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BACKGROUND: There are no data comparing the 6–9 month oral three-drug Nix regimen (bedaquiline, pretomanid and linezolid [BPaL]) to conventional regimens containing bedaquiline (B, BDQ) and linezolid (L, LZD).METHODS: Six-month post end-of-treatment outcomes were compared between Nix-TB (n = 109) and 102 prospectively recruited extensively drug-resistant TB patients who received an ˜18-month BDQ-based regimen (median of 8 drugs). A subset of patients received BDQ and LZD (n = 86), and a subgroup of these (n = 75) served as individually matched controls in a pairwise comparison to determine differences in regimen efficacy.RESULTS: Favourable outcomes (%) were significantly better with BPaL than with the B–L-based combination regimen (98/109, 89.9% vs. 56/86, 65.1%; adjusted relative risk ratio [aRRR] 1.35; P < 0.001) and in the matched pairwise analysis (67/75, 89.3% vs. 48/75, 64.0%; aRRR 1.39; P = 0.001), despite significantly higher baseline bacterial load and prior second-line drug exposure in the BPaL cohort. Time to culture conversion (P < 0.001), time to unfavourable outcome (P < 0.01) and time to death (P < 0.03) were significantly better or lower with BPaL than the B-L-based combinations.CONCLUSION: The BPaL regimen (and hence substitution of multiple other drugs by pretomanid and/or higher starting-dose LZD) may improve outcomes in drug-resistant TB patients with poor prognostic features. However, prospective controlled studies are required to definitively answer this question.

STAND was sponsored by TB Alliance with support from the UK Department for International Development, UK Department of Health (London, UK), Bill and Melinda Gates Foundation (Seattle, WA, USA), US Agency for International Development (Washington DC, USA), Directorate General for International Cooperation of the Netherlands (Amsterdam, The Netherlands), Irish Aid (Dublin, Ireland), Australia Department of Foreign Affairs and Trade (Canberra ACT, Australia) and the Federal Ministry for Education and Research of Germany (Berlin, Germany) through KfW (Kreditanstalt fur Wiederaufbau) and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (NIH; Bethesda, MD, USA) under Award Numbers UM1 AI068634 and UM1 AI068636. AMC and AJN are supported by Medical Research Council Grant: MC_UU_12023/27 Tuberculosis Treatment Trials. BACKGROUND: Treatment for TB is lengthy and toxic, and new regimens are needed. METHODS: Participants with pulmonary drug-susceptible TB (DS-TB) were randomised to receive: 200 mg pretomanid (Pa, PMD) daily, 400 mg moxifloxacin (M) and 1500 mg pyrazinamide (Z) for 6 months (6Pa200MZ) or 4 months (4Pa200MZ); 100 mg pretomanid daily for 4 months in the same combination (4Pa100MZ); or standard DS-TB treatment for 6 months. The primary outcome was treatment failure or relapse at 12 months post-randomisation. The non-inferiority margin for between-group differences was 12.0%. Recruitment was paused following three deaths and not resumed. RESULTS: Respectively 4/47 (8.5%), 11/57 (19.3%), 14/52 (26.9%) and 1/53 (1.9%) DS-TB outcomes were unfavourable in patients on 6Pa200MZ, 4Pa200MZ, 4Pa100MZ and controls. There was a 6.6% (95% CI –2.2% to 15.4%) difference per protocol and 9.9% (95%CI –4.1% to 23.9%) modified intention-to-treat difference in unfavourable responses between the control and 6Pa200MZ arms. Grade 3+ adverse events affected 68/203 (33.5%) receiving experimental regimens, and 19/68 (27.9%) on control. Ten of 203 (4.9%) participants on experimental arms and 2/68 (2.9%) controls died. CONCLUSION: PaMZ regimens did not achieve non-inferiority in this under-powered trial. An ongoing evaluation of PMD remains a priority. Publisher PDF

