N-Acyl phenothiazines as mycobacterial ATP synthase inhibitors: Rational design, synthesis and in vitro evaluation against drug sensitive, RR and MDR-TB.

The mycobacterial F-ATP synthase is responsible for the optimal growth, metabolism and viability of Mycobacteria, establishing it as a validated target for the development of anti-TB therapeutics. Herein, we report the discovery of an N-acyl phenothiazine derivative, termed PT6, targeting the mycobacterial F-ATP synthase. PT6 is bactericidal and active against the drug sensitive, Rifampicin-resistant as well as Multidrug-resistant tuberculosis strains. Compound PT6 showed noteworthy inhibition of F-ATP synthesis, exhibiting an IC50 of 0.788 µM in M. smegmatis IMVs and was observed that it could deplete intracellular ATP levels, exhibiting an IC50 of 30 µM. PT6 displayed a high selectivity towards mycobacterial ATP synthase compared to mitochondrial ATP synthase. Compound PT6 showed a minor synergistic effect in combination with Rifampicin and Isoniazid. PT6 demonstrated null cytotoxicity as confirmed by assessing its toxicity against VERO cell lines. Further, the binding mechanism and the activity profile of PT6 were validated by employing in silico techniques such as molecular docking, Prime MM/GBSA, DFT and ADMET analysis. These results suggest that PT6 presents an attractive lead for the discovery of a novel class of mycobacterial F-ATP synthase inhibitors.

Effectiveness, cost, and safety of four regimens recommended by WHO for RR/MDR-TB treatment: a cohort study in Eastern China.

BACKGROUND: To compare the effectiveness, cost, and safety of four regimens recommended by the World Health Organization (WHO) for rifampicin resistance/multidrug-resistance tuberculosis (RR/MDR-TB) Treatment in Eastern China. METHODS: We performed a cohort study among patients with RR/MDR between 2020 and 2022 in Jiangsu Province. The treatment success rate, cost, and drug adverse reaction rate were compared. RESULTS: Between 2020 and 2022, 253 RR/MDR-TB patients were enrolled in the study. 37 (14.62%), 76 (30.04%), 74 (29.25%), and 66 (26.09%) patients had the short-term regimens, the new long-term oral regimens, the new long-term injectable regimens, and the traditional long-term regimens, respectively. The treatment success rate was the highest among patients treated with the short-term regimen (75.68%) and was the lowest among patients treated with the traditional long-term regimens (60.61%). The estimated mean cost per favorable outcome was 142.61 thousand Chinese Yuan (CNY), and the short-term regimens showed the lowest cost in the four regimes (88.51 thousand CNY vs. 174.24 thousand CNY, 144.00 thousand CNY, and 134.98 thousand CNY). Incremental cost-effectiveness ratios of the short-term regimens, the new long-term oral regimen, and the new long-term injectable regimens were -3083.04, 6040.09, and 819.68 CNY compared to the traditional long-term regimens. CONCLUSIONS: For RR/MDR-TB patients in China who meet the criteria for short-term regimens, the short-term regimens were proven to be the most cost-effective of the four regimens recommended by WHO. For RR/MDR-TB patients in China who don't meet the criteria for short-term regimens, the new long-term injectable regimens are more cost-effective than the remaining two regimens.

This is the first study to evaluate the effectiveness, cost, and safety of four regimens recommended by the WHO for RR/MDR-TB treatment in China.For RR/MDR-TB patients in China who meet the criteria for the short-term regimens, the short-term regimens were proven to be the most cost-effective of the four regimens recommended by WHO.

Descriptors of multidrug-resistant TB deaths in Ethiopia.

Deaths related to multidrug-resistant TB among patients who had received a second-line anti-TB drugs in Ethiopia were analysed. Respectively 38/704 (5.4%) and 44/995 (4.4%) deaths were identified in two cohorts (2015 and 2022). In the 2015 cohort, severe malnutrition was less prevalent, previous treatment rates were three times higher, hypokalaemia was more frequent, and the use of the Xpert® MTB/RIF assay, respiratory failure and severe anaemia/pancytopenia were less common than in the 2022 cohort. We observed that there were variations in adverse events when different treatment regimens were used over different time periods. To ensure proper patient care, correct guidance must be consistently implemented.

