post-operative surgical scar cab labelled as PDR cases. These cases on histology ascertained TB and were proven DR on genotypic and phenotypic DST and are treated successfully. The patients of histologically ascertained TB and no/indeterminate phenotypic and genotypic DST were successfully treated as clinical drug resistance on MDR protocol. Conclusions: We described an algorithm. We must suspect PDR(TRD) based on criteria described. The tissue must be procured and submitted for AFB smear, histology and phenotypic and genotypic DST for diagnosis of TB. Genotypic and phenotypic DST will be useful to prove (90% instances) type of drug resistance. Remaining on strong clinical suspicion of DR and yet inconclusive on phenotypic/genotypic DST (<10%), may be treated as CDR as MDR. The adverse drug reactions and hepatic side-effects should be monitored diligently and these cases to be treated till healed status is demonstrated.

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.

Modulation of Cystatin F in Human Macrophages Impacts Cathepsin-Driven Killing of Multidrug-Resistant Mycobacterium tuberculosis.

Tuberculosis (TB) treatment relies primarily on 70-year-old drugs, and prophylaxis suffers from the lack of an effective vaccine. Among the 10 million people exhibiting disease symptoms yearly, 450,000 have multidrug or extensively drug-resistant (MDR or XDR) TB. A greater understanding of host and pathogen interactions will lead to new therapeutic interventions for TB eradication. One of the strategies will be to target the host for better immune bactericidal responses against the TB causative agent Mycobacterium tuberculosis (Mtb). Cathepsins are promising targets due to their manipulation of Mtb with consequences such as decreased proteolytic activity and improved pathogen survival in macrophages. We recently demonstrated that we could overcome this enzymatic blockade by manipulating protease inhibitors such as cystatins. Here, we investigate the role of cystatin F, an inhibitor that we showed previously to be strongly upregulated during Mtb infection. Our results indicate that the silencing of cystatin F using siRNA increase the proteolytic activity of cathepsins S, L, and B, significantly impacting pathogen intracellular killing in macrophages. Taken together, these indicate the targeting of cystatin F as a potential adjuvant therapy for TB, including MDR and XDR-TB.

Multidrug-Resistant TB (MDR-TB) and Extensively Drug-Resistant TB (XDR-TB) Among Children: Where We Stand Now.

Drug-resistant tuberculosis (DR-TB) has continued to be a global health cataclysm. It is an arduous condition to tackle but is curable with the proper choice of drug and adherence to the drug therapy. WHO has introduced newer drugs with all-oral shorter regimens, but the COVID-19 pandemic has disrupted the achievements and raised the severity. The COVID-19 controlling mechanism is based on social distancing, using face masks, personal protective equipment, medical glove, head shoe cover, face shield, goggles, hand hygiene, and many more. Around the globe, national and international health authorities impose lockdown and movement control orders to ensure social distancing and prevent transmission of COVID-19 infection. Therefore, WHO proposed a TB control program impaired during a pandemic. Children, the most vulnerable group, suffer more from the drug-resistant form and act as the storehouse of future fatal cases. It has dire effects on physical health and hampers their mental health and academic career. Treatment of drug-resistant cases has more success stories in children than adults, but enrollment for treatment has been persistently low in this age group. Despite that, drug-resistant childhood tuberculosis has been neglected, and proper surveillance has not yet been achieved. Insufficient reporting, lack of appropriate screening tools for children, less accessibility to the treatment facility, inadequate awareness, and reduced funding for TB have worsened the situation. All these have resulted in jeopardizing our dream to terminate this deadly condition. So, it is high time to focus on this issue to achieve our Sustainable Development Goals (SDGs), the goal of ending TB by 2030, as planned by WHO. This review explores childhood TB's current position and areas to improve. This review utilized electronic-based data searched through PubMed, Google Scholar, Google Search Engine, Science Direct, and Embase.

