Mechanistic Insights to Combating NDM- and CTX-M-Coproducing Klebsiella pneumoniae by Targeting Cell Wall Synthesis and Outer Membrane Integrity.

Autor: Smith NM; Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.; New York State Center of Excellence in Life Sciences and Bioinformatics, Buffalo, New York, USA., Boissonneault KR; Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.; New York State Center of Excellence in Life Sciences and Bioinformatics, Buffalo, New York, USA., Chen L; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, USA.; Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, New Jersey, USA., Petraitis V; Transplantation-Oncology Infectious Disease Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA., Petraitiene R; Transplantation-Oncology Infectious Disease Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA., Tao X; Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Floridagrid.15276.37, Orlando, Florida, USA., Zhou J; Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Floridagrid.15276.37, Orlando, Florida, USA., Lang Y; Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Floridagrid.15276.37, Orlando, Florida, USA., Kavaliauskas P; Transplantation-Oncology Infectious Disease Program, Division of Infectious Diseases, Department of Medicine, Weill Cornell Medicine of Cornell University, New York, New York, USA., Bulman ZP; Department of Pharmacy Practice, University of Illinois Chicago, Chicago, Illinois, USA., Holden PN; Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.; New York State Center of Excellence in Life Sciences and Bioinformatics, Buffalo, New York, USA., Cha R; Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.; New York State Center of Excellence in Life Sciences and Bioinformatics, Buffalo, New York, USA., Bulitta JB; Center for Pharmacometrics and Systems Pharmacology, Department of Pharmaceutics, College of Pharmacy, University of Floridagrid.15276.37, Orlando, Florida, USA., Kreiswirth BN; Hackensack Meridian Health Center for Discovery and Innovation, Nutley, New Jersey, USA., Walsh TJ; Department of Medical Sciences, Hackensack Meridian School of Medicine, Nutley, New Jersey, USA.; Department of Pediatrics, Weill Cornell Medicine of Cornell University, New York, New York, USA.; Department of Microbiology & Immunology, Weill Cornell Medicine of Cornell University, New York, New York, USA.; Center for Innovative Therapeutics and Diagnostics, Richmond, Virginia, USA., Tsuji BT; Laboratory for Antimicrobial Pharmacodynamics, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, Buffalo, New York, USA.; New York State Center of Excellence in Life Sciences and Bioinformatics, Buffalo, New York, USA.
Jazyk: angličtina
Zdroj: Antimicrobial agents and chemotherapy [Antimicrob Agents Chemother] 2022 Sep 20; Vol. 66 (9), pp. e0052722. Date of Electronic Publication: 2022 Aug 04.
DOI: 10.1128/aac.00527-22
Abstrakt: 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  < 0.05). A neutropenic rabbit pneumonia model demonstrated that aztreonam plus ceftazidime-avibactam with or without polymyxin B resulted in similar bacterial killing, and these combination therapies were statistically significantly better than monotherapies ( P  < 0.05). However, only the polymyxin B-containing combination therapy produced a statistically significant decrease in lung weights ( P  < 0.05), indicating a decreased inflammatory process. Altogether, adding polymyxin B to the combination of aztreonam plus ceftazidime-avibactam for NDM- and CTX-M-producing K. pneumoniae improved bacterial killing effects, reduced lung inflammation, suppressed resistance amplification, and limited virulence changes.
Databáze: MEDLINE