Les décès liés à la TB multirésistante chez les patients ayant reçu des médicaments antituberculeux de seconde ligne en Éthiopie ont été analysés. Respectivement 38/704 (5,4%) et 44/995 (4,4%) décès ont été identifiés dans deux cohortes (2015 et 2022). Dans la cohorte 2015, la malnutrition sévère était moins fréquente, les taux de traitement antérieur étaient trois fois plus élevés, l'hypokaliémie était plus fréquente, et l'utilisation du test Xpert® MTB/RIF, l'insuffisance respiratoire et l'anémie/pancytopénie sévère étaient moins fréquentes que dans la cohorte 2022. Nous avons observé des variations dans les effets indésirables lorsque différents schémas thérapeutiques étaient utilisés sur différentes périodes. Pour garantir des soins adéquats aux patients, des consignes appropriées doivent être appliquées de manière régulière.

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

Purpose: The emergence of drug-resistant tuberculosis (DR-TB) represents a threat to the control of tuberculosis. This study aimed to estimate the patterns and trends of DR-TB in patients with suspected DR-TB. In addition, risk factors for multidrug-resistant tuberculosis (MDR-TB) were identified among suspected DR-TB patients in Dalian, China. Patients and Methods: A total of 5661 patients with suspected DR-TB from Jan 1, 2013 to Dec 31, 2020 were included in the final analysis. The resistance pattern of all resistant strains was determined by drug susceptibility testing (DST) using the conventional Lowenstein-Jensen Proportion Method (LJ). DR-TB trends were estimated from 2013 to 2020. During the research period, the chi-square test was employed to analyze the significance of linear drug-resistance trends across time. Bivariate and multivariate logistic regression were performed to assess factors associated with MDR-TB. Results: From 2013 to 2020, the resistance rates of rifampicin (RFP) and isoniazid (INH) decreased significantly, whereas the resistance rates of ethambutol (EMB) and streptomycin (SM) increased in patients with suspected DR-TB. From 2013 to 2020, the prevalence of DR-TB decreased in all patients from 34.71% to 28.01% with an average annual decrease of 3.02%. Among new cases, from 2013 to 2020, the prevalence of DR-TB (from 26.67% to 24.75%), RFP-resistant TB (RR-TB) (from 15.09% to 3.00%) and MDR-TB (from 6.08% to 2.62%) showed a significant downward trend. Among patients with a previous treatment history, DR-TB (from 54.70% to 37.50%), RR-TB (from 44.16% to 11.49%) and MDR-TB (from 26.90% to 10.34%) showed a significant downward trend from 2013 to 2020. Males (AOR 1.28, 95% CI 1.035-1.585), patients 45 to 64 years of age (AOR 1.75, 95% CI 1.342-2.284), patients 65 years and older (AOR 1.65, 95% CI 1.293-2.104), rural residents (AOR 1.24, 95% CI 1.014-1.519) and a previous treatment history (AOR 3.94, 95% CI 3.275-4.741) were risk factors for MDR-TB. Conclusion: The prevalence of DR-TB, RR-TB and MDR-TB was significantly reduced from 2013 to 2020. Considerable progress has been made in the prevention and treatment of DR-TB during this period. However, the increasing rate of drug resistance in EMB and SM should be taken seriously. Suspected DR-TB patients who are male, older than 45 years of age, live in rural areas, and have a history of TB treatment should be given priority by health care providers.

Discordance of the Repeat GeneXpert MTB/RIF Test for Rifampicin Resistance Detection Among Patients Initiating MDR-TB Treatment in Uganda.

