Impact of ceftolozane/tazobactam concentrations in continuous infusion against extensively drug-resistant Pseudomonas aeruginosa isolates in a hollow-fiber infection model

Abstract

Ceftolozane/tazobactam (C/T) has emerged as a potential agent for the treatment of extensively drug-resistant (XDR) Pseudomonas aeruginosa infections. As it is a time-dependent antimicrobial, prolonged infusion may help achieve pharmacokinetic/pharmacodynamic (PK/PD) targets. To compare alternative steady-state concentrations (Css) of C/T in continuous infusion (CI) against three XDR P. aeruginosa ST175 isolates with C/T minimum inhibitory concentration (MIC) values of 2 to 16 mg/L in a hollow-fiber infection model (HFIM). Duplicate 10-day HFIM assays were performed to evaluate Css of C/T in CI: one compared 20 and 45 mg/L against the C/T-susceptible isolate while the other compared 45 and 80 mg/L against the two C/T-non-susceptible isolates. C/T resistance emerged when C/T-susceptible isolate was treated with C/T in CI at a Css of 20 mg/L; which showed a deletion in the gene encoding AmpC β-lactamase. The higher dosing regimen (80 mg/L) showed a slight advantage in effectiveness. The higher dosing regimen has the greatest bactericidal effect, regardless of C/T MIC. Exposure to the suboptimal Css of 20 mg/L led to the emergence of C/T resistance in the susceptible isolate. Antimicrobial regimens should be optimized through C/T levels monitoring and dose adjustments to improve clinical management.

Figure 1

Study flow showing in vitro 10-day HFIM assays conducted with three XDR Pseudomonas aeruginosa ST175 isolates with C/T MICs ranging from 2 to 16 mg/L using different Css of C/T in CI: 20 and 45 mg/L to test the emergence of C/T resistance in the susceptible ST175 (10-023) isolate, and 45 and 80 mg/L to test the effectiveness of C/T against the non-susceptible isolates ST175 (09-012) and ST175 (07-016). C/T, ceftolozane/tazobactam; HFIM, hollow-fiber infection model; MIC, minimum inhibitory concentration; XDR, extensively-drug resistant; Css, steady-state concentration; CI, continuous infusion.

Figure 2

Mean reduction in bacterial density during the 10-day HFIM assays with ST175 (10-023), ST175 (09-012) and ST175 (07-016) isolates treated with different Css of C/T (20, 45 and 80 mg/L) in CI. Respective C/T MIC values of 2, 8 and 16 mg/L. C/T, ceftolozane/tazobactam; CI, continuous infusion; Css, steady-state concentration; LLOD, lower limit of detection; MIC, minimum inhibitory concentration.

Figure 3

Emergence of C/T resistance in the ST175 (10-023) isolate using Css of 20 and 45 mg/L in CI. C/T, ceftolozane/tazobactam; CI, continuous infusion; Css, steady-state concentration; MIC, minimum inhibitory concentration.