Multidrug-resistant Tuberculosis Patients Research Articles

Diabetes mellitus affects the treatment outcomes of drug-resistant tuberculosis: a systematic review and meta-analysis

BackgroundBoth tuberculosis (TB) and diabetes mellitus (DM) are major public health problems threatening global health. TB patients with DM have a higher bacterial burden and affect the absorption and metabolism for anti-TB drugs. Drug-resistant TB (DR-TB) with DM make control TB more difficult.MethodsThis study was completed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) guideline. We searched PubMed, Excerpta Medica Database (EMBASE), Web of Science, ScienceDirect and Cochrance Library for literature published in English until July 2022. Papers were limited to those reporting the association between DM and treatment outcomes among DR-TB and multidrug-resistant TB (MDR-TB) patients. The strength of association was presented as odds ratios (ORs) and their 95% confidence intervals (CIs) using the fixed-effects or random-effects models. This study was registered with PROSPERO, number CRD: 42,022,350,214.ResultsA total of twenty-five studies involving 16,905 DR-TB participants were included in the meta-analysis, of which 10,124 (59.89%) participants were MDR-TB patients, and 1,952 (11.54%) had DM history. In DR-TB patients, the pooled OR was 1.56 (95% CI: 1.24–1.96) for unsuccessful outcomes, 0.64 (95% CI: 0.44–0.94) for cured treatment outcomes, 0.63 (95% CI: 0.46–0.86) for completed treatment outcomes, and 1.28 (95% CI: 1.03–1.58) for treatment failure. Among MDR-TB patients, the pooled OR was 1.57 (95% CI: 1.20–2.04) for unsuccessful treatment outcomes, 0.55 (95% CI: 0.35–0.87) for cured treatment outcomes, 0.66 (95% CI: 0.46–0.93) for treatment completed treatment outcomes and 1.37 (95% CI: 1.08–1.75) for treatment failure.ConclusionDM is a risk factor for adverse outcomes of DR-TB or MDR-TB patients. Controlling hyperglycemia may contribute to the favorite prognosis of TB. Our findings support the importance for diagnosing DM in DR-TB /MDR-TB, and it is needed to control glucose and therapeutic monitoring during the treatment of DR-TB /MDR-TB patients.

Study on the resistance of rifampicin-resistant Mycobacterium tuberculosis to anti-tuberculosis drugs in group A

Objective: To summarize the resistance of rifampicin-resistant Mycobacterium tuberculosis to anti-tuberculosis drugs in group A. Methods: In the retrospective study, a total of 1 226 clinical isolates from suspected multidrug-resistant pulmonary tuberculosis patients in Beijing TB control system from 2016 to 2021 were identified as Mycobacterium tuberculosis (MTB) strains by MPB64 antigen detection test. Rifampicin-resistant tuberculosis (RR-TB) strains were screened by the phenotypic drug susceptibility using the proportion method. The drug susceptibilities of Levofloxacin(LFX), Moxifloxacin(MFX), Bedaquiline(BDQ) and Linezolid(LZD)were detected by the phenotypic drug susceptibility with microplate method. The drug resistance rate, drug resistance level and minimum inhibitory concentration (MIC) distribution of four anti-tuberculosis drugs in group A were analyzed. We calculated the demographic distribution of RR-TB, multidrug-resistant tuberculosis(MDR-TB), pre-extensively drug resistant tuberculosis (pre-XDR-TB), extensively drug resistant tuberculosis (XDR-TB) patients and the cross resistance of LFX and MFX, then summarized the drug-resistance spectrum of BDQ-resistant and LZD-resistant strains and the treatment outcome of RR-TB patients. Measurement data were expressed as rate or composition ratio,χ2 test was used between and within groups, and P<0.05 was considered statistically significant. Results: Among the 1 226 suspected multidrug-resistant pulmonary tuberculosis patients, the detection rates of RR/MDR/pre-XDR/XDR-TB patients were 20.8%(255/1 226), 15.2%(186/1 226), 5.7%(70/1 226), 0.5%(6/1 226), respectively. There were statistically significant differences in the distribution of patients with the four types of drug resistance in terms of age and treatment history (χ2=14.95, P=0.020;χ2=15.91, P=0.001). The drug resistance rates of LFX, MFX, BDQ and LZD in RR-TB patients were 27.5% (70/255), 27.5% (70/255), 0.4% (1/255) and 2.4% (6/255), respectively. The MICs of LFX, MFX and LZD-susceptible MTB were mainly at 0.25 mg/L, and the MIC of BDQ-susceptible MTB was mainly concentrated at 0.03 mg/L. 25.1% (64/255) of the RR MTB were resistant to both LFX and MFX, and 6 strains were resistant to LFX or MFX, showing incomplete two-way cross resistance. One BDQ-resistant strain and six LZD-resistant strains were detected. The treatment success rate of RR-TB patients was 74.4% (151/203), and there were statistically significant differences in treatment outcomes between resistant and sensitive patients on the LFX-containing treatment regimen (Fisher's exact test, P=0.012). Conclusions: The prevalence of fluoroquinolones (LFX and MFX) resistance in rifampicin-resistant MTB is very serious. LFX and MFX show incomplete bidirectional cross-resistance. BDQ and LZD have the most promising future in the treatment of MDR-TB. Improve drug-resistance testing will help to further improve the success rate of treatment.