Pretomanid was approved by the U.S. FDA, via the limited population pathway for antibacterial and antifungal drugs, as part of a three-drug regimen with bedaquiline and linezolid for the treatment of extensively drug-resistant and treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. The recommended dose of pretomanid is 200 mg once daily with food. The objective of this work was to retrospectively evaluate this recommended dose by means of exposure-response (E-R) modeling applied to outcomes of both efficacy and safety., Pretomanid was approved by the U.S. FDA, via the limited population pathway for antibacterial and antifungal drugs, as part of a three-drug regimen with bedaquiline and linezolid for the treatment of extensively drug-resistant and treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. The recommended dose of pretomanid is 200 mg once daily with food. The objective of this work was to retrospectively evaluate this recommended dose by means of exposure-response (E-R) modeling applied to outcomes of both efficacy and safety. Cox proportional-hazards modeling was used, with the steady-state average pretomanid concentration as the exposure metric. The efficacy outcome was time to sputum culture conversion (TSCC) to negative. The safety outcomes were times to the first occurrence of adverse events in classes selected from either pretomanid’s investigator brochure or the new drug application (NDA) submission as recognized safety signals for pretomanid based on preclinical as well as clinical experience. Significant E-R relationships were found for TSCC and two adverse-event classes, vomiting (a single preferred term) and gastrointestinal (GI) symptoms (a collection of related terms). No significant E-R relationships were found for the single preferred terms nausea, alanine aminotransferase (ALT) increased, aspartate aminotransferase (AST) increased, and headache and for the collections hepatic disorders, transaminases increased, skin and subcutaneous tissue disorders, and headache. The results suggest that the recommended dose of pretomanid, 200 mg given in the fed state, is appropriate over the range of pharmacokinetic exposures.

Linezolid is increasingly used for the treatment of tuberculosis resistant to first-line agents, but the most effective dosing strategy is yet unknown. From November 2014 to November 2016, we randomized 114 drug-sensitive treatment-naive pulmonary tuberculosis patients from Cape Town, South Africa, to one of six 14-day treatment arms containing linezolid at 300 mg once daily (QD), 300 mg twice daily (BD), 600 mg QD, 600 mg BD, 1,200 mg QD, 1,200 mg three times per week (TIW), or a combination of isoniazid, rifampin, pyrazinamide, and ethambutol., Linezolid is increasingly used for the treatment of tuberculosis resistant to first-line agents, but the most effective dosing strategy is yet unknown. From November 2014 to November 2016, we randomized 114 drug-sensitive treatment-naive pulmonary tuberculosis patients from Cape Town, South Africa, to one of six 14-day treatment arms containing linezolid at 300 mg once daily (QD), 300 mg twice daily (BD), 600 mg QD, 600 mg BD, 1,200 mg QD, 1,200 mg three times per week (TIW), or a combination of isoniazid, rifampin, pyrazinamide, and ethambutol. Sixteen-hour sputum samples were collected overnight, and bactericidal activity was characterized by the daily percentage change in time to positivity (TTP) and the daily rate of change in log10(CFU). We also assessed the safety and pharmacokinetics of the study treatments. We found that bactericidal activity increased with increasing doses of linezolid. Based on the daily percentage change in TTP, activity was highest for 1,200 mg QD (4.5%; 95% Bayesian confidence interval [BCI], 3.3 to 5.6), followed by 600 mg BD (4.1%; BCI, 2.5 to 5.7), 600 mg QD (4.1%; BCI, 2.9 to 5.3), 300 mg BD (3.3%; BCI, 1.9 to 4.7), 300 mg QD (2.3%; BCI, 1.1 to 3.5), and 1,200 mg TIW (2.2%; BCI, 1.1 to 3.3). Similar results were seen with bactericidal activity characterized by the daily rate of change in CFU count. Antimycobacterial activity correlated positively with plasma drug exposure and percentage time over MIC. There were no unexpected adverse events. All linezolid doses showed bactericidal activity. For the same total daily dose, once-daily dosing proved to be at least as effective as a divided twice-daily dose. An intermittent dosing regimen, with 1,200 mg given three times weekly, showed the least activity. (This study has been registered at ClinicalTrials.gov under identifier NCT02279875.)

