2. Academic Validation
  3. An improved PKPD modeling approach to characterize the pharmacodynamic interaction over time between ceftazidime/avibactam and colistin from in vitro time-kill experiments against multidrug-resistant Klebsiella pneumoniae isolates

An improved PKPD modeling approach to characterize the pharmacodynamic interaction over time between ceftazidime/avibactam and colistin from in vitro time-kill experiments against multidrug-resistant Klebsiella pneumoniae isolates

  • Antimicrob Agents Chemother. 2023 Sep 8;e0030123. doi: 10.1128/aac.00301-23.
Romain Aubry 1,  Julien Buyck 1,  Laure Prouvensier 1 2,  Jean-Winoc Decousser 3 4,  Patrice Nordmann 5 6 7,  Sebastian G Wicha 8,  Sandrine Marchand 1 2,  Nicolas Grégoire 1 2
Affiliations

Affiliations

  • 1 Université de Poitiers, PHAR2, Inserm U1070 , Poitiers, France.
  • 2 Laboratoire de Toxicologie-Pharmacologie, CHU de Poitiers , Poitiers, France.
  • 3 Department of Bacteriology and Infection Control, University Hospital Henri Mondor, Assistance Publique - Hôpitaux de Paris , Créteil, France.
  • 4 Faculté de Médecine de Créteil, Ecole nationale vétérinaire d'Alfort (EnvA), EA 7380 Dynamyc Université Paris - Est Créteil (UPEC) , Créteil, France.
  • 5 Medical and Molecular Microbiology Unit, Faculty of Science and Medicine, University of Fribourg , Fribourg, Switzerland.
  • 6 Swiss National Reference Center for Emerging Antibiotic Resistance (NARA), University of Fribourg , Fribourg, Switzerland.
  • 7 Institute for Microbiology, University of Lausanne and University Hospital Centre , Lausanne, Switzerland.
  • 8 Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg , Hamburg, Germany.
PMID: 37681977 DOI: 10.1128/aac.00301-23
Abstract

In contrast to the checkerboard method, bactericidal experiments [time-kill curves (TKCs)] allow an assessment of pharmacodynamic (PD) interactions over time. However, TKCs in combination pose interpretation problems. The objective of this study was to characterize the PD interaction over time between ceftazidime/avibactam (CZA) and colistin (CST) using TKC against four multidrug-resistant Klebsiella pneumoniae susceptible to both Antibiotics and expressing a widespread carbapenemase determinant KPC-3. In vitro TKCs were performed and analyzed using pharmacokinetic/pharmacodynamic (PKPD) modeling. The general pharmacodynamic interaction model was used to characterize PD interactions between drugs. The 95% confidence intervals (95%CIs) of the expected additivity and of the observed interaction were built using parametric bootstraps and compared to evaluate the in vitro PD interaction over time. Further simulations were conducted to investigate the effect of the combination at varying concentrations typically observed in patients. Regrowth was observed in TKCs at high concentrations of drugs alone [from 4 to 32× minimum inhibitory concentrations (MIC)], while the combination systematically prevented the regrowth at concentrations close to the MIC. Significant synergy or antagonism were observed under specific conditions but overall 95%CIs overlapped widely over time indicating an additive interaction between Antibiotics. Moreover, simulations of typical PK profile at standard dosages indicated that the interaction should be additive in clinical conditions. The nature of the PD interaction varied with time and concentration in TKC. Against the four K. pneumoniae isolates, the bactericidal effect of CZA + CST combination was predicted to be additive and to prevent the emergence of resistance at clinical concentrations.

Keywords

PKPD modeling; antimicrobial combination; ceftazidime/avibactam; colistin.

Figures
Products