Gene mutation patterns of Mycobacterium tuberculosis complex and associated factors among suspected multidrug-resistant tuberculosis patients in Osun State, South-West, Nigeria

Tuberculosis (TB) drug resistance has become a substantial public health threat, posing a significant challenge to global TB control. Nigeria is one of the eight countries contributing two-thirds of the global TB cases in 2020, with a high rate of MDR/RR-TB. This study was designed to determine MDR-TB prevalence among suspected drug-resistant TB patients, MTBC mutation patterns, and the associated factors of MDR-TB in Osun State. We obtained fresh sputum samples from eligible participants who tested positive for rifampicin resistance on GeneXpert assay for analysis using the MTBDRplus LPA. SPSS version 23 was used for statistical analysis, significance was set at p<0.05. We recorded a prevalence of 58.6 %, 37.1 %, and 2.9 % for MDR-TB, rifampicin and isoniazid mono-resistance. Majority of the MDR-TB cases were males (56.1 %), below 40 years (80.5 %), low-level education (75.6 %), unemployed (75 %), and low-income earners (64.1 %). ‘Previous TB treatment’ had a statistically significant effect on MDR-TB (P<0.001, OR=65.46). Other factors that showed a strong odds ratio but were not statistically significant included: age (OR=2.52, P = 0.09), diabetes (OR=1.99, P = 0.25), smoking history (OR=1.51, P = 0.43) and hypertension (OR=1.34, P = 0.63). There were 67 and 46 reactions of the wild-type and mutant bands for rpoB gene, eight wild-type and five mutant bands for katG gene, and six wild-type and 24 mutant bands for inhA gene. WT8/MUT3 (64.2 %), WT/MUT1 (61.5 %), and MUT1 (80 %) were predominant for rpoB, katG, and inhA genes, respectively, with the occurrence of D516V rpoB gene mutation for the first time in Osun State. There is a need for the reinforcement of the current TB care system, empowerment and monitoring of TB-caregivers for adequate and effective follow-up of TB patients, and more citizens awareness, especially regarding TB/MDR-TB treatments. This is expected to improve the management of MDR-TB patients and mitigate the development and spread of MDR-TB in the community.

Survival status and risk factors for mortality among multidrug-resistant tuberculosis patients in Addis Ababa, Ethiopia: A retrospective follow-up study

BackgroundTuberculosis continues to be a major health concern around the world. It kills an estimated 1.6 million people each year. The World Health Organization (WHO) removed Ethiopia from its list of thirty countries having a high prevalence of MDR/RR-TB in 2021. As a result, the aim of this study was to assess the current context of survival status and risk factors of multidrug-resistant tuberculosis patients in Addis Ababa, Ethiopia, in 2022. MethodsAn institutional-based retrospective cohort study with 245 patients was undertaken using multidrug-resistant tuberculosis patients who were recruited from January 1st, 2018 to December 30th, 2021, in St. Peter's specialized hospital. To find independent predictors of survival status, Cox regression analysis was used. An adjusted hazard ratio with a 95% confidence interval and a p-value of < 0.05 was used to establish association and statistical significance. ResultsThe result of the study revealed that the incidence of mortality in this study was 13.1% (95% CI: 10.3–16.5). Moreover, being male (AOR = 3.7: 95% CI = 1.2, 11.4), old age (AOR = 14: 95% CI = 3.0, 60.4), site of TB (AOR = 0.2: 95% CI = 0.03, 0.6), and presence of comorbidity (AOR = 9.2: 95% CI = 2.4, 35.3), were independent predictors of time to death. ConclusionGenerally, the death rate among research participants was high. Moreover, male gender, old age, site of tuberculosis, and presence of other comorbidity were predictors of mortality among MDR-TB patients.

