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 0.75-6.0 μg/ml with MIC50 and MIC90 of 1 and 4 μg/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 15 ml/min, a regimen of 1 g twice daily achieved a 90% or more probability against the A. baumannii isolate population; however, 2 g four times daily was needed for a 90% or more probability in a patient with a CLcr of 90 ml/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.
  
  
  BACKGROUND
  UMIN000007356.
authors: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan; Department of Clinical Pharmacotherapy, Hiroshima University, Japan.
authors: Yuta
authors: Y
authors: Yokoyama
authors: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan.
authors: Kazuaki
authors: K
authors: Matsumoto
authors: Department of Clinical Pharmacotherapy, Hiroshima University, Japan.
authors: Kazuro
authors: K
authors: Ikawa
authors: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan.
authors: Erika
authors: E
authors: Watanabe
authors: Department of Clinical Pharmacotherapy, Hiroshima University, Japan.
authors: Norifumi
authors: N
authors: Morikawa
authors: Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Japan. Electronic address: takeda@m.kufm.kagoshima-u.ac.jp.
authors: Yasuo
authors: Y
authors: Takeda
mesh_terms: D000151:Acinetobacter Infections / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D040981:Acinetobacter baumannii / Q000187:drug effects*; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D006801:Humans; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D051437:Renal Insufficiency / Q000378:metabolism* / Q000382:microbiology; D013407:Sulbactam / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine
chemical_list: D000900:Anti-Bacterial Agents; D013407:Sulbactam
keywords: Acinetobacter baumannii; Dosing regimen; Monte Carlo simulation; Population pharmacokinetics; Sulbactam