This work was supported by the Global Alliance for TB Drug Development with support from the Bill and Melinda Gates Foundation, the European and Developing Countries Clinical Trials Partnership (grant IP.2007.32011.011), the US Agency for International Development, the UK Department for International Development, the Directorate General for International Cooperation of the Netherlands, Irish Aid, the Australia Department of Foreign Affairs and Trade, and the National Institutes of Health, AIDS Clinical Trials Group (ACTG). It was further supported by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (UM1AI068634, UM1AI068636, and UM1AI106701) and by NIAID grants to the University of KwaZulu-Natal, South Africa, ACTG site 31422 (1U01AI069469); to the Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, South Africa, ACTG site 12301 (1U01AI069453); and to the Durban International Clinical Trials Unit, South Africa, ACTG site 11201 (1U01AI069426). Background: Drug-induced liver injury (DILI) is a common complication of tuberculosis treatment. We utilised data from the REMoxTB clinical trial to describe the incidence of predisposing factors and the natural history in patients with liver enzyme levels elevated in response to tuberculosis treatment. Methods: Patients received either standard tuberculosis treatment (2EHRZ/4HR), or a 4-month regimen in which moxifloxacin replaced either ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Hepatic enzymes were measured at 0, 2, 4, 8, 12 and 17 weeks and as clinically indicated during reported adverse events. Patients included were those receiving at least one dose of drug and with two or more hepatic enzyme measurements. Results: A total of 1928 patients were included (639 2EHRZ/4HR, 654 2MHRZ/2MHR and 635 2EMRZ/2MR). DILI was defined as peak alanine aminotransferase (ALT) ≥ 5 times the upper limit of normal (5 × ULN) or ALT ≥ 3 × ULN with total bilirubin > 2 × ULN. DILI was identified in 58 of the 1928 (3.0%) patients at a median time of 28 days (interquartile range IQR 14–56). Of 639 (6.4%) patients taking standard tuberculosis therapy, 41 experienced clinically significant enzyme elevations (peak ALT ≥ 3 × ULN). On standard therapy, 21.1% of patients aged >55 years developed a peak ALT/aspartate aminotransferase (AST) ≥ 3 × ULN (p = 0.01) and 15% of HIV-positive patients experienced a peak ALT/AST ≥ 3 × ULN compared to 9% of HIV-negative patients (p = 0.160). The median peak ALT/AST was higher in isoniazid-containing regimens vs no-isoniazid regimens (p < 0.05), and lower in moxifloxacin-containing arms vs no-moxifloxacin arms (p < 0.05). Patients receiving isoniazid reached a peak ALT ≥ 3 × ULN 9.5 days earlier than those on the ethambutol arm (median time of 28 days vs 18.5 days). Of the 67 Asian patients with a peak ALT/AST ≥ 3 × ULN, 57 (85.1%) were on an isoniazid-containing regimen (p = 0.008). Conclusions: Our results provide evidence of the risk of DILI in tuberculosis patients on standard treatment. Older patients on standard therapy, HIV-positive patients, Asian patients and those receiving isoniazid were at higher risk of elevated enzyme levels. Monitoring hepatic enzymes during the first 2 months of standard therapy detected approximately 75% of patients with a peak enzyme elevation ≥3 × ULN, suggesting this should be a standard of care. These results provide evidence for the potential of moxifloxacin in hepatic sparing. Publisher PDF

Concentration-QTc modeling was applied to pretomanid, a new nitroimidazooxazine antituberculosis drug. Data came from eight phase 2 and phase 3 studies., Concentration-QTc modeling was applied to pretomanid, a new nitroimidazooxazine antituberculosis drug. Data came from eight phase 2 and phase 3 studies. Besides pretomanid alone, various combinations with bedaquiline, linezolid, moxifloxacin, and pyrazinamide were considered; special attention was given to the bedaquiline-pretomanid-linezolid (BPaL) regimen that has demonstrated efficacy in the Nix-TB study in subjects with extensively drug-resistant or treatment-intolerant or nonresponsive multidrug-resistant tuberculosis. Three heart rate corrections to QT were considered: Fridericia’s QTcF, Bazett’s QTcB, and a population-specific correction, QTcN. QTc increased with the plasma concentrations of pretomanid, bedaquiline’s M2 metabolite, and moxifloxacin in a manner described by a linear model in which the three slope coefficients were constant across studies, visits within study, and times postdose within visit but where the intercept varied across those dimensions. The intercepts tended to increase on treatment to a plateau after several weeks, a pattern termed the secular trend. The slope terms were similar for the three QTc corrections, but the secular trends differed, suggesting that at least some of the secular trend was due to the elevated heart rates of tuberculosis patients decreasing to normal levels on treatment. For pretomanid 200 mg once a day (QD) alone, a typical steady-state maximum concentration of drug in plasma (Cmax) resulted in a mean change from baseline of QTcN of 9.1 ms, with an upper 90% confidence interval (CI) limit of 10.2 ms. For the BPaL regimen, due to the additional impact of the bedaquiline M2 metabolite, the corresponding values were 13.6 ms and 15.0 ms. The contribution to these values from the secular trend was 4.0 ms.