Transforming growth factor-β, Interleukin-23 and interleukin-1β modulate TH22 response during active multidrug-resistant tuberculosis.

We previously reported that patients with multidrug-resistant tuberculosis (MDR-TB) showed low systemic and Mtb-induced Th22 responses associated to high sputum bacillary load and severe lung lesions suggesting that Th22 response could influence the ability of these patients to control bacillary growth and tissue damage. In MDR-TB patients, the percentage of IL-22+ cells inversely correlates with the proportion of senescent PD-1+ T cells. Herein, we aimed to evaluate the pathways involved on the regulation of systemic and Mtb-induced Th22 response in MDR-TB and fully drug-susceptible TB patients (S-TB) and healthy donors. Our results show that while IL-1β and IL-23 promote Mtb-induced IL-22 secretion and expansion of IL-22+ cells, TGF-β inhibits this response. Systemic and in vitro Mtb-induced Th22 response inversely correlates with TGF-β amounts in plasma and in PBMC cultures respectively. The number of circulating PD-1+ T cells directly correlates with plasmatic TGF-β levels and blockade of PD-1/PD-L1 signalling enhances in vitro Mtb-induced expansion of IL-22+ cells. Thus, TGF-β could also inhibit Th22 response through upregulation of PD-1 expression in T cells. Higher percentage of IL-23+ monocytes was observed in TB patients. In contrast, the proportion of IL-1β+ monocytes was lower in TB patients with bilateral lung cavities (BCC) compared to those patients with unilateral cavities (UCC). Interestingly, TB patients with BCC showed higher plasmatic and Mtb-induced TGF-β secretion than patients with UCC. Thus, high TGF-β secretion and subtle differences in IL-23 and IL-1β expression could diminish systemic and in vitro Mtb-induced Th22 response along disease progression in TB patients.

Assessment of drug-susceptible and multidrug-resistant tuberculosis (MDR-TB) in the Central Region of Somalia: A 3-year retrospective study.

Multidrug-resistant tuberculosis (MDR-TB) remains a public health emergency and a threat globally. Although increasing MDR-TB cases have been recently reported in Somalia, limited information is known. This study aims to determine the prevalence of drug-susceptible and MDR-TB in suspected patients referred to the TB Department in Mudug Hospital, Galkayo, Somalia, and identify potential factors associated with MDR-TB. A 3-year hospital laboratory-based retrospective study was conducted by manually reviewing laboratory records of Mycobacterium tuberculosis specimens and GeneXpert MTB/RIF results from January 2019 to December 2021 at the reference mycobacteria laboratory department in Mudug Hospital. A total of 714 positive GeneXpert-MTB results were identified: 619 (86.7%) were drug susceptible (no Rifampin resistance [RR] detected) and 95 (13.3%) with RR detected or defined as MDR-TB. Most of the MDR-TB patients were males (71.6%, 68/95) and between the ages of 15 to 24 (31.6%, 30/95). Most isolates were collected in 2021 (43.2%, 41/95). Multivariate analyses show no significant difference between patients having MDR-TB and/or drug-susceptible TB for all variables. This study showed an alarming frequency of MDR-TB cases among M. tuberculosis-positive patients at a regional TB reference laboratory in central Somalia.

Prolongation of Acid-Fast Bacilli Sputum Smear Positivity in Patients with Multidrug-Resistant Pulmonary Tuberculosis.

The study sought to determine factors associated with prolonged smear positivity in multidrug-resistant tuberculosis (MDR-TB) patients following appropriate management. Newly diagnosed patients were enrolled between June 2017 and May 2018. Sputum samples were collected for Xpert® MTB/RIF and line probe assays (LiPAs). Microscopic tests were performed at baseline and 4, 8, and 12 weeks post-anti-TB therapy. Of the 200 patients, 114 (57%) were HIV-positive. After 12 weeks of treatment, there was a significant microscopy conversion rate among DS-TB patients compared to MDR-TB patients irrespective of their HIV status (p = 0.0013). All MDR-TB patients who had a baseline smear grade ranging from scanty to +1 converted negative, while 25% ranging from +2 to +3 remained positive until the end of 12 weeks (p = 0.014). Factors associated with smear positivity included age <35 years (p = 0.021), initial CD4+ T-cell count ≥200 cells/mm3 (p = 0.010), and baseline smear grade ≥2+ (p = 0.014). Cox regression showed that only the baseline smear grade ≥2+ was independently associated with prolonged smear positivity in MDR-TB patients (p = 0.011) after adjusting for HIV status, CD4+ T-cell count, and age. Baseline sputum smear grade ≥2+ is a key determinant for prolonged smear positivity beyond 12 weeks of effective anti-TB therapy in MDR-TB patients.

