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BackgroundAdverse drug reactions (ADRs) frequently occur in patients using second-line anti-tuberculosis medicine for treatment of multidrug resistant tuberculosis (MDR-TB). ADRs contribute to treatment interruptions which can compromise treatment response and risk acquired drug resistance to critical newer drugs such as bedaquiline, while severe ADRs carry considerable morbidity and mortality. N-acetylcysteine (NAC) has shown promise in reducing ADRs for medications related to TB in case series or randomized controlled trials in other medical conditions, yet evidence is lacking in MDR-TB patients. TB endemic settings have limited capacity to conduct clinical trials. We designed a proof-of-concept clinical trial primarily to explore the preliminary evidence on the protective effect of NAC among people treated for MDR-TB with second-line anti-TB medications.MethodsThis is a proof-of-concept randomized open label clinical trial with 3 treatment arms including a control arm, an interventional arm of NAC 900 mg daily, and an interventional arm of NAC 900 mg twice-daily administered during the intensive phase of MDR-TB treatment. Patients initiating MDR-TB treatment will be enrolled at Kibong'oto National Center of Excellence for MDR-TB in the Kilimanjaro region of Tanzania. The minimum anticipated sample size is 66; with 22 participants in each arm. ADR monitoring will be performed at baseline and daily follow-up over 24 weeks including blood and urine specimen collection for hepatic and renal function and electrolyte abnormalities, and electrocardiogram. Sputum will be collected at baseline and monthly thereafter and cultured for mycobacteria as well as assayed for other molecular targets of Mycobacterium tuberculosis. Adverse drug events will be analysed over time using mixed effect models. Mean differences between arms in change of the ADRs from baseline (with 95% confidence intervals) will be derived from the fitted model.DiscussionGiven that NAC promotes synthesis of glutathione, an intracellular antioxidant that combats the impact of oxidative stress, it may protect against medication induced oxidative damage in organs such as liver, pancreas, kidney, and cells of the immune system. This randomized controlled trial will determine if NAC leads to fewer ADRs, and if this protection is dose dependent. Fewer ADRs among patients treated with MDR-TB may significantly improve treatment outcomes for multidrug regimens that necessitate prolonged treatment durations. Conduct of this trial will set the needed infrastructure for clinical trials.Trial registrationPACTR202007736854169 Registered 03 July 2020.

Rifampin or multidrug-resistant tuberculosis (RR/MDR-TB) treatment has largely transitioned to regimens free of the injectable aminoglycoside component, despite the drug class' purported bactericidal activity early in treatment. We tested whether Mycobacterium tuberculosis killing rates measured by tuberculosis molecular bacterial load assay (TB-MBLA) in sputa correlate with composition of the RR/MDR-TB regimen. Serial sputa were collected from patients with RR/MDR- and drug-sensitive TB at days 0, 3, 7, and 14, and then monthly for 4 months of anti-TB treatment. TB-MBLA was used to quantify viable M. tuberculosis 16S rRNA in sputum for estimation of colony forming units per ml (eCFU/ml). M. tuberculosis killing rates were compared among regimens using nonlinear-mixed-effects modeling of repeated measures. Thirty-seven patients produced 296 serial sputa and received treatment as follows: 13 patients received an injectable bedaquiline-free reference regimen, 9 received an injectable bedaquiline-containing regimen, 8 received an all-oral bedaquiline-based regimen, and 7 patients were treated for drug-sensitive TB with conventional rifampin/isoniazid/pyrazinamide/ethambutol (RHZE). Compared to the adjusted M. tuberculosis killing of -0.17 (95% confidence interval [CI] -0.23 to -0.12) for the injectable bedaquiline-free reference regimen, the killing rates were -0.62 (95% CI -1.05 to -0.20) log10 eCFU/ml for the injectable bedaquiline-containing regimen (P = 0.019), -0.35 (95% CI -0.65 to -0.13) log10 eCFU/ml for the all-oral bedaquiline-based regimen (P = 0.054), and -0.29 (95% CI -0.78 to +0.22) log10 eCFU/ml for the RHZE regimen (P = 0.332). Thus, M. tuberculosis killing rates from sputa were higher among patients who received bedaquiline but were further improved with the addition of an injectable aminoglycoside.

