Background Repurposing established antibiotics for TB has been successful, notably for fluoroquinolones, linezolid, and clofazimine. Meropenem co-administered with amoxicillin/clavulanate (A/Clav) demonstrated early bactericidal activity (EBA) in clinical trials (Diacon 2016; de Jager 2020; de Jager 2022). This study evaluated different regimens of carbapenems, A/Clav, and rifampicin, alone or in combinations.

Methods This phase 2a, open-label, randomized trial recruited 132 HIV-negative adults with newly diagnosed, smear-positive, rifampicin-susceptible pulmonary TB. Participants received 14 days of treatment in one of 8 experimental arms, or standard-of-care (HRZE). EBA was determined with mixed effects modelling and reported as change in time (hours) to sputum culture positivity (TTP0-14) of samples collected overnight with 95% confidence intervals. Adverse events (AE) were assessed daily.

Results A/Clav 2x1000/62.5mg orally twice daily showed no activity. TTP0-14 of other drugs in combination with A/Clav was, for meropenem 6g over 6 hours(6Mero6): 58.02 hours (18.72–192.92), meropenem 6g over 1 hour(6Mero1): 58.13 hours (27.26–121.83), meropenem 3g over 1 hour twice daily(3x2Mero): 60.07 hours (19.89–884.71), and meropenem 4g over 1 hour(4Mero1): 35.28 hours (25.31–84.74). Ertapenem 1g daily intravenously (ErtaIV) or intramuscularly (ErtaIM) was not active. The activity of rifampicin 35mg/kg daily plus A/Clav was 136.92 hours (103.21–400.64) and HRZE 134.30 hours (106.28–160.23). In 58 participants, 111 adverse events were reported. Most commonly diarrhoea (15 participants: four ErtaIM, three ErtaIV, four 6Mero6, two rifampicin, one each A/Clav and HRZE), injection site reactions (six participants: four ErtaIM, one each 6Mero6 and 3x2Mero), and raised transaminases (four participants: A/Clav, ErtaIM, Erta IV, rifampicin). Three SAEs occurred (pneumonia in ErtaIV, haemoptysis in rifampicin and 6Mero1) unrelated to treatment.

Conclusion Rifampicin-based treatments showed the highest EBA. A/Clav and meropenem given at 6g per day, in single or divided doses, had higher EBA than lower doses, and shorter infusions were better tolerated. Ertapenem-based treatments and A/Clav alone showed no anti-TB activity.

Funding: EDCTP 733079-H2020-SC1-2016-RTD