Diagnosis and Interim Treatment Outcomes from the First Cohort of Multidrug-Resistant Tuberculosis Patients in Tanzania.

Kibong'oto National Tuberculosis Hospital (KNTH), Kilimanjaro, Tanzania. Characterize the diagnostic process and interim treatment outcomes from patients treated for multidrug-resistant tuberculosis (MDR-TB) in Tanzania. A retrospective cohort study was performed among all patients treated at KNTH for pulmonary MDR-TB between November 2009 and September 2011. Sixty-one culture-positive MDR-TB patients initiated therapy, 60 (98%) with a prior history of TB treatment. Forty-one (67%) were male and 9 (14%) were HIV infected with a mean CD4 count of 424 (±106) cells/µl. The median time from specimen collection to MDR-TB diagnosis and from diagnosis to initiation of MDR-TB treatment was 138 days (IQR 101-159) and 131 days (IQR 32-233), respectively. Following treatment initiation four (7%) patients died (all HIV negative), 3 (5%) defaulted, and the remaining 54 (89%) completed the intensive phase. Most adverse drug reactions were mild to moderate and did not require discontinuation of treatment. Median time to culture conversion was 2 months (IQR 1-3) and did not vary by HIV status. In 28 isolates available for additional second-line drug susceptibility testing, fluoroquinolone, aminoglycoside and para-aminosalicylic acid resistance was rare yet ethionamide resistance was present in 9 (32%). The majority of MDR-TB patients from this cohort had survived a prolonged referral process, had multiple episodes of prior TB treatment, but did not have advanced AIDS and converted to culture negative early while completing an intensive inpatient regimen without serious adverse event. Further study is required to determine the clinical impact of second-line drug susceptibility testing and the feasibility of alternatives to prolonged hospitalization

Nontuberculous Mycobacteria in Respiratory Tract Infections, Eastern Asia

To characterize the distribution of nontuberculous mycobacteria (NTM) species isolated from pulmonary samples from persons in Asia and their association with pulmonary infections, we reviewed the literature. Mycobacterium avium complex bacteria were most frequently isolated (13%–81%) and were the most common cause of pulmonary NTM disease (43%–81%). Also pathogenic were rapidly growing mycobacteria (M. chelonae, M. fortuitum, M. abscessus). Among all NTM isolated from pulmonary samples, 31% (582/1,744) were considered clinically relevant according to American Thoracic Society diagnostic criteria. Most patients were male (79%) and had a history of tuberculosis (37%). In Asia, high prevalence of rapidly growing mycobacteria and a history of tuberculosis are distinct characteristics of pulmonary NTM disease. This geographic variation is not well reflected in the American Thoracic Society criteria for NTM infections and could be incorporated in future guidelines

Clinical Relevance of Nontuberculous Mycobacteria, Oman

Little is known about the clinical relevance of nontuberculous mycobacteria (NTM) in the Arabian Peninsula. We assessed the prevalence and studied a random sample of isolates at a reference laboratory in Muscat, Oman. NTM cause disease in this region, and their prevalence has increased

A new trial design to accelerate tuberculosis drug development : the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP)

The PanACEA consortium was funded by the European Developing Country Partnership through grants IP.2007.32011.011, IP.2007.32011.012, and IP.2007.32011.013. PN is supported by the NIAID of the National Institutes of Health (R01AI104589) and the TBTC. KED is supported by NIAID/NID (R01AI111992) and the TBTC.Background The standard 6-month four-drug regimen for the treatment of drug-sensitive tuberculosis has remained unchanged for decades and is inadequate to control the epidemic. Shorter, simpler regimens are urgently needed to defeat what is now the world’s greatest infectious disease killer. Methods We describe the Phase IIC Selection Trial with Extended Post-treatment follow-up (STEP) as a novel hybrid phase II/III trial design to accelerate regimen development. In the Phase IIC STEP trial, the experimental regimen is given for the duration for which it will be studied in phase III (presently 3 or 4 months) and patients are followed for clinical outcomes of treatment failure and relapse for a total of 12 months from randomisation. Operating characteristics of the trial design are explored assuming a classical frequentist framework as well as a Bayesian framework with flat and sceptical priors. A simulation study is conducted using data from the RIFAQUIN phase III trial to illustrate how such a design could be used in practice. Results With 80 patients per arm, and two (2.5 %) unfavourable outcomes in the STEP trial, there is a probability of 0.99 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.91 that the proportion of unfavourable outcomes would be less than 8 %. With six (7.5 %) unfavourable outcomes, there is a probability of 0.82 that the proportion of unfavourable outcomes in a potential phase III trial would be less than 12 % and a probability of 0.41 that it would be less than 8 %. Simulations using data from the RIFAQUIN trial show that a STEP trial with 80 patients per arm would have correctly shown that the Inferior Regimen should not proceed to phase III and would have had a high chance (0.88) of either showing that the Successful Regimen could proceed to phase III or that it might require further optimisation. Conclusions Collection of definitive clinical outcome data in a relatively small number of participants over only 12 months provides valuable information about the likelihood of success in a future phase III trial. We strongly believe that the STEP trial design described herein is an important tool that would allow for more informed decision-making and accelerate regimen development.Publisher PDFPeer reviewe

