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=12

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=<p><bold>Background:</bold> 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) <italic>Mycobacterium tuberculosis</italic> (<italic>Mtb</italic>).</p><p><bold>Methods:</bold> Minimum inhibitory concentration (MIC) experiments were performed with <italic>Mtb</italic> 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 <italic>Mtb</italic> 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<sub>max</sub> model was used to describe the relationship between the drug exposure and bacterial burden.</p><p><bold>Results:</bold> Cefdinir MIC for <italic>Mtb</italic> 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<sub>10</sub> CFU/ml <italic>Mtb</italic> 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 <italic>Mtb</italic> sterilizing efficacy was identified as the ratio of area under the concentration-time curve to MIC (AUC<sub>0–24</sub>/MIC) and optimal exposure was calculated as AUC<sub>0–24</sub>/MIC of 578.86. There was no resistance emergence to cefdinir in the HFS-TB.</p><p><bold>Conclusion:</bold> 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.</p>