Srivastava, ShashikantThomas, TaniaHowe, DaveMalinga, Lesibana AnthonyRaj, PrithviAlffenaar, Jan-WillemGumbo, Tawanda2022-03-032022-03-032021-06-07Srivastava, S., Thomas, T., Howe, D., Malinga, L., Raj, P., Alffenaar, J.-W. & Gumbo, T. (2021) Cefdinir and β-Lactamase Inhibitor Independent Efficacy Against Mycobacterium tuberculosis. Frontiers in Pharmacology 12:677005. DOI: 10.3389/fphar.2021.677005.1663-9812 (online)10.3389/fphar.2021.677005http://hdl.handle.net/2263/84319BACKGROUND : There is renewed interest in repurposing β-lactam antibiotics for treatment of tuberculosis (TB). We investigated efficacy of cefdinir, that withstand the β-lactamase enzyme present in many bacteria, against drug-susceptible and multi-drug resistant (MDR) Mycobacterium tuberculosis (Mtb). METHODS : Minimum inhibitory concentration (MIC) experiments were performed with Mtb H37Ra, eight drug-susceptible, and 12 MDR-TB clinical isolates with and without the β-lactamase inhibitor, avibactam at 15 mg/L final concentration. Next, we performed dose-response study with Mtb H37Ra in test-tubes followed by a sterilizing activity study in the pre-clinical hollow fiber model of tuberculosis (HFS-TB) study using an MDR-TB clinical strain. Inhibitory sigmoid Emax model was used to describe the relationship between the drug exposure and bacterial burden. RESULTS : Cefdinir MIC for Mtb H37Ra was 4 and 2 mg/L with or without avibactam, respectively. The MIC of the clinical strains ranged between 0.5 and 16 mg/L. In the test-tube experiments, cefdinir killed 4.93 + 0.07 log10 CFU/ml Mtb H37Ra in 7 days. In the HFS-TB studies, cefdinir showed dose-dependent killing of MDR-TB, without combination of avibactam. The cefdinir PK/PD index linked to the Mtb sterilizing efficacy was identified as the ratio of area under the concentration-time curve to MIC (AUC0–24/MIC) and optimal exposure was calculated as AUC0–24/MIC of 578.86. There was no resistance emergence to cefdinir in the HFS-TB. CONCLUSION : In the HFS-TB model, cefdinir showed efficacy against both drug susceptible and MDR-TB without combination of β-lactamase inhibitor. However, clinical validation of these findings remains to be determined.en© 2021 Srivastava, Thomas, Howe, Malinga, Raj, Alffenaar and Gumbo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY).CephalosporinsAvibactamHollow fiber modelPharmacokinetics/ pharmacodynamicsMultidrug-resistant (MDR)Minimum inhibitory concentration (MIC)Tuberculosis (TB)Article