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.
Highlights
Bedaquiline and delamanid are the new addition to the anti-TB armament to combat multi-drug resistant tuberculosis (MDRTB) (Gler et al, 2012; Cox and Laessig, 2014), the emergence of drug resistance to these newly developed drugs, designed for Mycobacterium tuberculosis (Mtb), was quickly reported (Andries et al, 2014; Bloemberg et al, 2015; Hoffmann et al, 2016)
Mtb can be present in different metabolic populations (Mitchison, 1979), it is of interest to continue the screening for a β-lactam that have efficacy against different Mtb metabolic populations
On study day 28, for both time to positive (TTP) (Figures 5A–C) and log10 colony forming unit (CFU)/ml (Figures 5D–F), AUC0-24/MIC had lower Akaike Information Criteria score (AIC) score compare to %TMIC or Cmax/MIC
Summary
Bedaquiline and delamanid are the new addition to the anti-TB armament to combat multi-drug resistant tuberculosis (MDRTB) (Gler et al, 2012; Cox and Laessig, 2014), the emergence of drug resistance to these newly developed drugs, designed for Mycobacterium tuberculosis (Mtb), was quickly reported (Andries et al, 2014; Bloemberg et al, 2015; Hoffmann et al, 2016). Repurposing of antibiotics that are already in clinical use appear to be an attractive, fast and pragmatic way to identify drugs with antiTB activity (Maitra et al, 2015; Ramon-Garcia et al, 2016; Alffenaar et al, 2019). Cefdinir is a third-generation oral semisynthetic cephalosporin used for the treatment of Gram-positive and Gram-negative infections. It binds to the penicillin binding proteins, leading to the damage of the cell wall, cell lysis and death of drug susceptible bacteria. An elsewhere published drug screening study suggest cefdinir as a potential candidate for evaluation against Mtb (Ramon-Garcia et al, 2016). 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)
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