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Continuous infusion of ceftolozane/tazobactam is associated with a higher probability of target attainment in patients infected with Pseudomonas aeruginosa

  • Benoît PilmisEmail author
  • Grégoire Petitjean
  • Philippe Lesprit
  • Matthieu Lafaurie
  • Najoua El Helali
  • Alban Le Monnier
  • on behalf the ATB PK/PD study group
Original Article

Abstract

Ceftolozane/tazobactam (CTZ/TZ) exhibits time-dependent antimicrobial activity, and prolonged infusion can better achieve the pharmacodynamic target than an intermittent bolus. We aimed to compare the use of prolonged or continuous infusion with intermittent administration of CTZ/TZ for the treatment of infections caused by multidrug-resistant Pseudomonas aeruginosa. We performed a multicentric prospective cohort study to evaluate continuous, prolonged, or intermittent infusion of CTZ/TZ. We assessed the plasma concentration as a function of the duration of infusion and then performed a simulation of the percentage of patients who would reach the PK/PD targets, set at 100% ƒT> MIC or 100% ƒT>4 MIC. Seventy-two patients were enrolled with a median [IQR] age of 48.5 [32.4–63.2] years. Fifty-seven (79%) were hospitalized in an intensive care unit. Thirty-seven (51.4%) were immunosuppressed, and the in-hospital mortality rate was 15.2%. The major site of infection was the respiratory tract (66.7%). The PK/PD objectives (100% ƒT>4 MIC) were achieved for all patients infected with strains with CTZ/TZ MICs < 4 mg/L, regardless of the mode of administration. In contrast, intermittent bolus administration and prolonged infusion did not achieve the PK/PD objectives when the CTZ/TZ MICs were ≥ 4 mg/L. However, the PK/PD objectives (100% ƒT>4 MIC) were achieved for strains with MICs up to 8 mg/L in patients receiving continuous infusion of CTZ/TZ. A dosing regimen of 2 g/1 g CTZ/TZ administered every 8 h as a 1-h intravenous infusion, as currently recommended, did not provided adequate coverage to achieve a sufficient probability of target attainment for P. aeruginosa strains with MICs ≥ 4 mg/L.

Keywords

Pseudomonas aeruginosa Ceftolozane/tazobactam Pharmacokinetic/pharmacodynamic Multidrug resistant 

Abbreviations

AST

Antimicrobial susceptibility tests

CTZ/TZ

Ceftolozane/tazobactam

HRAM

High-resolution accurate mass

IQR

Interquartile range

MIC

Minimal inhibitory concentrations

PD

Pharmacodynamic

PK

Pharmacokinetic

UHPLC

Ultra-high performance liquid chromatography

Notes

Acknowledgment

Alex Edelman is acknowledged for careful reading.

PK/PD Study group

Aurelien Dinh, Marine de Laroche, François Parquin (Intensive Care Unit), Dominique Grenet (Pulmonary medicine), Eric Farfour (Clinical Biology), Antoine Roux (Pulmonary medicine), Sandra de Miranda (Pulmonary medicine), Gauthier Péan de Ponfilly (Clinical Biology), Matthieu Legrand (Serious Burn Unit), François Dépret (Serious Burn Unit), Mourad BENYAMINA (Serious Burn Unit).

Compliance with ethical standards

Conflict of interest

BP: MSD: conference invitation, lecture fees

GP: None reported

PL: None reported

ML: None reported

NEH: None reported

ALM: MSD: conference invitation

Ethical approval

Not applicable

Informed consent

Not applicable

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Benoît Pilmis
    • 1
    • 2
    Email author
  • Grégoire Petitjean
    • 3
    • 2
  • Philippe Lesprit
    • 4
  • Matthieu Lafaurie
    • 5
  • Najoua El Helali
    • 3
    • 6
  • Alban Le Monnier
    • 3
    • 2
    • 6
  • on behalf the ATB PK/PD study group
  1. 1.Equipe Mobile de Microbiologie Clinique, Groupe Hospitalier Paris Saint-JosephParisFrance
  2. 2.EA4043 Unité Bactéries Pathogènes et Santés (UBaPS)Université Paris-Sud SaclayOrsayFrance
  3. 3.Plateforme de Dosage des Anti-infectieuxGroupe Hospitalier Paris Saint-JosephParisFrance
  4. 4.Service de Biologie CliniqueHôpital FochSuresnesFrance
  5. 5.Unité d’Intervention en Infectiologie (U2i)Hôpital Saint-LouisParisFrance
  6. 6.Laboratoire de Microbiologie CliniqueGroupe Hospitalier Paris Saint-JosephParisFrance

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