A Phase 2a Study of the Early Bactericidal Activity of Rifampin (RIF) in Combination With Meropenem Plus Amoxicillin/Clavulanate Among Adults With Rifampin-resistant or Rifampin-susceptible Pulmonary Tuberculosis

Brief Summary

Detailed Description

This is a proof-of-concept study to determine whether, in humans infected with M. tuberculosis that is resistant or susceptible to rifampin based on conventional drug susceptibility testing, the combination of meropenem, amoxicillin/clavulanate, and rifampin has activity that is sufficiently promising to proceed with further drug development along these lines. Rifampin has an incompletely understood but critical role in eradication of M. tuberculosis persisters and consequently the shortening of the duration of treatment for 'rifampin susceptible' tuberculosis (TB). For Multi-Drug Resistant (MDR) / Extensively Drug Tuberculosis (XDR) TB, the ability to recoup rifampin's antituberculosis activity through rational combination with a carbapenem and a β-lactamase inhibitor with or without amoxicillin could transform the treatment of this disease. This proof-of-concept study is designed such that a negative outcome would refute the hypothesis that the combination of a carbapenem and amoxicillin/clavulanate with rifampin will have greater activity than either component alone against M. tuberculosis strains having Minimum Inhibitory Concentrations (MIC) in the range considered resistant to rifampin. A positive study outcome would catalyze further research to identify optimal dosing strategies for all regimen components as well as development of carbapenems optimized for TB treatment with respect to targets of activity, stability against hydrolysis, and oral formulation. The study hypothesis cannot be tested satisfactorily in traditional animal models of tuberculosis chemotherapy due to the rapid inactivation of carbapenems (as well as other beta-lactams) by dehydropeptidases that are expressed at high levels in mouse, rabbit, and guinea pig tissues. However, all of the study drugs are Food and Drug Administration (FDA) -approved for various infectious disease indications, are in routine clinical use, and have good safety profiles, such that proceeding with the proposed clinical trial based on in vitro data is justified. This study will also characterize the relationship between meropenem exposure (in combination with amoxicillin/clavulanate) and early bactericidal activity in order to identify the pharmacokinetic drivers of activity and pharmacokinetic targets for desired effects. This will inform the identification of more feasible meropenem dosing strategies in the near term, as well as the dose selection for novel oral carbapenems that may be available for tuberculosis treatment in the future. The proportion of the dosing interval for which free drug concentrations exceed MIC (T\>MIC) is the pharmacokinetic (PK) / pharmacodynamic(PD) parameter most closely correlated with efficacy of carbapenems against common fast-growing bacteria such as Enterobacteriaceae that cause infections for which meropenem is currently approved. A commonly accepted target for efficacy in these infections is 40% T\>MIC, which requires multiple daily doses to achieve. Whether this PK/PD parameter and target value is optimal for carbapenem treatment of infections with M. tuberculosis, which has a much longer doubling time, is unknown. In the trial by Diacon et al, meropenem 2 grams thrice daily plus amoxicillin/clavulanate resulted in a median T\>MIC of 76% \[90% Confidence Interval (CI): 66-93\] whereas faropenem sodium 600 mg thrice daily plus amoxicillin/clavulanate resulted in T\>MIC of 13% (90% CI: 0-33), indicating that if T\>MIC is the single parameter most strongly linked to efficacy in tuberculosis, then the target for bactericidal effect is between 13% and 76%, and lower and/or less frequent doses (or use of oral carbapenems with lower bioavailability) may still have significant efficacy. If T\>MIC is not the efficacy-linked PK/PD parameter, less frequent administration of the same total dose is likely to remain equally effective.

Primary Outcomes

Secondary Outcomes

• Estimate the Antimycobacterial Activity Based on Liquid Culture Time-to-positivity(14 days)
• Distribution of Minimum Inhibitory Concentration (MIC) of Rifampin(14 days)
• Frequency of Grade 2 or Higher Adverse Events(From the time a study participant receives the first dose of study drug through the final study visit, up to 28 days)