A complementary approach to measure construct validity of WHO QOL BREF in Indian multidrug-resistant tuberculosis (MDR-TB) patients through psychometric property and factor analysis

Background: Multidrug-resistant tuberculosis (MDR TB) affects the physical, psychosocial and inter-relationship structure and thus quality of life (QoL) of an individual. WHO QOL BREF is presumed to capture the QoL construct. This study investigates the diagnostic accuracy and construct of WHO QOL BREF from a psychometric perspective and complements and converges findings through classical test theory. Methods: The instrument validity study was conducted in a district of Central India amongst the microbiologically confirmed MDR TB cohort of year 2017 (n=98). We calculated global and domain-specific Cronbach alpha and Inter-domain Pearson correlations. The dichotomized items were fitted through Rasch model for item endorsement, response pattern and for variation inconsistencies. Item Characteristic Curves and person item maps were also plotted. We performed DIF (Differential Item Functioning) to check the effect of subgroups on underlying traits. This was complimented with an Exploratory Factor Analysis (EFA) using oblique ProMax rotation. The optimum number of factors were identified by Scree plot and parallel analysis approach and the emerging factor structure was compared with the result obtained through the Rasch model. Results: The global Cronbach’s alpha was 0.94 (95% CI 0.92-0.96). Social relationship domain had poor correlations with all three domains (r=0.42, r=0.41 r=0.58), higher beta values and less discrimination. DIF showed a differential response by gender. There was a visual clustering and a non-uniform distribution of items across the perceived QoL. A 3-factor model emerged through EFA and was reframed on the notion of self-concept. Items related to pain, medical aid had significant misfit and weak factor loading while items of sexual activity and social support had relatively poor performance in Infit, Wald, DIF on factor loading parameters. Conclusions: The study indicates the possible deviation of scale from theorized dimensional construct in Indian MDR TB context more with the items of the social relationship domain.

Rv1453 is associated with clofazimine resistance in Mycobacterium tuberculosis.

Clofazimine (CFZ) has been repurposed for treating tuberculosis (TB), especially multidrug-resistant tuberculosis (MDR-TB). However, the mechanisms of resistance to clofazimine are poorly understood. We previously reported a mutation located in the intergenic region of Rv1453 that was linked to resistance to CFZ and demonstrated that an Rv1453 knockout resulted in an increased minimum inhibitory concentration (MIC) of CFZ. The current study aims to go back and describe in detail how the mutation was identified and further explore its association with CFZ resistance by testing additional 30 isolates. We investigated MICs of clofazimine against 100 clinical strains isolated from MDR-TB patients by microplate alamarBlue assay. Whole-genome sequencing (WGS) was performed on 11 clofazimine-resistant and 7 clofazimine-susceptible strains, including H37Rv. Among the 11 clofazimine-resistant mutants subjected to WGS, the rate of mutation in the intergenic region of the Rv1453 gene was 55% (6/11) in clofazimine-resistant strains. Among another 30 clofazimine-resistant clinical isolates, 27 had mutations in the intergenic region of the Rv1453 gene. A mutation in the Rv1453 gene associated with clofazimine resistance was identified, which shed light on the mechanisms of action and resistance of clofazimine. IMPORTANCE Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis, especially the emergence of multidrug-resistant tuberculosis (MDR-TB) brings great distress to humans. Clofazimine (CFZ) plays an important role in the treatment of MDR-TB. To understand the underlying mechanism of clofazimine resistance better, in this study, we review and detail the findings of the mutation of intergenic region of Rv1453 and find additional evidence that this mutation is related to clofazimine resistance in 30 additional isolates. The significance of our research is to contribute to a comprehensive understanding of clofazimine-resistant mechanisms, which is critical for reducing the emergence of resistance and for anti-TB drug discovery.

