Population pharmacokinetic-pharmacodynamic target attainment analysis of sulbactam in patients with impaired renal function

Dosing considerations for Acinetobacter baumannii infections

Yuta Yokoyama, Kazuaki Matsumoto, Kazuro Ikawa, Erika Watanabe, Norifumi Morikawa, Yasuo Takeda

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

This study aimed to perform a pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analysis of sulbactam against Acinetobacter baumannii in patients with impaired renal function. The PK data (188 plasma samples and 27 urine samples) were modeled simultaneously. The mean population parameters were CL<inf>r</inf> (l/h)=0.0792×CL<inf>cr</inf> (ml/min), CL<inf>nr</inf> (l/h)=2.35, V<inf>c</inf> (l)=12.2, Q (l/h)=4.68 and V<inf>p</inf> (l)=4.44, where CL<inf>r</inf> and CL<inf>nr</inf> are the renal and non-renal clearances, V<inf>c</inf> and V<inf>p</inf> are the distribution volumes of the central and peripheral compartments and Q is intercompartmental clearance. The creatinine clearance (CL<inf>cr</inf>) was the most significant covariate. The determined MIC of sulbactam against A.baumannii clinical isolates (n=27) was 0.75-6.0μg/ml with MIC<inf>50</inf> and MIC<inf>90</inf> of 1 and 4μg/ml, respectively. For sulbactam regimens, a Monte Carlo simulation estimated the probabilities of attaining the bactericidal target (60% of the time above the MIC) and determined the PK-PD breakpoints (the highest MICs at which the probabilities were 90% or more). In a patient with a CL<inf>cr</inf> of 15ml/min, a regimen of 1g twice daily achieved a 90% or more probability against the A.baumannii isolate population; however, 2g four times daily was needed for a 90% or more probability in a patient with a CL<inf>cr</inf> of 90ml/min. The results of the PK-PD target attainment analysis are useful when choosing the sulbactam regimen based on the CL<inf>cr</inf> of the patient and the susceptibility of A.baumannii. Registration number: UMIN000007356.

Original languageEnglish
Pages (from-to)284-289
Number of pages6
JournalJournal of Infection and Chemotherapy
Volume21
Issue number4
DOIs
Publication statusPublished - 2015 Apr 1
Externally publishedYes

Fingerprint

Acinetobacter Infections
Sulbactam
Acinetobacter baumannii
Pharmacokinetics
Kidney
Population
Creatinine
Urine

Keywords

  • Acinetobacter baumannii
  • Dosing regimen
  • Monte carlo simulation
  • Population pharmacokinetics
  • Sulbactam

ASJC Scopus subject areas

  • Microbiology (medical)
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

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title = "Population pharmacokinetic-pharmacodynamic target attainment analysis of sulbactam in patients with impaired renal function: Dosing considerations for Acinetobacter baumannii infections",
abstract = "This study aimed to perform a pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analysis of sulbactam against Acinetobacter baumannii in patients with impaired renal function. The PK data (188 plasma samples and 27 urine samples) were modeled simultaneously. The mean population parameters were CLr (l/h)=0.0792×CLcr (ml/min), CLnr (l/h)=2.35, Vc (l)=12.2, Q (l/h)=4.68 and Vp (l)=4.44, where CLr and CLnr are the renal and non-renal clearances, Vc and Vp are the distribution volumes of the central and peripheral compartments and Q is intercompartmental clearance. The creatinine clearance (CLcr) was the most significant covariate. The determined MIC of sulbactam against A.baumannii clinical isolates (n=27) was 0.75-6.0μg/ml with MIC50 and MIC90 of 1 and 4μg/ml, respectively. For sulbactam regimens, a Monte Carlo simulation estimated the probabilities of attaining the bactericidal target (60{\%} of the time above the MIC) and determined the PK-PD breakpoints (the highest MICs at which the probabilities were 90{\%} or more). In a patient with a CLcr of 15ml/min, a regimen of 1g twice daily achieved a 90{\%} or more probability against the A.baumannii isolate population; however, 2g four times daily was needed for a 90{\%} or more probability in a patient with a CLcr of 90ml/min. The results of the PK-PD target attainment analysis are useful when choosing the sulbactam regimen based on the CLcr of the patient and the susceptibility of A.baumannii. Registration number: UMIN000007356.",
keywords = "Acinetobacter baumannii, Dosing regimen, Monte carlo simulation, Population pharmacokinetics, Sulbactam",
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AU - Matsumoto, Kazuaki

AU - Ikawa, Kazuro

AU - Watanabe, Erika

AU - Morikawa, Norifumi

AU - Takeda, Yasuo

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AB - This study aimed to perform a pharmacokinetic (PK)-pharmacodynamic (PD) target attainment analysis of sulbactam against Acinetobacter baumannii in patients with impaired renal function. The PK data (188 plasma samples and 27 urine samples) were modeled simultaneously. The mean population parameters were CLr (l/h)=0.0792×CLcr (ml/min), CLnr (l/h)=2.35, Vc (l)=12.2, Q (l/h)=4.68 and Vp (l)=4.44, where CLr and CLnr are the renal and non-renal clearances, Vc and Vp are the distribution volumes of the central and peripheral compartments and Q is intercompartmental clearance. The creatinine clearance (CLcr) was the most significant covariate. The determined MIC of sulbactam against A.baumannii clinical isolates (n=27) was 0.75-6.0μg/ml with MIC50 and MIC90 of 1 and 4μg/ml, respectively. For sulbactam regimens, a Monte Carlo simulation estimated the probabilities of attaining the bactericidal target (60% of the time above the MIC) and determined the PK-PD breakpoints (the highest MICs at which the probabilities were 90% or more). In a patient with a CLcr of 15ml/min, a regimen of 1g twice daily achieved a 90% or more probability against the A.baumannii isolate population; however, 2g four times daily was needed for a 90% or more probability in a patient with a CLcr of 90ml/min. The results of the PK-PD target attainment analysis are useful when choosing the sulbactam regimen based on the CLcr of the patient and the susceptibility of A.baumannii. Registration number: UMIN000007356.

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