No abstract

Background: The prolonged treatment duration for multidrug-resistant (MDR) tuberculosis (TB) makes dosing linezolid difficult because of adverse effects associated with long-term use. We sought to find the optimal dosing regimen for linezolid given different MIC values. Methods: Pharmacokinetic (PK) data from TB patients were included from Brazil, Georgia, and two U.S. sites. Population PK modeling and simulation were performed. We used fAUC/MIC >119 as the pharmacokinetic/pharmacodynamic (PK/PD) target, and Cmin of 2 and 7 mg/L as thresholds for toxicity. The PK/PD breakpoint was defined as the highest MIC at which the probability of target attainment is >90%. Results: A total of 104 patients with pulmonary TB were included, with a median age and weight of 37 years and 60 kilograms. 81% had drug-resistant TB. The PK data were best described by a one-compartment model. The PK/PD breakpoint was 0.125 mg/L for a total daily dose of 300 mg, while the daily dose of 450-600 mg and 900-1200 mg had PK/PD breakpoints of 0.25 and 0.50 mg/L, respectively. The probability of achieving Cmin ≤2 mg/L was higher when the dose was given at once versus dividing it to two doses. Conclusion: Linezolid daily dose of 300 mg may not be optimal. We predicted excellent and comparable efficacy of linezolid using total daily doses of 900 and 1200 mg for MICs ≤0.5 mg/L, but with a potential for more toxicity compared to 600 mg daily. The increase in Cmin was noticeable when the daily dose was divided and may incur greater toxicity.

Background Bedaquiline and delamanid are newly available drugs for treating multidrug-resistant tuberculosis (MDR TB); however, there is limited data guiding their use and no comparison studies. Methods We conducted a prospective observational study among patients with MDR TB in Georgia receiving a bedaquiline or delamanid-based treatment regimen. Monthly sputum cultures, minimal inhibitory concentration testing, and adverse event monitoring were performed. Primary outcomes were culture conversion rates and clinical outcomes. Targeted maximum likelihood estimation (TMLE) and superlearning were utilized to produce a covariate-adjusted proportion of outcomes for each regimen. Results Among 156 patients with MDR TB, 100 were enrolled and 95 were receiving a bedaquiline (n=64) or delamanid (n=31) based regimen. Most were male (82%) and the median age was 38 years. Rates of previous treatment (56%) and cavitary disease (61%) were high. The most common companion drugs included linezolid, clofazimine, cycloserine and a fluoroquinolone. Median effective drugs received among patients on bedaquiline (4, IQR 4-4) and delamanid (4, IQR 3.5-5) based regimens were similar. Rates of acquired drug resistance were significantly higher among patients receiving delamanid versus bedaquiline (36% vs. 10%, p <0.01). Adjusted rates of sputum culture conversion at two months (67 vs. 47%, p=0.10) and six months (95 vs. 74%, p<0.01) and favorable clinical outcomes (96 vs. 72%, p<0.01) were higher among patients receiving bedaquiline versus delamanid. Conclusions Among patients with MDR TB, bedaquiline-based regimens were associated with higher rates of sputum culture conversion and favorable outcomes and a lower rate of acquired drug resistance versus delamanid-based regimens.

Our results show that internationally recommended MDR-TB treatment regimens were infrequently used and that ART use and viral suppression was well below the target of 90%, reflecting the challenging patient population and the environment in which health care is provided. Urgent improvement of management of patients with TB/HIV in EE, in particular for those with MDR-TB, is needed and includes widespread access to rapid TB diagnostics, better access to and use of second-line TB drugs, timely ART initiation with viral load monitoring, and integration of TB/HIV care.