Selecting an appropriate all-oral short-course regimen for patients with multidrug-resistant or pre-extensive drug-resistant tuberculosis in China: A multicenter prospective cohort study

ObjectivesLong, ineffective, and toxic regimens hinder the treatment of patients with multidrug-resistant tuberculosis (MDR-TB) and pre-extensive drug-resistant tuberculosis (pre-XDR-TB). MethodsWe conducted a multicenter cohort study to prospectively evaluate the safety and efficacy of three 9-month, all-oral, 5-drug regimens. Regimen A (bedaquiline [Bdq]+linezolid [Lzd]+moxifloxacin [Mfx]+cycloserine [Cs]+pyrazinamide [Pza]) and Regimen B (Lzd+Mfx+Cs+clofazimine [Cfz]+Pza) were used to treat MDR-TB patients (Groups A and B, respectively, assigned according to the patient's treatment preference), while Regimen C (Bdq+Lzd+Cs+Cfz+Pza) was used to treat pre-XDR-TB patients (Group C). The primary endpoint was the occurrence of an unfavorable outcome within 12 months of treatment completion, regardless of regimen. ResultsA total of 104 patients (34 in Group A, 46 in Group B, and 24 in Group C), with a median age of 35.5 (29.0-54.0) years, were included in the analysis population. At 12 months after treatment completion, five patients were deemed non-assessable. Of the remaining 99 participants, seven (7.1%) had an unfavorable outcome (including two deaths from any cause, four with treatment failure, and one loss to follow-up) and 92 (92.9%) had a favorable outcome. Culture conversion was achieved in 82.5% (80/97) of participants at month 2 and in 97.9% (94/97) of participants at month 6. Adverse events (AEs) resulting in drug adjustment occurred in 69.2% (72/104) of participants, mainly due to Lzd and Pza use. A QT interval prolongation of ≥ 500 ms occurred in 5.8% (6/104) of participants. ConclusionThe primary outcome of the three tailored, 9-month, all-oral, 5-drug regimens was satisfactory in the vast majority of MDR-TB and pre-XDR-TB patients, with manageable and reversible AEs.

Risk Factor Analysis of Adverse Effects of Kanamycin and Capreomycin on Kidney Function in Multidrug-Resistant TB Patients

Background: Multidrug-Resistant TB treatment's high side effects and long duration are barriers to successful TB therapy. Various side effects such as age, gender, body weight, comorbidities, and drug dose can cause severe side effects, including impaired renal function (nephrotoxic). Objectives: This study aimed to analyze the risk factors of side effects of the failure of kanamycin and capreomycin therapy that can cause impaired renal function in Multidrug-Resistant TB patients. Methods: Data were collected retrospectively by searching and recording the medical records of Multidrug-Resistant TB patients at the Multidrug-Resistant TB Polyclinic. There were 183 patients at Dr Soetomo Hospital who met the inclusion criteria. Results: There was a significant relationship between gender in the kanamycin group and the appearance of side effects of renal impairment (p= 0.035). There was no effect of age, comorbid diseases, body weight, and dose of drug administration on the side effects of kanamycin and capreomycin in treating Multidrug-Resistant TB on impaired renal function (nephrotoxic). However, nephrotoxic side effects in elderly patients were more common in the kanamycin group (p=0.001). Conclusion: Gender affects the side effects of kanamycin and capreomycin in treating Multidrug-Resistant TB in nephrotoxic patients. In addition, stricter supervision of the use of kanamycin in elderly patients (&gt;40 years) to minimize the incidence of side effects of impaired renal function in the treatment of Multidrug-Resistant TB.

Comparative safety of bedaquiline and delamanid in patients with multidrug resistant tuberculosis: A nationwide retrospective cohort study.

Bedaquiline and delamanid were recently approved for multidrug resistant tuberculosis (MDR-TB). Bedaquiline carries a black box warning of increased risk of death compared to the placebo arm, and there is a need to establish the risks of QT prolongation and hepatotoxicity for bedaquiline and delamanid. We retrospectively analyzed data of MDR-TB patients retrieved from the South Korea national health insurance system database (2014-2020) to assess the risks of all-cause death, long QT-related cardiac event, and acute liver injury associated with bedaquiline or delamanid, compared with conventional regimen. Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Stabilized inverse probability of treatment weighting based on propensity score was used to balance characteristics between the treatment groups. Of 1998 patients, 315 (15.8%) and 292 (14.6%) received bedaquiline and delamanid, respectively. Compared with conventional regimen, bedaquiline and delamanid did not increase risk of all-cause death at 24-month (HR 0.73 [95% CI, 0.42-1.27] and 0.89 [0.50-1.60], respectively). Bedaquiline-containing regimen increased risk of acute liver injury (1.76 [1.31-2.36]), while delamanid-containing regimen increased risk of long QT-related cardiac events (2.38 [1.05-3.57]) within 6 months of treatment. This study adds to the emerging evidence refuting the higher mortality rate observed in the bedaquiline trial population. Association between bedaquiline and acute liver injury needs careful interpretation considering for other background hepatotoxic anti-TB drugs. Our finding on delamanid and long QT-related cardiac events suggest careful risk-benefit assessment in patients with pre-existing cardiovascular disease.