The bedaquiline regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) in adults is a loading dose of 400 mg QD for 2 weeks followed by 200 mg thrice weekly (TIW) for 22 weeks. Most TB antibiotics administered with bedaquiline are given QD., The bedaquiline regimen for the treatment of multidrug-resistant tuberculosis (MDR-TB) in adults is a loading dose of 400 mg QD for 2 weeks followed by 200 mg thrice weekly (TIW) for 22 weeks. Most TB antibiotics administered with bedaquiline are given QD. Using pharmacokinetic simulations, we explored alternative QD bedaquiline regimens and determined that 200 mg QD for 8 weeks followed by 100 mg QD provides comparable exposures to the approved regimen. This simpler regimen is under clinical evaluation.

The recent approval of new tuberculosis (TB) drugs raises hope for new and more effective anti-tuberculosis treatment regimens. The Global Alliance for TB Drug Development (TB Alliance) is committed to ensuring that new anti-tuberculosis drugs fulfill the needs of patients, their families and the local health services that serve the communities. Here we present highlights of the TB Alliance's pipeline of regimen development, with novel regimens for patients with drug-susceptible, multidrug-resistant and extensively drug-resistant TB. The ongoing clinical trials (STAND, NC-005, Nix-TB and LIN-CL001) are outlined and their rationale and goals presented.

New anti-tuberculosis regimens that are shorter, simpler, and less toxic than those that are currently available are needed as part of the global effort to address the tuberculosis epidemic. We aimed to investigate the bactericidal activity and safety profile of combinations of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide in the first 8 weeks of treatment of pulmonary tuberculosis.; In this multicentre, open-label, partially randomised, phase 2b trial, we prospectively recruited patients with drug-susceptible or rifampicin-resistant pulmonary tuberculosis from seven sites in South Africa, two in Tanzania, and one in Uganda. Patients aged 18 years or older with sputum smear grade 1+ or higher were eligible for enrolment, and a molecular assay (GeneXpert or MTBDRplus) was used to confirm the diagnosis of tuberculosis and to distinguish between drug-susceptible and rifampicin-resistant tuberculosis. Patients who were HIV positive with a baseline CD4 cell count of less than 100 cells per uL were excluded. Patients with drug-susceptible tuberculosis were randomly assigned (1:1:1) using numbered treatment packs with sequential allocation by the pharmacist to receive 56 days of treatment with standard tuberculosis therapy (oral isoniazid, rifampicin, pyrazinamide, and ethambutol; HRZE), or pretomanid (oral 200 mg daily) and pyrazinamide (oral 1500 mg daily) with either oral bedaquiline 400 mg daily on days 1-14 then 200 mg three times per week (B; load; PaZ) or oral bedaquiline 200 mg daily (B; 200; PaZ). Patients with rifampicin-resistant tuberculosis received 56 days of the B; 200; PaZ regimen plus moxifloxacin 400 mg daily (BPaMZ). All treatment groups were open label, and randomisation was not stratified. Patients, trial investigators and staff, pharmacists or dispensers, laboratory staff (with the exception of the mycobacteriology laboratory staff), sponsor staff, and applicable contract research organisations were not masked. The primary efficacy outcome was daily percentage change in time to sputum culture positivity (TTP) in liquid medium over days 0-56 in the drug-susceptible tuberculosis population, based on non-linear mixed-effects regression modelling of log; 10; (TTP) over time. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with ClinicalTrials.gov, NCT02193776, and all patients have completed follow-up.; Between Oct 24, 2014, and Dec 15, 2015, we enrolled 180 patients with drug-susceptible tuberculosis (59 were randomly assigned to B; load; PaZ, 60 to B; 200; PaZ, and 61 to HRZE) and 60 patients with rifampicin-resistant tuberculosis. 57 patients in the B; load; PaZ group, 56 in the B; 200; PaZ group, and 59 in the HRZE group were included in the primary analysis. B; 200; PaZ produced the highest daily percentage change in TTP (5·17% [95% Bayesian credibility interval 4·61-5·77]), followed by B; load; PaZ (4·87% [4·31-5·47]) and HRZE group (4·04% [3·67-4·42]). The bactericidal activity in B; 200; PaZ and B; load; PaZ groups versus that in the HRZE group was significantly different. Higher proportions of patients in the B; load; PaZ (six [10%] of 59) and B; 200; PaZ (five [8%] of 60) groups discontinued the study drug than in the HRZE group (two [3%] of 61) because of adverse events. Liver enzyme elevations were the most common grade 3 or 4 adverse events and resulted in the withdrawal of ten patients (five [8%] in the B; load; PaZ group, three [5%] in the B; 200; PaZ group, and two [3%] in the HRZE group). Serious treatment-related adverse events affected two (3%) patients in the B; load; PaZ group and one (2%) patient in the HRZE group. Seven (4%) patients with drug-susceptible tuberculosis died and four (7%) patients with rifampicin-resistant tuberculosis died. None of the deaths were considered to be related to treatment.; B; 200; PaZ is a promising regimen to treat patients with drug-susceptible tuberculosis. The bactericidal activity of both these regimens suggests that they have the potential to shorten treatment, and the simplified dosing schedule of B; 200; PaZ could improve treatment adherence in the field. However, these findings must be investigated further in a phase 3 trial assessing treatment outcomes.; TB Alliance, UK Department for International Development, Bill & Melinda Gates Foundation, US Agency for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and the Federal Ministry for Education and Research of Germany.

Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.

New regimens to shorten tuberculosis treatment and manage patients with drug-resistant tuberculosis who are infected with HIV are urgently needed. Experimental and clinical evidence suggests that the new drugs bedaquiline (B) and pretomanid (Pa), combined with an existing drug, pyrazinamide (Z), and a repurposed drug, clofazimine (C), may assist treatment shortening of drug-susceptible and drug-resistant tuberculosis.To evaluate the 14-day bactericidal activity of C and Z in monotherapy and in combinations with Pa and B.Groups of 15 treatment-naive, sputum smear-positive patients with pulmonary tuberculosis were randomized to receive combinations of B with Z-C, Pa-Z, Pa-Z-C, and Pa-C, or C or Z alone, or standard combination treatment for 14 days. The primary endpoint was the mean daily fall in log10 Mycobacterium tuberculosis CFU per milliliter sputum estimated by joint nonlinear mixed-effects Bayesian regression modeling.Estimated activities were 0.167 (95% confidence interval [CI], 0.075-0.257) for B-Pa-Z, 0.151 (95% CI, 0.071-0.232) for standard treatment, 0.124 (95% CI, 0.035-0.214) for B-Z-C, 0.115 (95% CI, 0.039-0.189) for B-Pa-Z-C, and 0.076 (95% CI, 0.005-0.145) for B-Pa-C. Z alone had modest activity (0.036; 95% CI, -0.026 to 0.099). C had no activity alone (-0.017; 95% CI, -0.085 to 0.053) or in combinations. Treatments were well tolerated and safe.B-Pa-Z, including two novel agents without resistance in prevalent M. tuberculosis strains, is a potential new tuberculosis treatment regimen. C had no measurable activity in the first 14 days of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01691534).

