Generating genotype-specific aminoglycoside combinations with ceftazidime/Avibactam for KPC-Producing Klebsiella pneumoniae

Yanqin Huang, Karol Sokolowski, Amisha Rana, Nidhi Singh, Jiping Wang, Ke Chen, Yinzhi Lang, Jieqiang Zhou, Neera Kadiyala, Fiorella Krapp, Egon A. Ozer, Alan R. Hauser, Jian Li, Jürgen B. Bulitta, Zackery P. Bulman*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Antibiotic combinations, including ceftazidime/avibactam (CAZ/AVI), are frequently employed to combat KPC-producing Klebsiella pneumoniae (KPC-Kp), though such combinations have not been rationally optimized. Clinical KPC-Kp isolates with common genes encoding aminoglycoside-modifying enzymes (AMEs), aac (69)-Ib9 or aac(69)-Ib, were used in static time-kill assays (n = 4 isolates) and the hollow- fiber infection model (HFIM; n = 2 isolates) to evaluate the activity of gentamicin, amikacin, and CAZ/AVI alone and in combinations. A short course, one-time aminoglycoside dose was also evaluated. Gentamicin plus CAZ/AVI was then tested in a mouse pneumonia model. Synergy with CAZ/AVI was more common with amikacin for aac(69)-Ib9-containing KPC-Kp but more common with gentamicin for aac(69)-Ibcontaining isolates in time-kill assays. In the HFIM, although the isolates were aminoglycoside- susceptible at baseline, aminoglycoside monotherapies displayed variable initial killing, followed by regrowth and resistance emergence. CAZ/AVI combined with amikacin or gentamicin resulted in undetectable counts 50 h sooner than CAZ/ AVI monotherapy against KPC-Kp with aac(69)-Ib9. CAZ/AVI monotherapy failed to eradicate KPC-Kp with aac(69)-Ib and a combination with gentamicin led to undetectable counts 70 h sooner than with amikacin. A one-time aminoglycoside dose with CAZ/AVI provided similar killing to aminoglycosides dosed for 7 days. In the mouse pneumonia model (n = 1 isolate), gentamicin and CAZ/AVI achieved a 6.0-log10CFU/ lung reduction at 24 h, which was significantly greater than either monotherapy (P<0.005). Aminoglycosides in combination with CAZ/AVI were promising for KPC-Kp infections; this was true even for a one-time aminoglycoside dose. Selecting aminoglycosides based on AME genes or susceptibilities can improve the pharmacodynamic activity of the combination.

Original languageEnglish (US)
Article numbere00692-21
JournalAntimicrobial agents and chemotherapy
Volume65
Issue number9
DOIs
StatePublished - Sep 2021

Keywords

  • Aminoglycoside-modifying enzymes
  • Aminoglycosides
  • Antimicrobial combinations
  • Carbapenemase
  • KPC
  • Klebsiella

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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