Epidemiology of tuberculosis in the Pacific island countries and areas, 2000–2020

@#Objective: Tuberculosis (TB) is one of the most important infectious diseases with an estimated 9.9 million people falling ill globally in 2020. We describe the epidemiology of TB in the Pacific island countries and areas (PICs) to inform potential priority actions to implement the Western Pacific Regional Framework to End TB 2021–2030. Methods: A descriptive analysis was conducted using annual TB surveillance data submitted by national TB programmes to the World Health Organization (WHO) and TB burden estimates (incidence rates and number of deaths) generated by WHO for the PICs, for the period 2000–2020. We also analysed TB case numbers, multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB), recent risk factor indicators and treatment outcomes. Results: The estimated TB incidence rate in the PICs increased between 2000 and 2020 from 62 to 69 per 100 000 population, with an 8% reduction observed since 2015. TB cases increased by 29% during 2000–2020, with 1746 cases in 2020 and a high proportion in children (19%). Bacteriological diagnosis was used for 58% of total TB cases, although some countries reported clinical diagnoses in over 60% of cases. From 2015 to 2019, 52 MDR/RR-TB cases were reported and there were 94 TB/HIV coinfected cases in 2015–2020. Treatment success was 74% in 2019 due to 18% of cases being unevaluated. In 2020, the estimated proportion of TB cases attributable to smoking, malnutrition, alcohol abuse and diabetes was 17%, 16%, 11% and 9%, respectively. Discussion: There was an increasing trend in TB cases, estimated incidence and deaths between 2000 and 2020. Laboratory services were scaled up in some PICs and case-finding activities greatly contributed to the detection of cases. In order to end the incidence of TB, continued efforts on case finding, contact investigation and scaling up TB preventive treatment should be prioritized. At the same time, collaboration with other sectors for risk factor management and decentralized management need to be considered.

Quality of Life Amongst Multidrug-Resistant TB Patients: An Exploratory Study About Distributive Dimensions and Interactions.

BACKGROUND: Multidrug-resistant (MDR)-TB has emerged as a major challenge to eliminate TB as envisioned at policy level. Distinctive traits associated with the disease such as physical, psychosocial and environmental dimensions may influence the treatment outcome in both directions. Quality of life (QoL) indicators may capture these traits distinctively. OBJECTIVE: To quantify the differential effect of MDR-TB on specific QoL domains, their distributions across the strata and to check for possible interactions. METHOD:  This community-based cross-sectional study was conducted on 98 MDR-TB patients registered in the calendar year 2017 under National Tuberculosis Elimination Programme (NTEP) in a central Indian district using the WHO-QoL BREF Scale by patients in their vicinity. The transformed domain scores were descriptively summarized, stratified and exploratory visualised. Likert mapping for each item was done. A two-way ANOVA test was applied to check differences across strata and interaction effects were calculated. RESULT: Participants perceived a higher QoL in the social domain (median score 69, IQR 56-75) while the psychological health domain (median 31 IQR 20.5-44) was professed as most negotiated by disease. More than 50% of participants were found to be dissatisfied with their assumed physical status in item-wise analysis. A statistically significant interaction (p=0.008) was detected with education strata to income tertile most evident in the physical domain while psychological domain alone (p=0.017) without significant interaction with treatment duration (p=0.316) was associated with the type of TB. Overall QoL scores were tilted in favour of an urban setting, male gender and towards a relatively younger population. CONCLUSION:  The overall deficits in QoL are evident in the study, per se in the psychological and physical domains. Moreover there is an inequitable distribution of these scores as revealed in the study. Inclusion of an additional parameter of periodical QoL assessment may thus predict the outcome at individual level and may address this inequity at policy level.

High fluoroquinolone resistance proportions among multidrug-resistant tuberculosis driven by dominant L2 Mycobacterium tuberculosis clones in the Mumbai Metropolitan Region.

