Intrapulmonary penetration of ceftolozane/tazobactam and piperacillin/tazobactam
in healthy adult subjects.
Author(s): Chandorkar G, Huntington JA, Gotfried MH, Rodvold KA, Umeh O.
Affiliation(s): Cubist Pharmaceuticals, Inc., 65 Hayden Avenue, Lexington, MA 02421, USA.
gurudatt.chandorkar@cubist.com
Publication date & source: 2012, J Antimicrob Chemother. , 67(10):2463-9
OBJECTIVES: Appropriate antibiotic exposure at the site of infection is important
for clinically effective therapy. This study compared the epithelial lining fluid
(ELF) penetration of ceftolozane/tazobactam, which has potent in vitro activity
against many Gram-negative pathogens causing nosocomial pneumonia, with that of
piperacillin/tazobactam in healthy adult volunteers.
METHODS: In this Phase 1, open-label trial, 51 healthy adult subjects were
randomized to receive three doses of either ceftolozane/tazobactam 1.5 g
administered every 8 h via a 60 min infusion or piperacillin/tazobactam 4.5 g
administered every 6 h via a 30 min infusion. Serial blood samples were obtained
for determination of plasma drug concentrations. Bronchoscopy and bronchoalveolar
lavage were performed at pre-specified timepoints in five subjects per timepoint
in each treatment group to determine the ELF drug concentration. The penetration
of individual analytes into the ELF was determined from the ratio of the area
under the plasma concentration-time curve in ELF to that in plasma
(AUC(ELF)/AUC(plasma)).
RESULTS: Plasma and ELF concentrations of ceftolozane, piperacillin and
tazobactam increased rapidly, reaching maximal concentrations at the end of the
infusion. Mean maximum concentration and AUC from time 0 to the end of the dosing
interval (AUC(0-τ)) for ceftolozane in ELF were 21.8 mg/L and 75.1 mg·h/L,
respectively. Corresponding values for piperacillin were 58.8 mg/L and 94.5
mg·h/L. The ELF/plasma AUC ratio for ceftolozane was 0.48 compared with 0.26 for
piperacillin.
CONCLUSION: This study demonstrated that ceftolozane penetrated well into the ELF
following parenteral administration of ceftolozane/tazobactam.
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