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Beta-Lactams Against TB: Teaching a New Trick to an Old Dog
Andreas H. Diacon1; Lize van der Merwe2; Marinus Barnard2; Florian Von Groote-Bidlingmaier2; Christoph Lange3; Alberto L. García-Basteiro4; Esperança Sevene5; Lluís Ballell6; David Barros-Aguirre6
1Stellenbosch Univ, Bellville, South Africa;2Task Applied Science, Bellville, South Africa;3Rsr Cntr Borstel, Borstel, Germany;4Barcelona Inst for Global Hlth, Barcelona, Spain;5Manhiça Hlth Rsr Cntr (CISM), Manhiça, Mozambique;6Diseases of the Developing World, GlaxoSmithKline, Tres Cantos, Madrid, Spain
It is generally accepted that ß-lactam antibiotics are ineffective against Mycobacterium tuberculosis. Carbapenems are relatively resistant to mycobacterial ß-lactamases in vitro. We investigated whether the carbapenems meropenem and faropenem combined with amoxicillin and clavulanic acid (A/CA) have antituberculosis activity in humans.
Groups of 15 patients with newly diagnosed, smear-positive, drug-sensitive pulmonary tuberculosis received one of three treatments for 14 days: meropenem 2g intravenously or faropenem 600mg orally, both combined with oral A/CA 500mg/125mg, all given three times per day, or standard antituberculosis treatment as control. We collected sputum overnight for colony forming unit (CFU) counting on solid agar plates and for assessing time to culture positivity (TTP) in liquid medium. Full pharmacokinetic profiling was performed on day 14. Patients were hospitalised for daily safety assessments.
The viable mycobacterial sputum load was significantly reduced with standard treatment (validating the laboratory assays) and with meropenem A/CA but not with faropenem A/CA (Table). Meropenem exposures were much higher than faropenem exposures (Table). AUC and Cmax were significantly associated with meropenem activity measured by CFU (r2=0.62; p=0.002 and r2=0.49; p=0.066, respectively). Mild intermittent diarrhea was reported by >50% of patients in both carbapenem groups and was probably related to A/CA.
The combination of intravenous meropenem and oral A/CA has antituberculosis activity in humans of similar magnitude as previously reported for rifampin (10mg/kg), pyrazinamide, bedaquiline and PA-824 over the first 2 weeks of treatment. This establishes ß-lactams as a class with clinical antituberculosis activity. Oral faropenem combined with A/CA was ineffective owing to insufficient exposure. Both treatments were safe. Meropenem A/CA should be considered for all patients with highly resistant tuberculosis in whom intravenous treatment is feasible.