BACKGROUND: Multidrug-resistant (MDR) Mycobacterium tuberculosis complex (MTBC) strains are a serious health problem in India, also contributing to one-fourth of the global MDR tuberculosis (TB) burden. About 36% of the MDR MTBC strains are reported fluoroquinolone (FQ) resistant leading to high pre-extensively drug-resistant (pre-XDR) and XDR-TB (further resistance against bedaquiline and/or linezolid) rates. Still, factors driving the MDR/pre-XDR epidemic in India are not well defined. METHODS: In a retrospective study, we analyzed 1852 consecutive MTBC strains obtained from patients from a tertiary care hospital laboratory in Mumbai by whole genome sequencing (WGS). Univariate and multivariate statistics was used to investigate factors associated with pre-XDR. Core genome multi locus sequence typing, time scaled haplotypic density (THD) method and homoplasy analysis were used to analyze epidemiological success, and positive selection in different strain groups, respectively. RESULTS: In total, 1016 MTBC strains were MDR, out of which 703 (69.2%) were pre-XDR and 45 (4.4%) were XDR. Cluster rates were high among MDR (57.8%) and pre-XDR/XDR (79%) strains with three dominant L2 (Beijing) strain clusters (Cl 1-3) representing half of the pre-XDR and 40% of the XDR-TB cases. L2 strains were associated with pre-XDR/XDR-TB (P < 0.001) and, particularly Cl 1-3 strains, had high first-line and FQ resistance rates (81.6-90.6%). Epidemic success analysis using THD showed that L2 strains outperformed L1, L3, and L4 strains in short- and long-term time scales. More importantly, L2 MDR and MDR + strains had higher THD success indices than their not-MDR counterparts. Overall, compensatory mutation rates were highest in L2 strains and positive selection was detected in genes of L2 strains associated with drug tolerance (prpB and ppsA) and virulence (Rv2828c). Compensatory mutations in L2 strains were associated with a threefold increase of THD indices, suggesting improved transmissibility. CONCLUSIONS: Our data indicate a drastic increase of FQ resistance, as well as emerging bedaquiline resistance which endangers the success of newly endorsed MDR-TB treatment regimens. Rapid changes in treatment and control strategies are required to contain transmission of highly successful pre-XDR L2 strains in the Mumbai Metropolitan region but presumably also India-wide.

Genotypic and phenotypic drug-resistance detection and prevalence of heteroresistance in patients with isoniazid- and multidrug-resistant tuberculosis in Ethiopia.

Objective: To assess the agreement between genotypic and phenotypic methods for detecting drug resistance, and examine the prevalence of heteroresistance among isoniazid (INH)- and multidrug/rifampicin-resistant (MDR/RR) TB. Method: In total, 127 Mycobacterium tuberculosis (Mtb) isolates, including 65 MDR/RR and 62 INH resistant, were used. First-line drug susceptibility testing (DST) was performed using the LJ method to determine the percentage of resistant bacteria. All drug-resistant isolates underwent testing with LPA. Heteroresistance was defined as simultaneous detection of wild-type and resistance-conferring mutations using LPA. Result: The sensitivity of LPA (compared with LJ DST) was 96% for any INH-resistant TB and 94% for any RR TB. The prevalence of heteroresistance among the 123. Mtb isolates was 9.8%. The percentage of resistant bacteria ranged from 1% to 10% for heteroresistant TB. Rifampicin heteroresistance was detected in 1.6% of MDR TB patients. INH heteroresistance was detected in 1.6% and 16.7% of MDR and INH-resistant TB patients, respectively. The proportion of INH heteroresistance was significantly higher (p = 0.030) in persons living with HIV. Conclusion: Some phenotypic drug resistances were not captured by LPA. The prevalence and percentage of resistant bacteria among heteroresistant TB highlight the importance of LPA for early detection of heteroresistant TB.

Socioepidemiological status and clinical outcome of MDR TB patients in a tertiary medical college in Southern Odisha.

Introduction: India accounts for one-fourth of the global TB burden. The load of drug-resistant TB is of foremost attention and concern at international, regional, and national levels. As per estimates of TB burden in India in 2018, the MDR/RR-TB incidence was 1.30 lakhs. Objectives: Socioepidemiological status and clinical outcome of MDR TB patients in a teaching hospital in tribal area of southern Odisha from 2012-2020. Material and Methods: This is a retrospective observational study accepted by the Institutional Ethics Committee of this tertiary medical college & hospital to which the DRTB centre is attached with the agreement of the program administrators. Inclusion Criteria: Patients with >15 years of age, those patients with pulmonary and extrapulmonary tuberculosis with normal liver enzymes. Exclusion Criteria: Patients having abnormal liver enzymes before treatment, pregnant ladies and children <15 years of age. Results: A total of 40 MDR TB patients were included. The patients' mean age was 36.65 ± 11.75 years. 65% of the patients had BMI below 18.5 kg/m2. 17.5% of patients had comorbidities. Approximately 45% had successful treatment outcomes. Poor treatment outcome includes loss to follow-up in 22.5% and mortality in 12.5%. We did not find any treatment failure. Conclusion: Treatment success outcomes occurred in less than half of the cases. The main predictors of mortality among MDR-TB patients were the presence of comorbidities like anaemia, baseline leucocytosis or lymphopenia, hypoproteinaemia, HIV sero-positivity and smaller baseline BMI.