Whole-Genome Sequencing to Predict Mycobacterium tuberculosis Drug Resistance: A Retrospective Observational Study in Eastern China.

Pulmonary tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (MTB). Whole-genome sequencing (WGS) holds great promise as an advanced technology for accurately predicting anti-TB drug resistance. The development of a reliable method for detecting drug resistance is crucial in order to standardize anti-TB treatments, enhance patient prognosis, and effectively reduce the risk of transmission. In this study, our primary objective was to explore and determine the potential of WGS for assessing drug resistance based on genetic variants recommended by the World Health Organization (WHO). A total of 1105 MTB strains were selected from samples collected from 2014-2018 in Zhejiang Province, China. Phenotypic drug sensitivity tests (DST) of the anti-TB drugs were conducted for isoniazid (INH), rifampicin (RFP), streptomycin, ethambutol, fluoroquinolones (levofloxacin and moxifloxacin), amikacin, kanamycin, and capreomycin, and the drug-resistance rates were calculated. The clean WGS data of the 1105 strains were acquired and analyzed. The predictive performance of WGS was evaluated by the comparison between genotypic and phenotypic DST results. For all anti-TB drugs, WGS achieved good specificity values (>90%). The sensitivity values for INH and RFP were 91.78% and 82.26%, respectively; however, they were ≤60% for other drugs. The positive predictive values for anti-TB drugs were >80%, except for ethambutol and moxifloxacin, and the negative predictive values were >90% for all drugs. In light of the findings from our study, we draw the conclusion that WGS is a valuable tool for identifying genome-wide variants. Leveraging the genetic variants recommended by the WHO, WGS proves to be effective in detecting resistance to RFP and INH, enabling the identification of multi-drug resistant TB patients. However, it is evident that the genetic variants recommended for predicting resistance to other anti-TB drugs require further optimization and improvement.

Prevalence And Risk Factors Of Multi Drug Resistant Tuberculosis In Children.

To assess the prevalence of drug-resistant tuberculosis and to identify possible risk factors in children. The descriptive, interview-based study was conducted at the Pulmonology outdoor clinic of Jinnah Hospital, Lahore, Pakistan, from January to August 2019, and comprised children aged up to 14 years who were either contacts of a multi-drug resistant tuberculosis patients or non-contacts. Data related to their demography as well as clinical and social characteristics was collected using a questionnaire. Data was analysed using SPSS version 22. Of the 202 subjects, 115(56.9%) were girls and 87(43.1%) were boys. There were 70(34.7%) subjects aged >13 years, followed by 45(22.3%) aged 9-12 years, 44(21.8%) aged £4 years and 43(21.3%) aged 5-8 years. Overall, there were 26(12.9%) cases positive for multi-drug resistant tuberculosis; 16(61.5%) girls and 10(38.5%) boys. In terms of age, 17(65.4) cases were positive in those aged >13 years. Age, previous history of tuberculosis, co- infection with any immune-compromising disease and close contact with patients of multi-drug resistant tuberculosis were significant risk factors identified. The prevalence of multi-drug resistant tuberculosis was high in contacts of multi-drug resistant pulmonary tuberculosis patients, more prevalent in children aged 13-14 years.

Sociodemographic Profile, Clinical Factors and Quality of Life of Multi-Drug Resistant Tuberculosis Patients in Pampanga

Sociodemographic Profile, Clinical Factors and Quality of Life of Multi-Drug Resistant Tuberculosis Patients in Pampanga

Discharge Outcomes of Severely Sick Patients Hospitalized with Multidrug-Resistant Tuberculosis, Comorbidities, and Serious Adverse Events in Kyrgyz Republic, 2020-2022.

