In vitro Optimization of Ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae

Author:

Huang Yanqin,Wu Tiffany,Perez Omar,Rana Amisha P.,Chen Liang,Kreiswirth Barry N.,Satlin Michael J.,Bulman Zackery P.

Abstract

Ceftazidime/avibactam is an important treatment option for infections caused by Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp), however, resistance can emerge during treatment. The objective of the study was to define the ceftazidime/avibactam concentrations required to suppress bacterial regrowth in ceftazidime/avibactam susceptible isolates and identify active therapies against ceftazidime/avibactam-resistant KPC-Kp. Time-kill assays were performed against twelve ST258 KPC-Kp isolates that harbored blaKPC2 or blaKPC3. Nine KPC-Kp isolates (KPC-Kp 5A, 6A, 7A, 8A, 9A, 24A, 25A, 26A, and 27A) were susceptible to ceftazidime/avibactam, two (KPC-Kp 6B and 7B) were ceftazidime/avibactam resistant and meropenem susceptible, and one (KPC-Kp 1244) was resistant to both ceftazidime/avibactam and meropenem. Sequencing of the blaKPC genes revealed mutations in KPC-Kp 6B (D179Y substitution) and 7B (novel 21 base pair deletion) that both affected the Ω-loop encoding portion of the gene. Time-kill assays showed that against ceftazidime/avibactam-susceptible KPC-Kp, ceftazidime/avibactam concentrations ≥40/7.5 mg/L caused mean 5.42 log10CFU/mL killing and suppressed regrowth. However, regrowth occurred for some KPC-Kp isolates with a ceftazidime/avibactam concentration of 20/3.75 mg/L. Against ceftazidime/avibactam-resistant and meropenem-susceptible KPC-Kp 6B and 7B, bactericidal activity and synergy was observed for ceftazidime/avibactam in combination with meropenem ≤3.125 mg/L, while meropenem concentrations ≥50 mg/L were bactericidal as monotherapy. In contrast, clinically achievable concentrations of ceftazidime/avibactam were bactericidal against KPC-Kp 1244, which was ceftazidime/avibactam-resistant and meropenem-resistant due to outer membrane porin mutations and elevated blaKPC expression. Achieving high ceftazidime/avibactam concentrations may help to suppress bacterial regrowth in the presence of ceftazidime/avibactam. The optimal treatment approach for ceftazidime/avibactam-resistant KPC-Kp likely depends on the mechanism of resistance. Additional studies are warranted to confirm these findings.

Funder

American College of Clinical Pharmacy Research Institute

National Center for Advancing Translational Sciences

National Institutes of Health

Publisher

Frontiers Media SA

Subject

Microbiology (medical),Microbiology

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