Drug resistance patterns, treatment outcomes and factors affecting unfavourable treatment outcomes among extensively drug resistant tuberculosis patients in Pakistan; a multicentre record review.

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., <75%). The poor success rate and high mortality are concerning, and requires immediate attention of the program managers and clinicians.

A Rare Case of Multidrug-Resistant Tuberculosis Affecting the Pleura.

The majority of cases with tuberculous pleuritis have negative acid-fast bacilli (AFB) on smear microscopy, making the diagnosis difficult. This case report is based on the successful diagnosis and management of an extra-pulmonary (EP) multidrug-resistant tuberculosis (MDR-TB) patient with a history of lymphoma. Initial tests revealed a right-sided pleural effusion and thickening of the pleura. The closed pleural biopsy, pleural fluid histopathology, culture, and drug sensitivity testing (DST) report revealed Mycobacterium tuberculosis with isoniazid and rifampicin resistance. Based on the DST report, the patient was labeled as a case of MDR-TB and successfully managed with an individualized drug-resistant TB (DR-TB) regimen. With initial negative microscopy and GeneXpert MTB/RIF (Sunnyvale, CA: Cepheid Inc.) reports, this case demonstrated that DR-TB could exist even in the absence of risk factors. Furthermore, it also unveils the importance of line probe assays (LPAs) and culture in identifying MDR-TB. Lymphocytic/exudative pleural effusions and pleural biopsy specimens should be subjected early on to investigations like Xpert/MTB RIF, cultures, and genotypic DST to timely diagnose and treat DR-TB.

Pharmacokinetic analysis of linezolid for multidrug resistant tuberculosis at a tertiary care centre in Mumbai, India.

Linezolid is an oxazolidinone used to treat multidrug-resistant tuberculosis (MDR-TB), including in the recently-endorsed shorter 6-month treatment regimens. Due to its narrow therapeutic index, linezolid is often either dose-adjusted or discontinued due to intolerance or toxicity during treatment, and the optimal balance between linezolid efficacy and toxicity remains unclear. India carries a significant burden of MDR-TB cases in the world, but limited information on the pharmacokinetics of linezolid and minimum inhibitory concentration (MIC) distribution is available from Indian MDR-TB patients. We enrolled participants from a tertiary care centre in Mumbai, India, treated for MDR-TB and receiving linezolid daily doses of 600 or 300 mg. Pharmacokinetic visits were scheduled between 1 and 15 months after treatment initiation to undergo intensive or sparse blood sampling. Linezolid concentration versus time data were analysed using non-linear mixed-effects modelling, with simulations to evaluate doses for different scenarios. We enrolled 183 participants (121 females), with a median age of 26 years (interquartile range [IQR] 21-35), weight 55.0 kg (IQR 45.6-65.8), and fat-free mass 38.7 kg (IQR 32.7-46.0). Linezolid pharmacokinetics was best described by a one-compartment model with first-order elimination allometrically scaled by fat-free mass and transit compartment absorption. The typical clearance value was 3.81 L/h. Simulations predicted that treatment with 300 mg daily achieves a high probability of target attainment (PTA) when linezolid MIC was ≤0.25 mg/L (61.5% of participant samples tested), while 600 mg daily would be required if MIC were 0.5 mg/L (29% of samples). While linezolid 300 mg daily is predicted to achieve effective targets for the majority of adults with MDR-TB, it failed to achieve the therapeutic target for 21% participants. A dose of 600 mg had a PTA >90% for all susceptible samples, but with a higher likelihood of exceeding toxicity thresholds (31% vs 9.6%). These data suggest potential benefit to individualized dosing taking host and microbial characteristics into account to improve the likelihood of treatment efficacy while minimizing risk of toxicity from linezolid for the treatment of MDR-TB. Further prospective evaluation in different clinical settings is urgently needed to inform safety and efficacy of these lower doses.

Genomic Analysis of Multidrug-Resistant Mycobacterium tuberculosis Strains From Patients in Kazakhstan.

