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Treatment options for highly drug-resistant tuberculosis are limited. In this study in South Africa, a new agent, pretomanid, was combined with bedaquiline and linezolid for a 26-week course to treat extensively drug-resistant and complicated multidrug-resistant pulmonary TB. Although there were toxic effects, 90% of patients had favorable outcomes.

A randomized trial of bedaquiline–pretomanid–linezolid for highly drug-resistant tuberculosis assessed the use of linezolid at 600 or 1200 mg for 9 or 26 weeks; the 600-mg dose for 26 weeks had a favorable profile.

Tuberculosis kills more people than any other infectious disease. Three pivotal trials testing 4-month regimens failed to meet non-inferiority margins; however, approximately four-fifths of participants were cured. Through a pooled analysis of patient-level data with external validation, we identify populations eligible for 4-month treatment, define phenotypes that are hard to treat and evaluate the impact of adherence and dosing strategy on outcomes. In 3,405 participants included in analyses, baseline smear grade of 3+ relative to <2+, HIV seropositivity and adherence of ≤90% were significant risk factors for unfavorable outcome. Four-month regimens were non-inferior in participants with minimal disease defined by <2+ sputum smear grade or non-cavitary disease. A hard-to-treat phenotype, defined by high smear grades and cavitation, may require durations >6 months to cure all. Regimen duration can be selected in order to improve outcomes, providing a stratified medicine approach as an alternative to the ‘one-size-fits-all’ treatment currently used worldwide. Analysis of tuberculosis drug trials identifies features to stratify patients for longer or shorter treatment duration than the standard of care, in order to improve therapeutic outcomes.

Tuberculosis (TB) is the world’s second leading infectious killer. Cases of multidrug-resistant (MDR-TB) and extremely drug-resistant (XDR-TB) have increased globally. Therapeutic drug monitoring (TDM) remains a standard clinical technique for using plasma drug concentrations to determine dose. For TB patients, TDM provides objective information for the clinician to make informed dosing decisions. Some patients are slow to respond to treatment, and TDM can shorten the time to response and to treatment completion. Normal plasma concentration ranges for the TB drugs have been defined. For practical reasons, only one or two samples are collected post-dose. A 2-h post-dose sample approximates the peak serum drug concentration (C max ) for most TB drugs. Adding a 6-h sample allows the clinician to distinguish between delayed absorption and malabsorption. TDM requires that samples are promptly centrifuged, and that the serum is promptly harvested and frozen. Isoniazid and ethionamide, in particular, are not stable in human serum at room temperature. Rifampicin is stable for more than 6 h under these conditions. Since our 2002 review, several papers regarding TB drug pharmacokinetics, pharmacodynamics, and TDM have been published. Thus, we have better information regarding the concentrations required for effective TB therapy. In vitro and animal model data clearly show concentration responses for most TB drugs. Recent studies emphasize the importance of rifamycins and pyrazinamide as sterilizing agents. A strong argument can be made for maximizing patient exposure to these drugs, short of toxicity. Further, the very concept behind ‘minimal inhibitory concentration’ (MIC) implies that one should achieve concentrations above the minimum in order to maximize response. Some, but not all clinical data are consistent with the utility of this approach. The low ends of the TB drug normal ranges set reasonable ‘floors’ above which plasma concentrations should be maintained. Patients with diabetes and those infected with HIV have a particular risk for poor drug absorption, and for drug–drug interactions. Published guidelines typically describe interactions between two drugs, whereas the clinical situation often is considerably more complex. Under ‘real–life’ circumstances, TDM often is the best available tool for sorting out these multi-drug interactions, and for providing the patient safe and adequate doses. Plasma concentrations cannot explain all of the variability in patient responses to TB treatment, and cannot guarantee patient outcomes. However, combined with clinical and bacteriological data, TDM can be a decisive tool, allowing clinicians to successfully treat even the most complicated TB patients.

