1. Mechanistic Insights to Combating NDM- and CTX-M-Coproducing Klebsiella pneumoniae by Targeting Cell Wall Synthesis and Outer Membrane Integrity
- Author
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Nicholas M. Smith, Katie Rose Boissonneault, Liang Chen, Vidmantas Petraitis, Ruta Petraitiene, Xun Tao, Jieqiang Zhou, Yinzhi Lang, Povilas Kavaliauskas, Zackery P. Bulman, Patricia N. Holden, Raymond Cha, Jürgen B. Bulitta, Barry N. Kreiswirth, Thomas J. Walsh, and Brian T. Tsuji
- Subjects
Pharmacology ,Microbial Sensitivity Tests ,Clinical Therapeutics ,Ceftazidime ,beta-Lactamases ,Anti-Bacterial Agents ,Aztreonam ,Drug Combinations ,Klebsiella pneumoniae ,Infectious Diseases ,Cell Wall ,Klebsiella ,Animals ,Pharmacology (medical) ,Rabbits ,Azabicyclo Compounds ,Polymyxin B - Abstract
Metallo-β-lactamase (MBL)-producing Gram-negative bacteria cause infections associated with high rates of morbidity and mortality. Currently, a leading regimen to treat infections caused by MBL-producing bacteria is aztreonam combined with ceftazidime-avibactam. The purpose of the present study was to evaluate and rationally optimize the combination of aztreonam and ceftazidime-avibactam with and without polymyxin B against a clinical Klebsiella pneumoniae isolate producing NDM-1 and CTX-M by use of the hollow fiber infection model (HFIM). A novel de-escalation approach to polymyxin B dosing was also explored, whereby a standard 0-h loading dose was followed by maintenance doses that were 50% of the typical clinical regimen. In the HFIM, the addition of polymyxin B to aztreonam plus ceftazidime-avibactam significantly improved bacterial killing, leading to eradication, including for the novel de-escalation dosing strategy. Serial samples from the growth control and monotherapies were explored in a Galleria mellonella virulence model to assess virulence changes. Weibull regression showed that low-level ceftazidime resistance and treatment with monotherapy resulted in increased G. mellonella mortality (P
- Published
- 2023