Bedaquiline is a new antituberculosis agent targeting ATP synthase. This randomized, double-blinded study enrolling 68 sputum smear-positive pulmonary tuberculosis patients evaluated the 14-day early bactericidal activity of daily doses of 100 mg, 200 mg, 300 mg, and 400 mg bedaquiline, preceded by loading doses of 200 mg, 400 mg, 500 mg, and 700 mg, respectively, on the first treatment day and 100 mg, 300 mg, 400 mg, and 500 mg on the second treatment day. All groups showed activity with a mean (standard deviation) daily fall in log 10 CFU over 14 days of 0.040 (0.068), 0.056 (0.051), 0.077 (0.064), and 0.104 (0.077) in the 100-mg, 200-mg, 300-mg, and 400-mg groups, respectively. The linear trend for dose was significant ( P = 0.001), and activity in the 400-mg dose group was greater than that in the 100-mg group ( P = 0.014). All of the bedaquiline groups showed significant bactericidal activity that was continued to the end of the 14-day evaluation period. The finding of a linear trend for dose suggests that the highest dose compatible with safety considerations should be taken forward to longer-term clinical studies.

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Summary Background New drugs, but also shorter, better-tolerated regimens are needed to tackle the high global burden of tuberculosis complicated by drug resistance and retroviral disease. We investigated new multiple-agent combinations over the first 14 days of treatment to assess their suitability for future development. Methods In this prospective, randomised, early bactericidal activity (EBA) study, treatment-naive, drug-susceptible patients with uncomplicated pulmonary tuberculosis were admitted to hospitals in Cape Town, South Africa, between Oct 7, 2010, and Aug 19, 2011. Patients were randomised centrally by computer-generated randomisation sequence to receive bedaquiline, bedaquiline-pyrazinamide, PA-824-pyrazinamide, bedaquiline-PA-824, PA-824-moxifloxacin-pyrazinamide, or unmasked standard antituberculosis treatment as positive control. The primary outcome was the 14-day EBA assessed in a central laboratory from the daily fall in colony forming units (CFU) of M tuberculosis per mL of sputum in daily overnight sputum collections. Bilinear regression curves were fitted for each group separately and groups compared with ANOVA for ranks, followed by pair-wise comparisons adjusted for multiplicity. Clinical staff were partially masked but laboratory personnel were fully masked. This study is registered, NCT01215851. Findings The mean 14-day EBA of PA-824-moxifloxacin-pyrazinamide (n=13; 0·233 [SD 0·128]) was significantly higher than that of bedaquiline (14; 0·061 [0·068]), bedaquiline-pyrazinamide (15; 0·131 [0·102]), bedaquiline-PA-824 (14; 0·114 [0·050]), but not PA-824-pyrazinamide (14; 0·154 [0·040]), and comparable with that of standard treatment (ten; 0·140 [0·094]). Treatments were well tolerated and appeared safe. One patient on PA-824-moxifloxacin-pyrazinamide was withdrawn because of corrected QT interval changes exceeding criteria prespecified in the protocol. Interpretation PA-824-moxifloxacin-pyrazinamide is potentially suitable for treating drug-sensitive and multidrug-resistant tuberculosis. Multiagent EBA studies can contribute to reducing the time needed to develop new antituberculosis regimens. Funding The Global Alliance for TB Drug Development (TB Alliance).

New regimens based on two or more novel agents are sought to shorten or simplify treatment of tuberculosis (TB). Pretomanid (PMD) is a nitroimidazole in phase 3 trials that has significant bactericidal activity alone and in combination with bedaquiline (BDQ) and/or pyrazinamide (PZA). We previously showed that the novel combination of BDQ+PMD plus the oxazolidinone sutezolid (SZD) had sterilizing activity superior to that of the first-line regimen in a murine model of TB. The present experiments compared the activity of different oxazolidinones in combination with BDQ+PMD with or without PZA in the same model. The 3-drug regimen of BDQ+PMD plus linezolid (LZD) had sterilizing activity approaching that of BDQ+PMD+SZD and superior to that of the first-line regimen. The addition of PZA further enhanced activity. Reducing the duration of LZD to 1 month did not significantly affect the activity of the regimen. Halving the LZD dose or replacing LZD with RWJ-416457 modestly reduced activity over the first month but not after 2 months. AZD5847 and tedizolid also increased the bactericidal activity of BDQ+PMD, but they were less effective than the other oxazolidinones. These results provide optimism for safe, short-course oral regimens for drug-resistant TB that may also be superior to the current first-line regimen for drug-susceptible TB.