Tuberculosis (TB) is an infectious disease that remains an essential public health problem in many countries. Despite decreasing numbers of new cases worldwide, the incidence of antibiotic-resistant forms (multidrug resistant and extensively drug-resistant) of TB is increasing. Next-generation sequencing technologies provide a high-throughput approach to identify known and novel potential genetic variants that are associated with drug resistance in Mycobacterium tuberculosis (Mtb). There are limited reports and data related to whole-genome characteristics of drug-resistant Mtb strains circulating in Kazakhstan. Here, we report whole-genome sequencing and analysis results of eight multidrug-resistant strains collected from TB patients in Kazakhstan. Genotyping and validation of all strains by MIRU-VNTR and spoligotyping methodologies revealed that these strains belong to the Beijing family. The spectrum of specific and potentially novel genomic variants (single-nucleotide polymorphisms, insertions, and deletions) related to drug resistance was identified and annotated. ResFinder, CARD, and CASTB antibiotic resistance databases were used for the characterization of genetic variants in genes associated with drug resistance. Our results provide reference data and genomic profiles of multidrug-resistant isolates for further comparative studies and investigations of genetic patterns in drug-resistant Mtb strains.

Epidemiological profile of multidrug-resistant and extensively drug-resistant Mycobacterium Tubrculosis among Congolese patients.

BACKGROUND: There is paucity of data on the prevalence and distribution of multidrug- Resistant-Tuberculosis (MDR-TB) in the Republic of Congo. Among the challenges resides the implementation of a robust TB resistance diagnostic program using molecular tools. In resource limited settings there is a need to gather data to enable prioritization of actions. The objective of this study was is to implement molecular tools as a best of diagnosing MDR and XDR-TB among presumptive tuberculosis patients referred to reference hospital of Makelekele in Brazzaville, Republic of the Congo. METHODS: We have conducted a cross-sectional study, including a total of 92 presumptive pulmonary tuberculosis patients and who had never received treatment recruited at the reference hospital of Makelekele from October 2018 to October 2019. The socio-demographic and clinical data were collected as well as sputum samples. Rifampicin resistance was investigated using Xpert (Cepheid) and second-line TB drugs Susceptibility testing were performed by the Brucker HAIN Line Probe Assay (GenoType MTBDRsl VER 2.0 assay) method. RESULTS: From the 92 recruited patients, 57 (62%) were found positive for the Mycobacterium tuberculosis complex. The prevalence of rifampicin-resistant tuberculosis (RR-TB) was 9.8% (9/92) and importantly 2.2% were pre-XDR/XDR. CONCLUSION: This study showed a high rate of rifampicin resistance and the presence of extensively drug-resistant tuberculosis in the study area in new patients. This study highlights the need for further studies of TB drug resistance in the country.

Rifampicin-Monoresistant Tuberculosis Is Not the Same as Multidrug-Resistant Tuberculosis: a Descriptive Study from Khayelitsha, South Africa.

Rifampin monoresistance (RMR; rifampin resistance and isoniazid susceptibility) accounts for 38% of all rifampin-resistant tuberculosis (RR-TB) in South Africa and is increasing. We aimed to compare RMR-TB with multidrug-resistant TB (MDR-TB) in a setting with high TB, RR-TB, and HIV burdens. Patient-level clinical data and stored RR Mycobacterium tuberculosis isolates from 2008 to 2017 with available whole-genome sequencing (WGS) data were used to describe risk factors associated with RMR-TB and to compare RR-conferring mutations between RMR-TB and MDR-TB. A subset of isolates with particular RR-conferring mutations were subjected to semiquantitative rifampin phenotypic drug susceptibility testing. Among 2,041 routinely diagnosed RR-TB patients, 463 (22.7%) had RMR-TB. HIV-positive individuals (adjusted odds ratio [aOR], 1.4; 95% confidence interval [CI], 1.1 to 1.9) and diagnosis between 2013 and 2017 versus between 2008 and 2012 (aOR, 1.3; 95% CI, 1.1 to 1.7) were associated with RMR-TB. Among 1,119 (54.8%) patients with available WGS data showing RR-TB, significant differences in the distribution of rpoB RR-conferring mutations between RMR and MDR isolates were observed. Mutations associated with high-level RR were more commonly found among MDR isolates (811/889 [90.2%] versus 162/230 [70.4%] among RMR isolates; P < 0.0001). In particular, the rpoB L430P mutation, conferring low-level RR, was identified in 32/230 (13.9%) RMR isolates versus 10/889 (1.1%) in MDR isolates (P < 0.0001). Among 10 isolates with an rpoB L430P mutation, 7 were phenotypically susceptible using the critical concentration of 0.5 µg/ml (range, 0.125 to 1 µg/ml). The majority (215/230 [93.5%]) of RMR isolates showed susceptibility to all other TB drugs, highlighting the potential benefits of WGS for simplified treatment. These data suggest that the evolution of RMR-TB differs from MDR-TB with a potential contribution from HIV infection.