Patients with multidrug-resistant tuberculosis (MDR-TB) who have comorbidities, complications, and experience serious adverse events (SAEs) are at substantial risk of having unfavorable hospital outcomes. We assessed characteristics and discharge outcomes of 138 MDR-TB patients hospitalized in the National Referral Center of Bishkek, Kyrgyz Republic, from January 2020 to August 2022. The main clinical characteristics included pulmonary complications (23%), malnutrition (33%), severe anemia (17%), diabetes mellitus (13%), viral hepatitis B and C (5%), and HIV infection (3%). Of those patients, 95% were successfully managed and discharged from hospital. Seven patients had unfavorable discharge outcomes (three patients died and four had a worsened clinical condition). Comorbidities (diabetes, and/or HIV), severe anemia, pulmonary complications, cardiovascular disorders, alcohol abuse, and SAEs were associated with unfavorable discharge outcomes. Sixty-five percent of the patients had SAEs, with electrolyte imbalance (25%), gastrointestinal disease (18%), hepatotoxicity (16%), and anemia (14%) being the most frequent. Successful resolution occurred in 91% of patients with SAEs. In summary, our study documented that sick patients who were hospitalized with MDR-TB were well managed and had good hospital discharge outcomes, despite the fact that they had comorbidities, complications, and SAEs. This information should assist in the referral and management of such patients in the future.

Treatment outcomes of multidrug-resistant tuberculosis patients receiving ambulatory treatment in Shenzhen, China: a retrospective cohort study.

WHO recommended multidrug-resistant tuberculosis (MDR-TB) should be treated mainly under ambulatory model, but outcome of ambulatory treatment of MDR-TB in China was little known. The clinical data of 261 MDR-TB patients treated as outpatients in Shenzhen, China during 2010-2015 were collected and analyzed retrospectively. Of 261 MDR-TB patients receiving ambulatory treatment, 71.1% (186/261) achieved treatment success (cured or completed treatment), 0.4% (1/261) died during treatment, 11.5% (30/261) had treatment failure or relapse, 8.0% (21/261) were lost to follow-up, and 8.8% (23/261) were transferred out. The culture conversion rate at 6 months was 85.0%. Although 91.6% (239/261) of patients experienced at least one adverse event (AE), only 2% of AEs caused permanent discontinuation of one or more drugs. Multivariate analysis showed that previous TB treatment, regimens containing capreomycin and resistance to FQs were associated with poor outcomes, while experiencing three or more AEs was associated with good outcomes. Good treatment success rates and early culture conversions were achieved with entirely ambulatory treatment of MDR-TB patients in Shenzhen, supporting WHO recommendations. Advantageous aspects of the local TB control program, including accessible and affordable second-line drugs, patient support, active monitoring and proper management of AEs and well-implemented DOT likely contributed to treatment success rates.

Characterization of Genetic Mutations in Multi-Drug-Resistant Isolates of Mycobacterium tuberculosis Bacilli Conferring Resistance to a Second-Line Anti-tuberculosis Drug.

Multi-drug-resistant tuberculosis (MDR-TB) has become a major public health concern globally. Mutations in first- and second-line drug targets such as katG, inhA, rpoB, rrs, eis, gyrA, and gyrB have been associated with drug resistance. Monitoring predominant mutations in the MDR-TB patient population is essential to monitor and devise future therapeutic regimes. The present study is aimed to characterize genetic mutations in MDR isolates of Mycobacterium tuberculosis (MTB)bacilli conferring resistance to a second-line anti-tuberculosis drug in the Eastern Indian population. This cross-sectional study was conducted in the Department of Microbiology, Indira Gandhi Institute of Medical Sciences, Patna, Bihar, and in the Tuberculosis Demonstration & Training Centre, Agamkuan, Patna. A total of 3270 patients suspected to have MDR-TB were recruited in the study. Two sputum samples, one on the spot, and the other in the morning were collected from each patient and the diagnosis ofrifampicin-sensitive (RS)/rifampicin-resistant (RR/MDR) TB was done by Gene-Xpert test. One hundred fifty RS-TB samples and 150 RR/MDR-TBsamples were considered for line probe assay (LPA). RSsamples were subjected to first-line LPA using Genotype® MTBDR Plus ver 2.0 and RR/MDRsamples were considered for second-line LPA using Genotype®MTBDRslver 2.0. All sputum samples were subjected to sputum smear microscopy using the Ziehl-Neelsen staining method.Statistical analysis was done using Statistical Package for Social Sciences (SPSS) version 26.0 (IBM Corp. Armonk, NY) and R (version 4.1; R Core Team 2021). In the present study, out of 3270 patients, we detected RR/MDR-TB in 235 patients (7.19%),RS-TB in 812 patients (24.83%), the rest of the patients negative for MTB (2223, 67.98%). Out of 150 RR/MDR-TB sputum samples tested, resistance to fluoroquinolone (FQ) was observed in 41 samples. The selected patients had predominantly FQ resistance due to the gyrA gene mutations (97.56%, n=40) compared to the gyrB gene mutations (2.44%, n=1). We observed >60% of the mutations in the gyrA gene in codon 94 (MUT3C (D94G), MUT3A (D94A), and MUT3D (D94H).In addition, we found the mutations MUT1 (A90V) and MUT2 (S91P)in the codons 90 and 91 of the gyrA gene in the considered MTB patient population. The identified genes can be further validated to be considered as therapeutic targets, but more therapeutics and advanced strategies should be applied in the management of MTB.

