Mycobactericidal Effects of Different Regimens Measured by Molecular Bacterial Load Assay among People Treated for Multidrug-Resistant Tuberculosis in Tanzania.

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.

Assessment of training and mentoring for DR-TB care decentralization in Tanzania.

INTRODUCTION: Drug-resistant TB (DR-TB) care shifted from centralized to decentralized care in Tanzania in 2015. This study explored whether DR-TB training and mentoring supported healthcare workers' (HCWs) DR-TB care performance. METHODS: This mixed study assessed HCWs' DR-TB care knowledge, the training quality, and the mentoring around 454 HCWs who were trained across 55 DR-TB sites between January 2016 and December 2017. Pre- and post-training tests, end-of-training evaluation, supervisor's interviews, DR-TB team self-assessment and team focus group discussion were conducted among trained HCWs. Interim and final treatment results of the national central site and the decentralized sites were compared. RESULTS: HCW's knowledge increased for 15-20% between pre-training and post-training. HCWs and supervisors perceived mentoring as most appropriate to further develop their DR-TB competencies. Culture negativity after 6 months of treatment was similar for the decentralized sites compared to the national central site, 81% vs 79%, respectively, whereas decentralized sites had less loss to follow-up (0% versus 3%) and fewer deaths (3% versus 12%). Delays in laboratory results, stigma, and HCWs shortage were reported the main challenges of decentralized care. CONCLUSIONS: Training and mentoring to provide DR-TB care at decentralized sites in Tanzania improved HCWs' knowledge and skills in DR-TB care and supported observed good interim and final patient treatment outcomes despite health system challenges.

Multidrug-resistant tuberculosis infection and disease in children: a review of new and repurposed drugs.

The World Health Organization estimates that 10 million new cases of tuberculosis (TB) occurred worldwide in 2017, of which 600,000 were rifampicin or multidrug-resistant (RR/MDR) TB. Modelling estimates suggest that 32,000 new cases of MDR-TB occur in children annually, but only a fraction of these are correctly diagnosed and treated. Accurately diagnosing TB in children, who usually have paucibacillary disease, and implementing effective TB prevention and treatment programmes in resource-limited settings remain major challenges. In light of the underappreciated RR/MDR-TB burden in children, and the lack of paediatric data on newer drugs for TB prevention and treatment, we present an overview of new and repurposed TB drugs, describing the available evidence for safety and efficacy in children to assist clinical care and decision-making.

Key Issues in the Management of Multi-Drug Resistant Tuberculosis: A Case Report.

BACKGROUND: Global tuberculosis (TB) epidemic is being driven to an increasing extent by the emergence and spread of drug-resistant strains of Mycobacterium tuberculosis complex (MTBC). We present a case of primary multidrug-resistant tuberculosis (MDR-TB), highlighting Macedonian MDR-TB management issues. CASE REPORT: A 39-year old previously healthy Caucasian male, with no previous history of TB or close contact to TB, was admitted in referral TB-hospital due to respiratory bleeding. Chest X-ray revealed opacity with cavernous lesions in the right upper lobe. Sputum samples showed no presence of acid-fast bacilli (AFB) on fluorescence microscopy, but molecular tests (real-time PCR-based assay and multiplex PCR-based reverse hybridisation Line Probe Assay) confirmed the presence of MTBC, also revealing rifampicin and isoniazid resistance and absence of resistance to second-line anti-tubercular drugs. The strain was considered multidrug-resistant, lately confirmed by conventional methods in liquid and solid culture. Following the protocol of the World Health Organization, we started the longer treatment of MDR-TB comprised of at least five effective anti-tubercular drugs. Due to patient's extreme non-adherence, we had to delay and modify the regimen (i.e. omitting parenteral aminoglycoside) and to discharge him from the hospital a month after directly observed therapy (DOT) in negative pressure room. As there is no legal remedy in our country regarding involuntary isolation, our patient continued the regimen under ambulatory control of referral TB-hospital. Ignoring the risk of additional acquisition of drug resistance and prolonged exposure of the community to MDR-TB strain - for which he was repeatedly advised - he decided to cease the therapy six months after beginning. CONCLUSION: The benefit of molecular tests in the early diagnosis of TB and drug resistance is unequivocal for adequate treatment of resistant forms of TB. Whole genome sequencing ensures additional knowledge of circulating strains and their resistance patterns. These are essentials of effective TB control programs and can provide evidence to medical and legal authorities for more active policies of screening, involuntary confinement and compliance with therapy, and alternative modalities for successful treatment, as a part of infection control.

Assessment of GeneXpert GxAlert platform for multi-drug resistant tuberculosis diagnosis and patients' linkage to care in Tanzania.

OBJECTIVE: The gap between patients diagnosed with multi-drug resistant tuberculosis (MDR-TB) and enrolment in treatment is one of the major challenges in tuberculosis control programmes. A 4-year (2013-2016) retrospective review of patients' clinical data and subsequent in-depth interviews with health providers were conducted to assess the effectiveness of the GeneXpert GxAlert platform for MDR-TB diagnosis and its impact on linkage of patients to care in Tanzania. RESULTS: A total of 782 new rifampicin resistant cases were notified, but only 242 (32.3%) were placed in an MDR-TB regimens. The remaining 540 (67.07%) patients were not on treatment, of which 103 patients had complete records on the GxAlert database. Of the 103 patients: 39 were judged as untraceable; 27 died before treatment; 12 were treated with first-line anti-TBs; 9 repeat tests did not show rifampicin resistance; 15 were not on treatment due to communication breakdown, and 1 patient was transferred outside the country. In-depth interviews with health providers suggested that the pre-treatment loss for the MDR-TB patients was primarily attributed to health system and patients themselves. We recommend strengthening the health system by developing and implementing well-defined interventions to ensure all diagnosed MDR-TB patients are accurately reported and timely linked to treatment.