Ceftazidime-avibactam has potent sterilizing activity against highly drug-resistant tuberculosis.

Autor:	Deshpande D; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA., Srivastava S; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA., Chapagain M; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA., Magombedze G; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA., Martin KR; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA., Cirrincione KN; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA., Lee PS; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA., Koeuth T; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA., Dheda K; Lung Infection and Immunity Unit, Division of Pulmonology and University of Cape Town (UCT) Lung Institute, Department of Medicine, UCT, Observatory, 7925, Cape Town, South Africa., Gumbo T; Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX 75204, USA.; Lung Infection and Immunity Unit, Division of Pulmonology and University of Cape Town (UCT) Lung Institute, Department of Medicine, UCT, Observatory, 7925, Cape Town, South Africa.
Jazyk:	angličtina
Zdroj:	Science advances [Sci Adv] 2017 Aug 30; Vol. 3 (8), pp. e1701102. Date of Electronic Publication: 2017 Aug 30 (Print Publication: 2017).
DOI:	10.1126/sciadv.1701102
Abstrakt:	There are currently many patients with multidrug-resistant and extensively drug-resistant tuberculosis. Ongoing transmission of the highly drug-resistant strains and high mortality despite treatment remain problematic. The current strategy of drug discovery and development takes up to a decade to bring a new drug to clinical use. We embarked on a strategy to screen all antibiotics in current use and examined them for use in tuberculosis. We found that ceftazidime-avibactam, which is already used in the clinic for multidrug-resistant Gram-negative bacillary infections, markedly killed rapidly growing, intracellular, and semidormant Mycobacterium tuberculosis in the hollow fiber system model. Moreover, multidrug-resistant and extensively drug-resistant clinical isolates demonstrated good ceftazidime-avibactam susceptibility profiles and were inhibited by clinically achievable concentrations. Resistance arose because of mutations in the transpeptidase domain of the penicillin-binding protein PonA1, suggesting that the drug kills M. tuberculosis bacilli via interference with cell wall remodeling. We identified concentrations (exposure targets) for optimal effect in tuberculosis, which we used with susceptibility results in computer-aided clinical trial simulations to identify doses for immediate clinical use as salvage therapy for adults and young children. Moreover, this work provides a roadmap for efficient and timely evaluation of antibiotics and optimization of clinically relevant dosing regimens.
Databáze:	MEDLINE
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