Introduction and objectives Drug-induced hepatotoxicity is a common complication of tuberculosis treatment.1 Guidelines based on expert opinion are available, but the natural history of liver enzyme measurements over the course of treatment and the most effective approach to monitoring on treatment remains unclear. We investigated the pattern of liver enzyme levels in the REMoxTB trial to describe the magnitude and timing of elevations, along with factors that could influence enzyme patterns, and related this to liver function monitoring. Methods Patients received either standard tuberculosis treatment (2EHRZ/4HR), or a four-month regimen with moxifloxacin substituted for ethambutol (isoniazid arm, 2MHRZ/2MHR) or isoniazid (ethambutol arm, 2EMRZ/2MR). Liver function tests were performed at weeks 0, 2, 4, 8, 12, 17, and during adverse events. The Chi Square or Fisher’s exact test was used for testing proportions among groups, log rank test for comparison of time, and Students t test for comparison of means. Results 639 patients were allocated to receive standard therapy as controls, 654 to the isoniazid arm, and 635 to the ethambutol arm (see Table 1). 60 patients (9.4%) taking standard therapy developed a peak ALT/AST ≥ 3 × ULN at median time 28 days (IQR 14–56). The mean difference in time to reach peak ALT was 7 days between isoniazid-containing regimens and the ethambutol arm, and a higher proportion of Asian patients elevated ALT/AST ≥ 3 × ULN in isoniazid-containing arms (51.0% vs 26.3%, (p Discussion Monitoring liver function routinely for the first two months of HRZE therapy would have detected approximately 75% of patients with a peak enzyme elevation of ≥3 × ULN, and we would recommend this as a standard of care based on these results. However, there is reassurance that over 90% of patients completed therapy without an ALT/AST result ≥3 xULN. HIV positive and Asian patients were at higher risk of liver enzyme elevation and there was a shorter time to peak ALT/AST for those receiving isoniazid. Reference Thompson N, Caplin M, Hamilton M, et al. Anti-tuberculosis medication and the liver: dangers and recommendations in management. Eur Respir J 1995;8:1384–1388.

Supported by the Global Alliance for TB Drug Development with support from the Bill and Melinda Gates Foundation, the European and Developing Countries Clinical Trials Partnership, U.S. Agency for International Development, U.K. Department for International Development, Directorate General for International Cooperation of the Netherlands, Irish Aid, Australia Department of Foreign Affairs and Trade, and National Institutes of Health, AIDS Clinical Trials Group and by grants from the National Institute of Allergy and Infectious Diseases (NIAID) (UM1AI068634, UM1 AI068636, and UM1AI106701) and by NIAID grants to the University of KwaZulu Natal, South Africa, AIDS Clinical Trials Group (ACTG) site 31422 (1U01AI069469); to the Perinatal HIV Research Unit, Chris Hani Baragwanath Hospital, South Africa, ACTG site 12301 (1U01AI069453); and to the Durban International Clinical Trials Unit, South Africa, ACTG site 11201 (1U01AI069426); Bayer Healthcare for the donation of moxifloxacin; and Sanofi for the donation of rifampin. Background: Early-phase and preclinical studies suggest that moxifloxacin-containing regimens could allow for effective 4-month treatment of uncomplicated, smear-positive pulmonary tuberculosis. Methods: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to test the noninferiority of two moxifloxacin-containing regimens as compared with a control regimen. One group of patients received isoniazid, rifampin, pyrazinamide, and ethambutol for 8 weeks, followed by 18 weeks of isoniazid and rifampin (control group). In the second group, we replaced ethambutol with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (isoniazid group), and in the third group, we replaced isoniazid with moxifloxacin for 17 weeks, followed by 9 weeks of placebo (ethambutol group). The primary end point was treatment failure or relapse within 18 months after randomization. Results: Of the 1931 patients who underwent randomization, in the per-protocol analysis, a favorable outcome was reported in fewer patients in the isoniazid group (85%) and the ethambutol group (80%) than in the control group (92%), for a difference favoring the control group of 6.1 percentage points (97.5% confidence interval [CI], 1.7 to 10.5) versus the isoniazid group and 11.4 percentage points (97.5% CI, 6.7 to 16.1) versus the ethambutol group. Results were consistent in the modified intention-to-treat analysis and all sensitivity analyses. The hazard ratios for the time to culture negativity in both solid and liquid mediums for the isoniazid and ethambutol groups, as compared with the control group, ranged from 1.17 to 1.25, indicating a shorter duration, with the lower bounds of the 95% confidence intervals exceeding 1.00 in all cases. There was no significant difference in the incidence of grade 3 or 4 adverse events, with events reported in 127 patients (19%) in the isoniazid group, 111 (17%) in the ethambutol group, and 123 (19%) in the control group. Conclusions: The two moxifloxacin-containing regimens produced a more rapid initial decline in bacterial load, as compared with the control group. However, noninferiority for these regimens was not shown, which indicates that shortening treatment to 4 months was not effective in this setting. (Funded by the Global Alliance for TB Drug Development and others; REMoxTB ClinicalTrials.gov number, NCT00864383.) Publisher PDF

