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

De Jongh, Raf;Hens, Ria;Basma, Violetta;Mouton, Johan W.;Carryn, Stéphane;et.al.
(2008) Journal of Antimicrobial Chemotherapy — Vol. 61, n° 2, p. 382-388 (2008)

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Authors
  • De Jongh, Raf
    Author
  • Hens, Ria
    Author
  • Basma, ViolettaUCLouvain
    Author
  • Mouton, Johan W.
    Author
  • Tulkens, Paul M.UCLouvain
    Author
  • Carryn, StéphaneUCLouvain
    Author
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Abstract
Background and aims: Temocillin, a 6 alpha-methoxy-penicillin stable towards most beta-lactamases (including extended-spectrum beta-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 (PTA(95)) versus MIC (based on time above MIC >= 40% for measured free drug). Results: Temocillin was stable at 37 degrees 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, C-max (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 PTA(95) (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.
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De Jongh, R., Hens, R., Basma, V., Mouton, J. W., Tulkens, P. M., & Carryn, S. (2008). 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. Journal of Antimicrobial Chemotherapy, 61(2), 382-388. https://doi.org/10.1093/jac/dkm467 (Original work published 2008)