Health-Related Quality of Life in Tuberculosis Patients in Eritrea: Comparison Among Drug-Susceptible and Rifampicin/Multidrug-Resistant Tuberculosis Patients.

BACKGROUND: Despite the negative impact of tuberculosis (TB) on patients' quality of life, TB control programs focus on biological and clinical parameters to manage and monitor TB patients. In our setting, patients' perception of their experience with TB and the impacts of TB on patients' physical, mental, and social wellbeing remain unknown. OBJECTIVE: The objective of this study was to evaluate the health-related quality of life (HRQOL) among rifampicin/multidrug-resistant TB (RR/MDR-TB) in comparison to drug-susceptible TB (DS-TB) patients in Eritrea. METHODS: A cross-sectional study was conducted in RR/MDR-TB and DS-TB patients under treatment. Anonymized data collected using the WHOQOL-BREF questionnaire were analyzed using SPSS version 23. Frequency, mean and standard deviation were used to describe the data. Mean group score comparison and relationship between variables were assessed using t-test. Domain score was calculated with a mean score of items within each domain and scaled positively, a higher (increasing) score denoting a higher quality of life. Internal consistency was measured using Cronbach's alpha and statistical significance was set at p < 0.05. RESULTS: A total of 92 patients (46 RR/MDR-TB and 46 DS-TB) participated in the study. Environmental (40.63 ± 10.72) and physical domains (61.80 ±17.18) were the two most affected domains in RR/MDR-TB and DS-TB patients, respectively. The psychological domain was the least affected domain in RR/MDR-TB (48.28 ± 20.83) and DS-TB patients (76.63 ±15.32). RR/MDR-TB patients had statistically lower mean scores in all domains than DS-TB patients. CONCLUSION: HRQOL was impaired in both groups, but RR/MDR-TB patients had a worse health-related quality of life.

Experiences of introducing new drugs for drug-resistant TB at the ALERT Hospital, Addis Ababa, Ethiopia, 2017-2019.

BACKGROUND: Drug-resistant TB (DR-TB) remains a major public health concern. DR-TB patient data from ALERT (All Africa Leprosy, Tuberculosis and Rehabilitation Training Centre) Hospital, Addis Ababa, Ethiopia, who received bedaquiline (BDQ) and/or delamanid (DLM) containing regimens were analysed. RESULTS: From 2017 to 2019, 51 DR-TB patients were enrolled. Of 33 patients, 31 (93.9%) had culture converted at 6 months. Of those with final outcomes, 77% (n = 10) were cured. Thirty (58.8%) developed adverse events, the most frequent of which were gastrointestinal disorders (70%), haematological disorders (16.7%) and QTc prolongation (16.7%). Twenty patients discontinued the offending drug permanently. CONCLUSION: With close monitoring, introduction of new DR-TB regimens brought good early results, which encouraged wider programmatic implementation in Ethiopia.

CONTEXTE: La TB pharmacorésistante (DR-TB) reste une préoccupation de santé publique majeure. Les données des patients DR-TB de l'hôpital ALERT (All Africa Leprosy, Tuberculosis and Rehabilitation Training Centre, Addis Ababa, Ethiopie) qui ont reçu des protocoles contenant de la bédaquiline et/ou du délamanide ont été analysées. RÉSULTATS: Des 51 patients DR-TB ont été enrôlés de 2017 à 2019, 90 ont eu une conversion de culture à 6 mois, 77% ont été guéris, 30 ont eu des effets secondaires, les plus fréquents étant des troubles gastro-intestinaux (70%), des troubles hématologique (16,7%) et un allongement de QTc (16,7%). Vingt patients ont définitivement arrêté le médicament incriminé. CONCLUSION: Moyennant une surveillance étroite, l'introduction de nouveaux protocoles DR-TB a eu de bons résultats précoces qui encouragent une mise en œuvre programmatique plus large en Ethiopie.