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bioRxiv · 10.1101/411181

In vitro and intracellular activity of imipenem combined with tedizolid, rifabutin, and avibactam against Mycobacterium abscessus

Le Run, E.·Arthur, M.·Mainardi, J.-l.
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Abstract

Mycobacterium abscessus has emerged as a significant pathogen responsible for chronic pulmonary infections in cystic fibrosis (CF) patients, which are difficult to treat due to resistance to a broad range of antibiotics. The initial phase of the recommended treatment in CF patients includes imipenem used without any {beta}-lactamase inhibitor in spite of the production of the {beta}-lactamase BlaMab. Here, we determine whether the addition of tedizolid, a once-daily oxazolidinone, improves the activity of imipenem alone or in combination with a {beta}-lactamase inhibitor, avibactam, and rifabutin.\n\nThe activity of the drugs was evaluated against M. abscessus CIP104536 by determining in vitro and intracellular antibacterial activities. The impact of BlaMab inhibition by avibactam on antibiotic activity was assessed by comparing CIP104536 and its {beta}-lactamase-deficient derivative ({Delta}blaMab).\n\nThe minimal inhibitory concentrations (MICs) of tedizolid against M. abscessus CIP104536 and {Delta}blaMab were 4 g/mL. Tedizolid combined with imipenem showed a moderate synergistic effect with fractional inhibitory concentration (FIC) indexes of 0.41 and 0.38 for CIP104536 and {Delta}blaMab, respectively. For both strains, the addition of tedizolid at 2 g/mL, corresponding to the peak serum concentration, increased the intracellular efficacy of imipenem at 8 and 32 g/mL. Addition of avibactam and rifabutin improved the activity of the imipenem-tedizolid combination against CIP104536S.\n\nThe imipenem-tedizolid combination should be further considered for the treatment of M. abscessus pulmonary infections in CF patients. The efficacy of the treatment might benefit from the use of a {beta}-lactamase inhibitor, such as avibactam, and the addition of rifabutin.

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Le Run, E., Arthur, M., Mainardi, J.-l.. 2018-09-07. In vitro and intracellular activity of imipenem combined with tedizolid, rifabutin, and avibactam against Mycobacterium abscessus. https://doi.org/10.1101/411181

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