Risk factors for multidrug-resistant tuberculosis in the Central African Republic: A case-control study

BackgroundThe emergence and spread of multidrug-resistant tuberculosis (MDR-TB) presents a challenge to the "End TB by 2035" strategy. This study aimed to identify the risk factors associated with MDR-TB in patients admitted to the pneumo-physiology clinic of the National University Hospital of Bangui in Central African Republic. MethodsThis was a “retrospective” chart review study. Cases were represented by patients more than 18 years of age treated for MDR-TB and controls were patients with “at least rifampicin-susceptible” TB treated "with first-line anti-TB regimen" and who at the end of treatment were declared cured. The status of “cured” was exclusively applicable to non-MDR TB. Risk factors associated with MDR-TB were identified by multivariate analysis. ResultsWe included 70 cases and 140 controls. The median age was 35 years, IQR (22;46 years). The main factors associated with the occurrence of MDR-TB in multivariate analysis were male gender (0 R = 3.02 [1.89–3.99], p = 0.001), residence in a peri-urban/urban area (0 R = 3.06 [2.21–4.01], p = 0.002), history of previous TB treatment (0 R= 3.99 [2.77–4.25], p < 0.001) and the presence of multidrug-resistant TB in the family (0 R=1.86 [1.27–2.45], p = 0.021). ConclusionThe emergence of MDR-TB can be reduced by implementing appropriate strategies, such as preventive therapy in contacts of MDR-TB patients and detecting and appropriately treating MDR-TB patients to prevent further spread of infection.

Effects of Bedaquiline Combined with Fluoroquinolone and/or Clofazimine on QT Interval in Patients with Multidrug-Resistant Tuberculosis: a Retrospective Study.

With the application of bedaquiline (Bdq), the success rate of multidrug-resistant tuberculosis (MDR-TB) treatment has been significantly improved; however, the cardiac safety of the patients during treatment cannot be ignored. Hence, this study compared the effects of bedaquiline alone and bedaquiline combined with fluoroquinolones (FQs) and/or clofazimine (CFZ) on the QT interval. This single-center retrospective cohort study analyzed the clinical data of MDR-TB patients treated with bedaquiline for 24 weeks from January 2020 to May 2021 in Xi'an Chest Hospital and compared the changes in QTcF between the two groups. Eighty-five patients were included in the study and grouped by types of anti-TB drugs affecting the QT interval they used. Group A included bedaquiline (n = 33), and group B included bedaquiline in combination with fluoroquinolones and/or clofazimine (n = 52). Out of patients with available corrected QT interval by Fridericia's formula (QTcF) data, 2.4% (2/85) experienced a postbaseline QTcF of ≥500 ms, and 24.7% (21/85) had at least one change of QTcF of ≥60 ms from baseline. In group A, 9.1% (3/33) had at least one ΔQTcF of >60 ms, as did 34.6% (18/52) of group B. Multivariate Cox regression analysis showed that the adjusted risk of QT prolongation was 4.82 times higher in group B (95% confidence interval [CI], 1.406 to 16.488). Bedaquiline combined with other anti-TB drugs affecting QT interval significantly increased the incidence of grade 3 or 4 QT prolongation; however, no serious ventricular arrhythmia and permanent drug withdrawal occurred. The use of bedaquiline combined with fluoroquinolone and/or clofazimine is an independent risk factor affecting QT interval. IMPORTANCE Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis. The emergence of MDR-TB is caused by an organism that is resistant to at least isoniazid and rifampin and is currently considered the major challenge for the global control of TB. Bedaquiline is the first new TB drug in 50 years with a unique mechanism of action, strong anti-M. tuberculosis activity. Yet unexplained excess deaths in the bedaquiline arms have been found in some phase II clinical trials; thus, the FDA has issued a "boxed warning." However, the cardiac safety of the patients during treatment cannot be ignored. Accordingly, further investigations are needed to establish whether bedaquiline combined with clofazimine, fluoroquinolones, or anti-TB drugs affecting the QT interval in a long-course or short-course treatment increases the risk of QT prolongation.