Cefdinir and β-Lactamase Inhibitor Independent Efficacy Against Mycobacterium tuberculosis

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

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Background: 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.

Original languageEnglish (US)
Article number677005
JournalFrontiers in Pharmacology
Volume12
DOIs
StatePublished - Jun 7 2021

Keywords

  • avibactam
  • cephalosporins
  • hollow fiber model
  • multi-drug resistance
  • pharmacokinetics/pharmacodynamics

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)

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