For decades, poor treatment options and low-quality evidence plagued care for patients with rifampin-resistant tuberculosis. The advent of new drugs to treat tuberculosis and enhanced funding now permit randomized, controlled trials of shortened-duration, all-oral treatments for rifampin-resistant tuberculosis. We conducted a phase 3, multinational, open-label, randomized, controlled noninferiority trial to compare standard therapy for treatment of fluoroquinolone-susceptible, rifampin-resistant tuberculosis with five 9-month oral regimens that included various combinations of bedaquiline (B), delamanid (D), linezolid (L), levofloxacin (Lfx) or moxifloxacin (M), clofazimine (C), and pyrazinamide (Z). Participants were randomly assigned (with the use of Bayesian response-adaptive randomization) to receive one of five combinations or standard therapy. The primary end point was a favorable outcome at week 73, defined by two negative sputum culture results or favorable bacteriologic, clinical, and radiologic evolution. The noninferiority margin was -12 percentage points. Among the 754 participants who underwent randomization, 699 were included in the modified intention-to-treat analysis, and 562 in the per-protocol analysis. In the modified intention-to-treat analysis, 80.7% of the patients in the standard-therapy group had favorable outcomes. The risk difference between standard therapy and each of the four new regimens that were found to be noninferior in the modified intention-to-treat population was as follows: BCLLfxZ, 9.8 percentage points (95% confidence interval [CI], 0.9 to 18.7); BLMZ, 8.3 percentage points (95% CI, -0.8 to 17.4); BDLLfxZ, 4.6 percentage points (95% CI, -4.9 to 14.1); and DCMZ, 2.5 percentage points (95% CI, -7.5 to 12.5). Differences were similar in the per-protocol population, with the exception of DCMZ, which was not noninferior in that population. The proportion of participants with grade 3 or higher adverse events was similar across the regimens. Grade 3 or higher hepatotoxic events occurred in 11.7% of participants overall and in 7.1% of those receiving standard therapy. Consistent results across all the analyses support the noninferior efficacy of three all-oral shortened regimens for the treatment of rifampin-resistant tuberculosis. (Funded by Unitaid and others; endTB ClinicalTrials.gov number, NCT02754765.).

Globally, there are more than 500,000 new infections with drug-resistant tuberculosis each year. In this trial involving patients with rifampin-resistant tuberculosis, a shorter, more intense course of treatment (9 to 11 months) was found to be noninferior to a standard 20-month regimen.

Despite concerted efforts over the past 2 decades at developing new diagnostics, drugs, and vaccines with expanding pipelines, tuberculosis remains a global emergency. Several novel diagnostic technologies show promise of better point-of-care rapid tests for tuberculosis including nucleic acid–based amplification tests, imaging, and breath analysis of volatile organic compounds. Advances in new and repurposed drugs for use in multi-drug-resistant (MDR) or extensively drug-resistant (XDR) tuberculosis have focused on development of several new drug regimens and their evaluation in clinical trials and now influence World Health Organization guidelines. Since the failure of the MVA85A vaccine 2 years ago, there have been no new tuberculosis vaccine candidates entering clinical testing. The current status quo of the lengthy treatment duration and poor treatment outcomes associated with MDR/XDR tuberculosis and with comorbidity of tuberculosis with human immunodeficiency virus and noncommunicable diseases is unacceptable. New innovations and political and funder commitment for early rapid diagnosis, shortening duration of therapy, improving treatment outcomes, and prevention are urgently required.

In this randomized, controlled trial involving children with household exposure to multidrug-resistant tuberculosis, levofloxacin led to a lower incidence of tuberculosis than placebo, but the difference was not significant.

There are limited therapeutic options for extensively drug-resistant tuberculosis. In this study from South Korea, linezolid was shown to have some activity in treating resistant tuberculosis; however, its use was associated with clinically significant toxicity. Linezolid (Zyvox, Pfizer) was approved in 2000 for drug-resistant, gram-positive bacterial infections. 1 A member of the oxazolidinone antibiotic class, linezolid inhibits protein synthesis by binding the 23S ribosomal RNA (rRNA) portion of the bacterial 50S ribosomal subunit. 2 In adults, linezolid is administered at a dose of 600 mg twice daily, with phase 3 and postmarketing trials showing an acceptable side-effect and adverse-event profile during the FDA-approved 28 days of therapy. 3 Data on longer-term use are limited, but serious neuropathies (e.g., peripheral and optic neuropathies), myelosuppression, and hyperlactatemia have been observed 4 , 5 and are considered to be related to the inhibition . . .

In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed. We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points. Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%). In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).