Background and Aims: Stroke is the leading cause of disability and the second most common cause of death after ischemic heart disease worldwide. Understanding predictors of early poststroke mortality provides opportunities for interventions and favorable outcomes. This study aimed to determine the incidence and predictors of 30‐day mortality among patients admitted with the first stroke at referral hospitals in Dodoma. Methods: A prospective longitudinal observational design enrolled patients with acute stroke confirmed by CT scan or MRI admitted at referral hospitals in Dodoma. The National Institute of Health Stroke Scale was used to assess stroke severity at baseline. A comparison of risk factors, clinical profiles, and mortality was done using the Chi‐square test. A logistic regression model was used to determine the predictors of 30‐day mortality in patients with the stroke while the 30‐day probability of survival was estimated using Kaplan−Meier analysis. Results: Out of 226 patients with first‐ever stroke, 121(54%) were males, and the population mean age was 63(15) years. The 140(62%) had Ischemic stroke, and 154(68%) survived at the 30th day. Patients with a history of smoking 2.4 [95% confidence interval (CI) (1.0−5.6), p = 0.048], loss of consciousness 2.7 [95% CI (1.2−6.4; p = 0.019] and unequal pupil size 13.7 [95% CI (4.1−58.1, p < 0.001 were significantly more associated with mortality within 30 days. The median survival was 7 (3−9) days, whereas alcohol drinkers and those aged above 60 years had a shorter time to mortality compared to non‐alcohol drinkers and those aged <60 years. Conclusion: The study showed a high incidence of mortality within 30 days after the first stroke episode, with the highest proportion dying within 7 days of being hospitalized. Advanced age of ≥60 years, smoking, alcohol use, and severe stroke at admission warrant special attention. [ABSTRACT FROM AUTHOR]

Objective: Diabetes mellitus (DM) has been known to compromise tuberculosis (TB) treatment outcomes. Association data are limited for early hyperglycaemia detection and TB treatment outcomes. Thus, we assessed treatment outcomes including time to sputum conversion and death in TB participants with or without hyperglycaemia.Methods: A prospective cohort study recruited TB participants receiving anti-TB treatment at health facilities in Tanzania between October 2019 and September 2020. Hyperglycaemia was defined as having pre-existing DM or pre-treatment random blood glucose of ≥7.8 mmol/L, in combination categorised as impaired glucose regulation (IGR). Those with IGR were further screened for hyperglycaemia severity using glycated haemoglobin. In case of unknown status, participants were tested for HIV. Time to death was determined at 6 months of TB treatment.Results: Of 1344 participants, 187 (13.9%) had IGR, of whom 44 (23.5%) were HIV co-infected. Overall treatment success was 1206 (89.7%), and was similar among participants with or without IGR (p > 0.05). Time to death for participants with and without IGR was 18 versus 28 days (p = 0.870), respectively. Age ≥ 40 years (p = 0.038), bacteriological positive (p = 0.039), HIV (p = 0.009), or recurrent TB (p = 0.017) predicted death or treatment success during TB treatment in adjusted multivariable models.Conclusion: IGR did not influence clinical outcomes in TB patients with or without IGR in a programme of early IGR diagnosis and integration TB, HIV and DM care. Early detection and co-management of multi-morbidities among people diagnosed with TB may reduce likelihood of poor treatment outcomes in a programmatic setting. [ABSTRACT FROM AUTHOR]

Background: Mortality from tuberculosis (TB) sepsis is common among patients living with human immunodeficiency virus (PLHIV). We aimed to detect M. tuberculosis (MTB) and additional sepsis etiologies, and mortality determinants in PLHIV. Methods: This prospective cohort study consented and followed-up PLHIV for 28 days in northern Tanzania. From May through December 2021, patients provided urine and sputum for TB testing in lateral-flow lipoarabinomannan (LF-LAM) and Xpert® MTB/RIF. Bacterial blood culture, cryptococcal antigen, malaria rapid diagnostic, C-reactive-protein (CRP), and international normalized ratio (INR) tests were also performed. Sepsis severity was clinically measured by Karnofsky and modified early warning signs (MEWS) scores. Anti-TB, broad-spectrum antibiotics, and antimalarial and antifungal agents were prescribed in accordance with Tanzania treatment guideline. An independent t-test and Chi-square or Fisher's exact tests compared means and proportions, respectively. P < 0.05 was statistically significant. Results: Among 98 patients, 59 (60.2%) were female. Their mean (standard deviation) age was 44 (12.9) years. TB detection increased from 24 (24.5%) by Xpert® MTB/RIF to 36 (36.7%) when LF-LAM was added. In total, 23 (23.5%) patients had other than TB etiologies of sepsis, including Staphylococcus aureus, Streptococcus pneumoniae, Cryptococcus spp., and Plasmodium spp. Twenty-four (94.4%) of 36 patients with TB had higher CRP (=10 mg/l) compared to 25 (40.3%) non-TB patients (P < 0.001). Nine (9.2%) patients died and almost all had INR =1.8 (n = 8), Karnofsky score <50% (n = 9), MEWS score >6 (n = 8), and malnutrition (n = 9). Conclusions: MTB and other microbes contributed to sepsis in PLHIV. Adding non-TB tests informed clinical decisions. Mortality was predicted by conventional sepsis and severity scoring, malnutrition, and elevated INR. [ABSTRACT FROM AUTHOR]

