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:
CreatorsEmailORCIDORCID Put Code
Al Jalali, VUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Woelfl-Duchek, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Taubert, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Matzneller, P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lackner, E.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Dorn, C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kratzer, A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wulkersdorfer, B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Oesterreicher, Z.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zeitlinger, M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
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:
KeywordsLanguage
IN-VIVO ACTIVITIES; DOUBLE-BLIND; PSEUDOMONAS-AERUGINOSA; PLUS METRONIDAZOLE; TAZOBACTAM; SAFETY; CEPHALOSPORIN; COMBINATION; TRIAL; INFECTIONSMultiple languages
Infectious Diseases; Microbiology; Pharmacology & PharmacyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/58235

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