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JAC Advance Access originally published online on December 10, 2007
Journal of Antimicrobial Chemotherapy 2008 61(2):382-388; doi:10.1093/jac/dkm467
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Original research

Continuous versus intermittent infusion of temocillin, a directed spectrum penicillin for intensive care patients with nosocomial pneumonia: stability, compatibility, population pharmacokinetic studies and breakpoint selection

Raf De Jongh1, Ria Hens1, Violetta Basma2, Johan W. Mouton3, Paul M. Tulkens2,* and Stéphane Carryn2

1 Dienst Voor Intensieve Zorgen, Ziekenhuis Oost-Limburg, B-3600 Genk, Belgium 2 Unité de Pharmacologie Cellulaire et Moléculaire, Université Catholique de Louvain, B-1200 Bruxelles, Belgium 3 Afdeling Medische Microbiologie en Infectieziekten, Canisius Whilhemina Ziekenhuis, NL-6500 GS Nijmegen, The Netherlands

Received 28 August 2007; returned 5 October 2007; revised 5 November 2007; accepted 12 November 2007

* Corresponding author. Tel: +32-2-764-7371; Fax: +32-2-764-7373; E-mail: tulkens{at}facm.ucl.ac.be

Background and aims: Temocillin, a 6{alpha}-methoxy-penicillin stable towards most β-lactamases (including extended-spectrum β-lactamase), is presented as an alternative to carbapenems for susceptible Enterobacteriaceae in microbiological surveys. We aimed at documenting its potential clinical usefulness in intensive care (IC) patients using pharmacokinetic/pharmacodynamic approaches applied to conventional (twice daily) and continuous infusion (CI) modes of administration.

Methods: (i) In vitro evaluation of temocillin stability and compatibility with other drugs under conditions pertinent of CI in IC patients; (ii) pharmacokinetic study in patients treated by CI (4 g/day; n = 6) versus [twice daily (2 g every 12 h); n = 6]; (iii) population pharmacokinetic analysis of twice daily with Monte Carlo simulations to determine 95% probability of target attainment (PTA95) versus MIC (based on time above MIC ≥40% for measured free drug).

Results: Temocillin was stable at 37°C in 8.34% solutions for 24 h and compatible with flucloxacillin and aminoglycosides, but not with several other antibiotic and non-antibiotic drugs. With CI, stable total serum concentrations were 73.5 ± 3.0 mg/L (SEM) and free concentration 29.3 ± 2.8 mg/L. With twice daily, Cmax (total drug) was 147 ± 12.3 mg/L (SEM; free drug: 50.3 ± 15.8 mg/L), lowest trough (total drug) 12.3 mg/L, and PTA95 (free drug) obtained for MIC ≤8 mg/L.

Conclusions: Temocillin (4 g/day) by CI yields stable free serum concentrations above the current breakpoint (16 mg/L), although individual variations may suggest lowering the breakpoint to 8 mg/L (as for twice daily) unless the daily dose or the frequency of administration is increased.

Keywords: HPLC , Monte Carlo simulation , target attainment


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