Objectives: Differences among Mycobacterium tuberculosis complex (MTC) species may predict drug resistance or treatment success. Thus, we optimised and deployed the genotype MTBC assay (gMTBC) to identify MTC to the species level, and then performed comparative genotypic drug‐susceptibility testing to anti‐tuberculosis drugs from direct sputum of patients with presumed multidrug‐resistant tuberculosis (MDR‐TB) by the MTBDRplus/sl reference method. Methods: Patients with positive Xpert® MTB/RIF (Xpert) results were consented to provide early‐morning‐sputum for testing by the gMTBC and the reference MTBDRplus/sl. Chi‐square or Fisher's exact test compared proportions. Modified Poisson regression modelled detection of MTC by gMTBC. Results: Among 73 patients, 53 (73%) were male and had a mean age of 43 (95% CI; 40–45) years. In total, 34 (47%), 36 (49%) and 38 (55%) had positive gMTBC, culture and MTBDR respectively. Forty patients (55%) had low quantity MTC by Xpert, including 31 (78%) with a negative culture. gMTBC was more likely to be positive in patients with chest cavity 4.18 (1.31–13.32, P = 0.016), high‐quantity MTC by Xpert 3.03 (1.35–6.82, P = 0.007) and sputum smear positivity 1.93 (1.19–3.14, P = 0.008). The accuracy of gMTBC in detecting MTC was 95% (95% CI; 86–98; κ = 0.89) compared to MTBDRplus/sl. All M. tuberculosis/canettii identified by gMTB were susceptible to fluoroquinolone and aminoglycosides/capreomycin. Conclusions: The concordance between the gMTBC assay and MTBDRplus/sl in detecting MTC was high but lagged behind the yield of Xpert MTB/RIF. All M. tuberculosis/canettii were susceptible to fluoroquinolones, a core drug in MDR‐TB treatment regimens. [ABSTRACT FROM AUTHOR]

Background: Suboptimal drug exposure in patients with drug-susceptible tuberculosis (DS-TB) can drive treatment failure. Pharmacodynamics (PD) biomarkers such as the plasma TB drug-activity (TDA) assay may guide dose finding studies and predict microbiological outcomes differently than conventional indices., Methods: A study was nested from phase 2b randomized double-blind controlled trial of Tanzanian patients who received a 600 mg, 900 mg, or 1200 mg with a standard dose for DS-TB. Serum at 6 weeks collected over 24-h at 2-h intervals was collected for rifampin area under the concentration-time curve relative to minimum inhibitory concentration (AUC 0-24 /MIC) or peak concentration and MIC (C max /MIC). TDA was the ratio of time-to-positive growth of the patient's Mycobacterium tuberculosis isolates with and without coculture of patient's plasma collected at C max . Spearman's rank correlation (r) between PD parameters and culture convention on both liquid and solid culture media., Results: Among 10 patients, 600 mg (3), 900 mg (3), and 1200 mg (4) of rifampin dosages. The mean ± standard deviation (SD) of AUC 0-24 /MIC for patients on 600 mg was 168 ± 159 mg·h/L, on 900 mg was 169 ± 166 mg·h/L, and on 1200 mg was 308 ± 238 mg·h/L. The mean-TDA (SD) was 2.56 (±0.75), 1.5 (±0.59), and 2.29 (±1.08) for patients on 600 mg, 900 mg, and 1200 mg rifampin doses, respectively. Higher TDA values correlated with faster time to culture convention on both liquid (r = -0.55, P = 0.099) and solid media (r = -0.65, P = 0.04)., Conclusions: TDA and rifampin AUC 0-24 /MIC did not trend as expected with rifampin dose, but TDA better predicted the time to sputum culture conversion. TDA may provide additional discrimination in predicting treatment response for some regimens distinct from plasma exposure relative to MIC or mg/kg dose., Competing Interests: None

Early and accurate diagnosis and rigorous clinical and microbiological monitoring of multidrug-resistant tuberculosis (MDR-TB) treatment can curb morbidity and mortality. While others are still under evaluation, the World Health Organization has recommended few novel molecular methods for MDR-TB diagnosis only. We present current molecular methods for diagnosis and monitoring of MDR-TB treatment in TB-endemic settings. A systematic meta-narrative review was conducted according to the RAMESES recommendations. Electronic databases were searched for relevant articles published in English language from January 2013 to June 2018. Based on predefined criteria, two independent reviewers extracted the key messages from relevant articles. Disagreement between them was resolved through discussion and the involvement of a third reviewer, if needed. Key messages were synthesized to create the meta-narratives for method's accuracy, drug-susceptibility capability, and laboratory infrastructure required. We included 33 articles out of 1213 records retrieved, of which 16 (48%) and 12 (36%) were conducted in high- and low-TB-endemic settings, respectively. Xpert ® MTB/RIF, GenoType MTBDRplus, GenoType MTBDRsl, FlouroType™ MTBDR, TB TaqMan ® array card, and DNA sequencers can accurately guide effective treatment regimens. Molecular bacterial load assay quantifies mycobactericidal impact of these regimens. Although they present inherent advantages compared to the current standard of care, they carry important limitations to implementation and/or scale-up. Therefore, considerable effort must now be directed to implementation and health systems research to maximize these forecasted benefits for individual patient's health outcomes., Competing Interests: None