The ultimate goal of evidence-based drug treatment is to produce a desired pharmacological response in a predictable manner and also to minimise adverse effects. This goal requires not only an increased awareness of the need to provide specific dosing recommendations aimed at specific patient groups, but also the implementation of a consistent integrative approach to recognise all factors contributing to the within- and between-subject variability in drug disposition and response. The assessment of new anti-tuberculosis agents and regimens in children requires a specific programme of investigation, and should be included early in human drug evaluation programmes. Appreciation of this principle is an important step forward towards the full integration of children into the tuberculosis research agenda and control programmes. The development of anti-tuberculosis drug formulations and regimens tailored to the requirements of children needs to consider physiological age-related differences for pharmacokinetics and toxicity between adults and children. Research based on these principles will create an evidence base that will inform the appropriate treatment of children with novel agents and regimens and will also inform future research, including the use of chemoprophylaxis and treatment-shortening strategies in children.

Introduction and objectives The current standard treatment for pulmonary tuberculosis (TB) has been in use for several decades and the major risks associated with each of the four drugs (HRZE) are well recognised. However, large prospective trials with regular review and documentation of adverse events while taking HRZE are lacking. We used the incidence of grade 3 and 4 adverse events (AEs) and serious adverse events (SAEs) in patients taking HRZE in the REMoxTB trial to investigate the overall tolerability of the regimen. Methods Grade 3 or 4 AEs and SAEs (of any grade) for patients taking standard TB therapy were analysed. Events were labelled as occurring in the intensive phase, continuation phase or in follow-up (up to 18 months after enrolment). ANOVA and chi-square testing was used to test for significant differences in the incidence of events across the treatment phases. Logistic regression was used to investigate associations between baseline characteristics and on-treatment SAEs and withdrawal from treatment, death or relapse/treatment failure. Results 201 (31.5%) of 639 patients taking standard therapy experienced grade 3/4 AEs or SAEs during treatment. AEs, SAEs, and withdrawals from treatment occurred most frequently in the intensive phase (see Table). Of 116 SAEs reported 84 (72.4%) improved or resolved and were most commonly respiratory (16.4%), gastrointestinal (6.9%), and infection (5.2%) related. There were 10 deaths in follow-up due to suicide, trauma, TB relapse, and acute illness. Logistic regression detected a significant association between on-treatment SAEs and withdrawal (p Discussion AEs and SAEs were predominantly reported in the intensive phase, probably due to a combination of TB and effects of medication. However most deaths occurred in follow-up and were unrelated, emphasising the impact that social circumstances have on TB patients. The lack of significant association between SAEs during treatment and relapse/treatment failure provides reassurance that a complicated treatment period can end with successful treatment of TB. The association between SAEs on treatment and lower weights at baseline and HIV infection reinforces the need to monitor these patients closely.

We developed a pyrazinamidase gene DNA-sequencing method to rapidly identify pyrazinamide resistance-causing mutations in GenoLyse-treated, smear-positive sputum specimens. The sensitivity and specificity were 90.9 and 100%, respectively, compared to those of MGIT drug susceptibility testing, after the exclusion of synonymous mutations and nonsynonymous mutations previously associated with susceptibility to pyrazinamide.