AUTHOR=Srivastava Shashikant , Thomas Tania , Howe Dave , Malinga Lesibana , Raj Prithvi , Alffenaar Jan-Willem , Gumbo Tawanda 

TITLE=Cefdinir and β-Lactamase Inhibitor Independent Efficacy Against Mycobacterium tuberculosis

JOURNAL=Frontiers in Pharmacology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2021.677005

DOI=10.3389/fphar.2021.677005

ISSN=1663-9812

ABSTRACT=Background. There is renewed interest in repurposing beta-lactam antibiotics for treatment of tuberculosis (TB). We investigated efficacy of cefdinir, that withstand the -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 Emax model was used to describe the relationship between the drug exposure and bacterial burden.
Results. Cefdinir MIC for Mtb H37Ra was 4 mg/L and 2 mg/L with or without avibactam, respectively. The MIC of the clinical strains ranged between 0.5 to 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 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 -lactamase inhibitor. However, clinical validation of these findings remains to be determined.