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.
OBJECTIVE
Temocillin, a 6alpha-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 > or = 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, 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 PTA(95) (free drug) obtained for MIC < or = 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.
De Jongh
Raf
R
Dienst Voor Intensieve Zorgen, Ziekenhuis Oost-Limburg, B-3600 Genk, Belgium.
Hens
Ria
R
Basma
Violetta
V
Mouton
Johan W
JW
Tulkens
Paul M
PM
Carryn
Stéphane
S
D000368:Aged; D003422:Critical Care / Q000379:methods*; D003428:Cross Infection / Q000188:drug therapy* / Q000378:metabolism; D004334:Drug Administration Schedule; D004347:Drug Interactions / Q000502:physiology; D004355:Drug Stability; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests / Q000379:methods; D008875:Middle Aged; D010406:Penicillins / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics*; D018410:Pneumonia, Bacterial / Q000188:drug therapy* / Q000378:metabolism; D011446:Prospective Studies
D010406:Penicillins; C031367:temocillin