BACKGROUND: The Global Laboratory Initiative (GLI) guidelines recommend repeat for GeneXpertMTB/RIF (XpertMTB/RIF) in patients with a low pretest probability of rifampicin resistance (RR). METHODS: This was a cross-sectional study using results of sputum specimens collected from participants screened for the STREAM 2 trial. We recruited all patients with XpertMTB/RIF RR-TB detected who were referred for RR/multidrug-resistant (MDR) TB treatment initiation at Mulago National Referral Hospital, Kampala, between September 2017 and October 2019. At baseline, smear microscopy, repeat XpertMTB/RIF, Xpert Ultra, and MTBDRplus assays were done on sputum specimens. Culture-based drug susceptibility testing (DST) was performed on discordant specimens. We analyzed the prevalence and factors associated with discordance between initial and repeat XpertMTB/RIF RR and false XpertMTB/RIF RR. False XpertMTB/RIF RR was defined as no RR detected by any of Xpert Ultra, LPA, or culture DST (reference comparator). RESULTS: A total of 126/130 patients had repeat XpertMTB/RIF results, of whom 97 (77.0%) had M. tuberculosis detected, 81 (83.5%) had RR detected, and 1 (1.0%) had RR indeterminate. The prevalence of discordant XpertMTB/RIF RR was 15/96 (15.6%), whereas false XpertMTB/RIF RR prevalence was 10/96 (10.4%).Low-bacillary load sputum specimens were more likely to have discordant XpertMTB/RIF RR and false XpertMTB/RIF RR results (adjusted odds ratio [aOR], 0.04; 95% CI, 0.00-0.37; P = .01; aOR, 0.02; 95% CI, 0.01-0.35; P = .01, respectively). CONCLUSIONS: Our findings show a high false-positive rifampicin resistance rate in low-TB burden patients, which calls for repeat testing in order to prevent unnecessary prescription of anti-MDR-TB therapy.

Khat Chewing and Clinical Conditions Determine the Epidemiology of Primary Drug Resistance Tuberculosis in Amhara Region of Ethiopia: A Multicenter Study.

BACKGROUND: Rifampicin and/or multidrug-resistant tuberculosis (RR/MDR-TB) remains an uncontrolled public health emergency that has been synergized by the recently increased person-to-person transmission in the community as primary RR/MDR-TB, which is defined as RR/MDR-TB in new TB patients with no prior exposure to anti-TB treatment for more than one month. This study aimed to measure the prevalence and associated factors of primary drug-resistance among drug-resistant tuberculosis patients, as evidenced by the Amhara region treatment initiating centers. METHODS: An institutional-based multicenter cross-sectional study was conducted from September 2010 to December 2017, among 580 RR/MDR-TB patients on the second-line anti-TB drug in the Amhara regional state. Data were collected from patient charts and registration books using a standardized data abstraction sheet. The data were entered using Epi-data 4.2.0.0 and transferred to Stata 14 software for further data management and analysis. A bivariable and multivariable binary logistic model was run subsequently, and finally, a p-value of less than 0.05 with a 95% confidence interval (CI) was used to declare the significance of the explanatory variable. RESULTS: The magnitude of primary drug resistance among drug-resistant tuberculosis patients was 15.69% (95% CI: 12.94, 18.89). Alcohol drinking (adjusted odds ratio [AOR] = 0.31, 95% CI: 0.12-0.82), khat chewing (AOR = 4.43; 95% CI: 1.67-11.76), ambulatory and bedridden functional status (AOR = 0.43; 95% CI: 0.24-0.76) and (AOR = 0.41; 95% CI: 0.19-0.91), respectively, positive sputum smear result (AOR = 0.48; 95% CI: 0.26-0.90), and HIV coinfection (AOR= 2.31; 95% CI: 1.31-4.06) remained statistically significant associated factors of primary RR/MDR-TB. CONCLUSION: Primary drug resistance is a public health problem in the study setting. Different behavioral and clinical conditions were significant factors of primary drug-resistant development. Mitigation strategies targeted on the patient's clinical condition, substance-related behaviors, and universal DST coverage might be very important for early detection and treatment of RR/MDR-TB to prevent community-level transmission.