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

Montero, Maria Milagro; Domene Ochoa, Sandra; López-Causapé, Carla; Luque Pardos, Sònia; Sorli Redó, M. Luisa; Campillo Ambrós, Núria; Padilla, Eduardo; Prim, Núria; Ferrer Alapont, Lorena; Angulo-Brunet, Ariadna; Grau Cerrato, Santiago; Oliver, Antonio; Horcajada Gallego, Juan Pablo

doi:http://dx.doi.org/10.1038/s41598-021-01784-4

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

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Montero MM, Domene-Ochoa S, López-Causapé C, Luque S, Sorlí L, Campillo N, Padilla E, Prim N, Ferrer-Alapont L, Angulo-Brunet A, Grau S, Oliver A, Horcajada JP. Impact of ceftolozane/tazobactam concentrations in continuous infusion against extensively drug-resistant Pseudomonas aeruginosa isolates in a hollow-fiber infection model. Sci Rep. 2021 Nov 12;11(1):22178. DOI: 10.1038/s41598-021-01784-4

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.