Repurposing Cefazolin-Avibactam for the Treatment of Drug Resistant Mycobacterium tuberculosis

Background: While tuberculosis (TB) is curable and preventable, the most effective first-line antibiotics cannot kill multi-drug resistant (MDR) Mycobacterium tuberculosis (Mtb). Therefore, effective drugs are needed to combat MDR-TB, especially in children. Our objective was to repurpose cefazolin for MDR-TB treatment in children using principles of pharmacokinetic/pharmacodynamics (PK/PD).Methods: Cefazolin minimum inhibitory concentration (MIC) was identified in 17 clinical Mtb strains, with and without combination of the β-lactamase inhibitor, avibactam. Next, dose-ranging studies were performed using the intracellular hollow fiber model of TB (HFS-TB) to identify the optimal cefazolin exposure. Monte Carlo experiments were then performed in 10,000 children for optimal dose identification based on cumulative fraction of response (CFR) and Mtb susceptibility breakpoint in three age-groups.Results: Avibactam reduced the cefazolin MICs by five tube dilutions. Cefazolin-avibactam demonstrated maximal kill of 4.85 log10 CFU/mL in the intracellular HFS-TB over 28 days. The % time above MIC associated with maximal effect (EC80) was 46.76% (95% confidence interval: 43.04–50.49%) of dosing interval. For 100 mg/kg once or twice daily, the CFR was 8.46 and 61.39% in children
Source: Frontiers in Pharmacology - Category: Drugs & Pharmacology Source Type: research

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Source: European Journal of Medical Research - Category: Research Source Type: research
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Source: Trials - Category: Research Source Type: clinical trials
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Source: IPS Inter Press Service - Health - Category: International Medicine & Public Health Authors: Tags: COVID-19 Editors' Choice Featured Global Health Human Rights Humanitarian Emergencies Inequity TerraViva United Nations #Sasakawa IPS UN Bureau leprosy Source Type: news
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Source: Johnson and Johnson - Category: Pharmaceuticals Tags: Innovation Source Type: news
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Source: Cell Research - Category: Cytology Authors: Source Type: research
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