title: Pharmacokinetics of cefoperazone/sulbactam in critically ill patients receiving continuous venovenous hemofiltration.
abstract: OBJECTIVE
  Cefoperazone/sulbactam (CFP/SUL) is a β-lactam/β-lactamase inhibitor combination with little data available for the development of effective dosing guidelines during continuous renal replacement therapy. This study aimed to investigate the pharmacokinetics (PK) of cefoperazone/sulbactam in critically ill patients on continuous venovenous hemofiltration (CVVH).
  
  
  METHODS
  A prospective, single-center, and open-label study was conducted. Critically ill patients receiving CVVH with 3 g cefoperazone/sulbactam (2.0/1.0 g) intravenously every 8 h were recruited. Serial blood and ultrafiltrate samples were paired collected for initial dose (occasion 1) and steady state (occasion 2). PK was assessed by non-compartmental analysis, and pharmacodynamics (PD) was evaluated by the percent of time for which drug concentrations exceed the minimum inhibitory concentration (%T >MIC).
  
  
  RESULTS
  Total fourteen patients were enrolled. Volume of distribution at steady state (V ss) of cefoperazone and sulbactam for initial doses (20.8 ± and 28.4 L, respectively) increased significantly compared with those in healthy volunteers (P = 0.009 for CFP, P = 0.030 for SUL). Both cefoperazone and sulbactam showed significantly lower total clearance (CLt) (46.2 and 117.6 mL/min, respectively) compared with healthy volunteers (P = 0.000 for CFP, P = 0.017 for SUL). There is no significant difference in PK between occasion 1 and occasion 2 (P > 0.05). For occasion 1, mean CVVH clearance accounted for 34.3 and 33.9 % for CLt of cefoperazone and sulbactam, respectively. The minimum PD target of 60%T >MIC was achieved in seven of eight patients. For occasion 2, eight of nine patients achieved cefoperazone concentrations that were above the MIC for the entire dosing interval.
  
  
  CONCLUSIONS
  PK of cefoperazone/sulbactam was altered in critically ill patients undergoing CVVH. Therapeutic drug monitoring would be recommended to individualize the dose regimen.
authors.affiliation: Institute of Clinical Pharmacology, the Second Affiliated Hospital, Harbin Medical University, Xuefu Road 246#, Nangang District, Harbin, 150086, Heilongjiang Province, China.
authors.forename: Chunlu
authors.initials: C
authors.lastname: Gao
authors.affiliation: Institute of Clinical Pharmacology, the Second Affiliated Hospital, Harbin Medical University, Xuefu Road 246#, Nangang District, Harbin, 150086, Heilongjiang Province, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Tong
authors.affiliation: The Second Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Kaijiang
authors.initials: K
authors.lastname: Yu
authors.affiliation: Department of Pharmacy of the Second Affiliated Hospital, Harbin Medical University, Harbin, China.
authors.forename: Zhidan
authors.initials: Z
authors.lastname: Sun
authors.affiliation: College of Pharmacy, Harbin Medical University, Harbin, China.
authors.forename: Ran
authors.initials: R
authors.lastname: An
authors.affiliation: Institute of Clinical Pharmacology, the Second Affiliated Hospital, Harbin Medical University, Xuefu Road 246#, Nangang District, Harbin, 150086, Heilongjiang Province, China. dzm1956@126.com.|Department of Pharmacy of the Second Affiliated Hospital, Harbin Medical University, Harbin, China. dzm1956@126.com.|Key Laboratory of Drug Research, Heilongjiang Higher Education Institutions, Harbin Medical University, Harbin, China. dzm1956@126.com.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Du
mesh_terms: D040981:Acinetobacter baumannii / Q000187:drug effects / Q000254:growth & development; D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D002438:Cefoperazone / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D016638:Critical Illness; D005260:Female; D006440:Hemofiltration; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000254:growth & development; D013407:Sulbactam / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D002438:Cefoperazone; D013407:Sulbactam
keywords: Antibiotics; CRRT; Cefoperazone; Critically ill; Pharmacokinetics; Sulbactam