Cefdinir and β-Lactamase Inhibitor Independent Efficacy Against Mycobacterium tuberculosis

Background: There is renewed interest in repurposing beta-lactam antibiotics for treatment of tuberculosis (TB). We investigated efficacy of cefdinir, that withstand the beta-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 beta-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 E-max 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 log(10) 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 (AUC(0-24)/MIC) and optimal exposure was calculated as AUC(0-24)/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 beta-lactamase inhibitor. However, clinical validation of these findings remains to be determined.

Automated summary

The study showed that cefdinir has potential efficacy against both drug-susceptible and multi-drug resistant tuberculosis, with the ability to kill Mtb strains in both in vitro and pre-clinical models. The pharmacokinetic/pharmacodynamic index AUC(0-24)/MIC of 578.86 was identified as the optimal exposure for sterilizing efficacy. Further clinical validation of these findings is needed.