Meropenem Plus Clavulanate and Rifampin for Treatment of Drug-Resistant TB

Results of a study called in to question the recommendation for meropenem with amoxicillin and clavulanate to be used as a second-line therapy for drug-resistant tuberculosis (TB). These findings were published in the American Journal of Respiratory and Critical Care Medicine.

The COamoxiclav Meropenem Rifampin Antimycobacterial Determination of Efficacy (COMRADE; ClinicalTrials.gov identifier: NCT03174184) study was a phase 2A, randomized clinical trial. Patients (N=60) with drug-resistant pulmonary TB were recruited from a single site in Cape Town, South Africa, between 2017 and 2018. Patients were randomly assigned in a 1:1:1:1 ratio to receive 2-g meropenem 3 times daily (TID) plus 20-mg/kg once daily rifampin (Arm C), 2-g meropenem with 500-mg amoxicillin and 125-mg clavulanate TID (Arm D), 1-g meropenem with 500-mg amoxicillin and 125-mg clavulanate TID (Arm E), or 3-g meropenem with 875-mg amoxicillin and 125-mg clavulanate once daily (Arm F). Safety and 14-day bactericidal activity were assessed.

Patients were aged median 36 (IQR, 29-46) years, 75% were men, 28% were Black, overall BMI was 18.7 (IQR, 17.6-20.4), baseline colony forming units (CFU) were 6.3 (IQR, 5.6-7.1) log₁₀ CFU/mL, 59% had cavitary disease of 4 cm or wider, and 23% were HIV positive. No significant baseline differences were observed between the 4 treatment arms.

Among all patients, the adverse events reported by 1 or more patients included nausea (n=3), elevated alanine aminotransferase or aspartate aminotransferase (n=2), lower back pain (n=2), and headache (n=2). No deaths or grade 4 events were observed.

Systemic exposure to meropenem increased concentrations near-linearly with dosage and was unaffected by combination with rifampin. The median maximum plasma concentration and half-life of meropenem for Arm C was 123 mg/L and 1.15 h, Arm D was 129 mg/L and 1.09 h, Arm E was 66 mg/L and 1.09 h, and Arm F was 174 mg/L and 1.00 h, respectively.

Bacterial activity was statistically related with baseline cavitary disease and CFU. The overall 14-day CFU was 3.0, 1.7, 0.83, and 0.75 log₁₀ CFU/mL and 14-day time to positivity was 0.34, 0.11, 0.094, and 0.12 log₁₀ h for the C, D, E, and F treatment arms, respectively.

The results of this study may not be generalizable for patients with drug-susceptible pulmonary TB.

This study found that, “the 14-day bactericidal activity of meropenem is modest when given at a total dose of 3 grams daily. While antimycobacterial activity appears to improve with doubling of the dose, this difference in activity was only evident using CFU counts on solid media and not [time to positivity] in liquid media. […] In this context, the role for meropenem in programmatic TB treatment appears minimal. Therefore, the field should focus on new carbapenem–β lactamase inhibitor pairs (or carbapenems that do not require a β -lactamase inhibitor) that are oral and better tolerated yet capable of achieving exposures sufficient for bactericidal activity.”

Reference

De Jager V, Gupte N, Nunes S, et al. Early bactericidal activity of meropenem plus clavulanate (+/-rifampin) for TB: The COMRADE Randomized, Phase 2 Trial. Am J Respir Crit Care Med. Published online March 3, 2022. doi:10.1164/rccm.202108-1976OC