Activity of the efflux pump inhibitor SILA 421 against drug-resistant tuberculosis

Organosilicon compounds are efflux pump inhibitors with potency as an antituberculosis drug. Of the organisilicon compounds tested, SILA 421 has been shown to have a highest potency as an antituberculosis drug (1). It shares the common pathways for antimycobacterial killing with other efflux pump inhibitors: it revealed direct in vitro activity against M. tuberculosis (1), it has been shown to modify resistance by inhibiting mdr-1 efflux pumps and has shown to enhance killing of M. tuberculosis by macrophages (1)

Effect of seven anti-tuberculosis treatment regimens on sputum microbiome : a retrospective analysis of the HIGHRIF study 2 and PanACEA MAMS-TB clinical trials

Funding: European and Developing Countries Clinical Trials Partnership and German Ministry of Education and Research.Background Respiratory tract microbiota has been described as the gatekeeper for respiratory health. We aimed to assess the impact of standard-of-care and experimental anti-tuberculosis treatment regimens on the respiratory microbiome and implications for treatment outcomes. Methods In this retrospective study, we analysed the sputum microbiome of participants with tuberculosis treated with six experimental regimens versus standard-of-care who were part of the HIGHRIF study 2 (NCT00760149 ) and PanACEA MAMS-TB (NCT01785186 ) clinical trials across a 3-month treatment follow-up period. Samples were from participants in Mbeya, Kilimanjaro, Bagamoyo, and Dar es Salaam, Tanzania. Experimental regimens were composed of different combinations of rifampicin (R), isoniazid (H), pyrazinamide (Z), ethambutol (E), moxifloxacin (M), and a new drug, SQ109 (Q). Reverse transcription was used to create complementary DNA for each participant's total sputum RNA and the V3-V4 region of the 16S rRNA gene was sequenced using the Illumina metagenomic technique. Qiime was used to analyse the amplicon sequence variants and estimate alpha diversity. Descriptive statistics were applied to assess differences in alpha diversity pre-treatment and post-treatment initiation and the effect of each treatment regimen. Findings Sequence data were obtained from 397 pre-treatment and post-treatment samples taken between Sept 26, 2008, and June 30, 2015, across seven treatment regimens. Pre-treatment microbiome (206 genera) was dominated by Firmicutes (2860 [44%] of 6500 amplicon sequence variants [ASVs]) at the phylum level and Streptococcus (2340 [36%] ASVs) at the genus level. Two regimens had a significant depressing effect on the microbiome after 2 weeks of treatment, HR20mg/kgZM (Shannon diversity index p=0·0041) and HR35mg/kgZE (p=0·027). Gram-negative bacteria were the most sensitive to bactericidal activity of treatment with the highest number of species suppressed being under the moxifloxacin regimen. By week 12 after treatment initiation, microbiomes had recovered to pre-treatment level except for the HR35mg/kgZE regimen and for genus Mycobacterium, which did not show recovery across all regimens. Tuberculosis culture conversion to negative by week 8 of treatment was associated with clearance of genus Neisseria, with a 98% reduction of the pre-treatment level. Interpretation HR20mg/kgZM was effective against tuberculosis without limiting microbiome recovery, which implies a shorter efficacious anti-tuberculosis regimen with improved treatment outcomes might be achieved without harming the commensal microbiota.Publisher PDFPeer reviewe

Protocol for a feasibility randomized controlled trial to evaluate the efficacy, safety and tolerability of N-acetylcysteine in reducing adverse drug reactions among adults treated for multidrug-resistant tuberculosis in Tanzania

Funding: This study receives financial supports from the European and Developed Countries Clinical Trials Partnership (EDCTP2) program supported by the European Union project through the Senior Fellowship Scheme TMA1463 awarded to Stellah G Mpagama.Background Adverse 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. Methods This 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. Discussion Given 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.Publisher PDFPeer reviewe

