Universität zu Köln

Al Jalali, V, Woelfl-Duchek, M., Taubert, M., Matzneller, P., Lackner, E., Dorn, C., Kratzer, A., Wulkersdorfer, B., Oesterreicher, Z. and Zeitlinger, M. (2021). Plasma and soft tissue pharmacokinetics of ceftolozane/tazobactam in healthy volunteers after single and multiple intravenous infusion: a microdialysis study. J. Antimicrob. Chemother., 76 (9). S. 2342 - 2352. OXFORD: OXFORD UNIV PRESS. ISSN 1460-2091

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Abstract

Objectives: To investigate ceftolozane/tazobactam pharmacokinetics (PK) in plasma and interstitial space fluid (ISF) of muscle and subcutaneous tissue and establish a population PK model. Methods: Eight healthy volunteers received four IV doses of 1000/500 mg ceftolozane/tazobactam q8h in a prospective, open-Labelled PK study. ISF concentration-time profiles were determined via in vivo microdialysis up to 8 h post-dose and efficacy of unbound ceftolozane and tazobactam was estimated using the time above MIC (%fT(>MIC)) and time above threshold concentration (%T->CT), respectively. A population PK model was established by merging derived plasma and soft tissue PK data. Results: Ceftolozane reached %fT(>MIC) mic values of 100% in plasma, muscle and subcutaneous ISF for Enterobacteriaceae and 87%, 89% and 87%, respectively, for Pseudomonas aeruginosa. Tazobactam %T->CT was 21%, 22% and 21% in plasma, muscle and subcutaneous ISF, respectively. Plasma protein binding was 6.3% for ceftolozane and 8.0% for tazobactam. Multiple-dose ceftolozane AUC(0-8) ISF/plasma ratios were 0.92 +/- 0.17 in muscle and 0.88 +/- 0.18 in subcutis, and tazobactam ratios were 0.89 +/- 0.25 in muscle and 0.87 +/- 0.21 in subcutis, suggesting substantial soft tissue penetration. Conclusions: Tazobactam %T->CT values were distinctly below proposed target values, indicating that tazobactam might be underdosed in the investigated drug combination. However, ISF/unbound plasma ratios of ceftolozane and tazobactam support their use in soft tissue infections. A plasma and soft tissue PK model adds important information on the PK profile of ceftolozane/tazobactam. Further investigations in patients suffering from wound infections are needed to confirm these findings.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Al Jalali, V UNSPECIFIED UNSPECIFIED UNSPECIFIED Woelfl-Duchek, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Taubert, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Matzneller, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lackner, E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Dorn, C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kratzer, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Wulkersdorfer, B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Oesterreicher, Z. UNSPECIFIED UNSPECIFIED UNSPECIFIED Zeitlinger, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-582353
DOI:	10.1093/jac/dkab166
Journal or Publication Title:	J. Antimicrob. Chemother.
Volume:	76
Number:	9
Page Range:	S. 2342 - 2352
Date:	2021
Publisher:	OXFORD UNIV PRESS
Place of Publication:	OXFORD
ISSN:	1460-2091
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language IN-VIVO ACTIVITIES; DOUBLE-BLIND; PSEUDOMONAS-AERUGINOSA; PLUS METRONIDAZOLE; TAZOBACTAM; SAFETY; CEPHALOSPORIN; COMBINATION; TRIAL; INFECTIONS Multiple languages Infectious Diseases; Microbiology; Pharmacology & Pharmacy Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/58235