Greater early bactericidal activity at higher rifampicin doses revealed by modeling and clinical trial simulations

This work was supported by the Swedish Research Council (grant 521-2011-3442 to R. J. S. and U. S. H. S.), the Innovative Medicines Initiative Joint Undertaking (award 115337, with contribution from the European Union’s Seventh Framework Programme [FP7/2007–2013] and the European Federation of Pharmaceutical Industries and Associations [in-kind contribution]), the European and Developing Countries Clinical Trials Partnership (awards IP.2007.32011.011, IP.2007.32011.012, and IP.2007.32011.013), the Netherlands-African Partnership for Capacity Development and Clinical Interventions Against Poverty-Related Diseases, and the Bill and Melinda Gates Foundation.Background The currently recommended rifampicin dose (10 mg/kg) for treating tuberculosis is suboptimal. The PanACEA HIGHRIF1 trial evaluated the pharmacokinetics and early bactericidal activity of rifampicin doses of up to 40 mg/kg. Conventional statistical analyses revealed no significant exposure-response relationship. Our objectives were to explore the exposure-response relationship for high-dose rifampicin by using pharmacokinetic-pharmacodynamic modeling and to predict the early bactericidal activity of 50 mg/kg rifampicin. Methods Data included time to Mycobacterium tuberculosis positivity of liquid cultures of sputum specimens from 83 patients with tuberculosis who were treated with 10 mg/kg rifampicin (n = 8; reference arm) or 20, 25, 30, 35, or 40 mg/kg rifampicin (n = 15/arm) for 7 days. We used a semimechanistic time-to-event approach to model the time-to-positivity data. Rifampicin exposure and baseline time to culture positivity were explored as covariates. Results The baseline time to culture positivity was a significant covariate on the predicted initial bacterial load, and rifampicin exposure was a significant covariate on the bacterial kill rate in sputum resulting in increased early bactericidal activity. The 90% prediction interval for the predicted median day 7 increase in time to positivity for 50 mg/kg rifampicin was 7.25–10.3 days. Conclusions A significant exposure-response relationship was found between rifampicin exposure and early bactericidal activity. Clinical trial simulations showed greater early bactericidal activity for 50 mg/kg rifampicin.PostprintPeer reviewe

Clinical Relevance of Nontuberculous Mycobacteria, Oman

Little is known about the clinical relevance of nontuberculous mycobacteria (NTM) in the Arabian Peninsula. We assessed the prevalence and studied a random sample of isolates at a reference laboratory in Muscat, Oman. NTM cause disease in this region, and their prevalence has increased

Drug interaction potential of high-dose rifampicin in patients with pulmonary tuberculosis

Accumulating evidence supports the use of higher doses of rifampicin for tuberculosis (TB) treatment. Rifampicin is a potent inducer of metabolic enzymes and drug transporters, resulting in clinically relevant drug interactions. To assess the drug interaction potential of higher doses of rifampicin, we compared the effect of high-dose rifampicin (40 mg/kg daily, RIF40) and standard-dose rifampicin (10 mg/kg daily, RIF10) on the activities of major cytochrome P450 (CYP) enzymes and P-glycoprotein (P-gp). In this open-label, single-arm, two-period, fixed-order phenotyping cocktail study, adult participants with pulmonary TB received RIF10 (days 1-15), followed by RIF40 (days 16-30). A single dose of selective substrates (probe drugs) was administered orally on days 15 and 30: caffeine (CYP1A2), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), midazolam (CYP3A), and digoxin (P-gp). Intensive pharmacokinetic blood sampling was performed over 24 hours after probe drug intake. In all, 25 participants completed the study. Geometric mean ratios (90% confidence interval) of the total exposure (area under the concentration versus time curve, RIF40 versus RIF10) for each of the probe drugs were as follows: caffeine, 105% (96%-115%); tolbutamide, 80% (74%-86%); omeprazole, 55% (47%-65%); dextromethorphan, 77% (68%-86%); midazolam, 62% (49%-78%), and 117% (105%-130%) for digoxin. In summary, high-dose rifampicin resulted in no additional effect on CYP1A2, mild additional induction of CYP2C9, CYP2C19, CYP2D6, and CYP3A, and marginal inhibition of P-gp. Existing recommendations on managing drug interactions with rifampicin can remain unchanged for the majority of co-administered drugs when using high-dose rifampicin. Clinical Trials registration number NCT04525235.</p