title: Repeated Piperacillin-Tazobactam Plasma Concentration Measurements in Severely Obese Versus Nonobese Critically Ill Septic Patients and the Risk of Under- and Overdosing.
abstract: OBJECTIVE
  Obesity and critical illness modify pharmacokinetics of antibiotics, but piperacillin-tazobactam continuous IV infusion pharmacokinetics has been poorly studied in obese critically ill patients. We aimed to compare pharmacokinetics of piperacillin in severely obese and nonobese patients with severe sepsis or septic shock. We hypothesized that plasma concentration variability would expose the critically ill to both piperacillin under and overdosing.
  
  
  METHODS
  Prospective comparative study. Consecutive critically ill severely obese (body mass index, > 35 kg/m) and nonobese patients (body mass index, < 30 kg/m) were treated with 16 g/2 g/24 hr continuous piperacillin-tazobactam infusion. Piperacillin plasma concentration was measured every 12 hours over a 7-day period by high-pressure liquid chromatography. Unbound piperacillin plasma concentration and fractional time of plasma concentration spent over 64 mg/L (4-fold the minimal inhibitory concentration for Pseudomonas aeruginosa) were compared between the two groups. We performed 5,000 Monte Carlo simulations for various dosing regimens and minimal inhibitory concentration and calculated the probability to spend 100% of the time over 64 mg/L.
  
  
  RESULTS
  We enrolled 11 severely obese and 12 nonobese patients and obtained 294 blood samples. We did not observe a statistically significant difference in piperacillin plasma concentrations over time between groups. The fractional time over 64 mg/L was 64% (43-82%) and 93% (85-100%) in obese and nonobese patients, respectively, p = 0.027 with intra- and intergroup variability. Five nonobese and two obese patients experienced potentially toxic piperacillin plasma concentrations. When 64 mg/L was targeted, Monte Carlo simulations showed that 12 g/1.5 g/24 hr was inadequate in both groups and 16 g/2 g/24 hr was adequate only in nonobese patients.
  
  
  CONCLUSIONS
  Using a conventional dosing of 16 g/2 g/24 hr continuous infusion, obese patients were more likely than nonobese patients to experience piperacillin underdosing when facing high minimal inhibitory concentration pathogens. The present study suggests that piperacillin drug monitoring might be necessary in the sickest patients who are at the highest risk of unpredictable plasma concentration exposing them to overdose, toxicity, underdosing, and treatment failure.
authors.affiliation: 1Department of Critical Care Medicine and Anesthesiology, Saint Eloi Teaching Hospital, Montpellier, France. 2Centre National de la Recherche Scientifique (CNRS 9214) - Institut National de la Santé et de la Recherche Médicale (INSERM U-1046), University of Montpellier, France. 3Laboratory of Clinical Pharmacokinetics and Clinical Pharmacy, PKPD Group, INSERM U1034, Haut-Lévêque hospital, CHU Bordeaux, University of Bordeaux, Pessac, France. 4Department of Microbiology, Arnaud de Villeneuve Teaching Hospital, Montpellier, France. 5Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, NY. 6Department of Medical Statistics, Arnaud de Villeneuve Teaching Hospital, Montpellier, France.
authors.forename: Boris
authors.initials: B
authors.lastname: Jung
authors.forename: Martin
authors.initials: M
authors.lastname: Mahul
authors.forename: Dominique
authors.initials: D
authors.lastname: Breilh
authors.forename: Rachel
authors.initials: R
authors.lastname: Legeron
authors.forename: Jeremy
authors.initials: J
authors.lastname: Signe
authors.forename: Helene
authors.initials: H
authors.lastname: Jean-Pierre
authors.forename: Anne-Catrin
authors.initials: AC
authors.lastname: Uhlemann
authors.forename: Nicolas
authors.initials: N
authors.lastname: Molinari
authors.forename: Samir
authors.initials: S
authors.lastname: Jaber
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015992:Body Mass Index; D016638:Critical Illness; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009010:Monte Carlo Method; D009765:Obesity / Q000453:epidemiology / Q000378:metabolism*; D010397:Penicillanic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010878:Piperacillin / Q000008:administration & dosage / Q000493:pharmacokinetics; D000077725:Piperacillin, Tazobactam Drug Combination; D011446:Prospective Studies; D012772:Shock, Septic / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology
chemical_list: D000900:Anti-Bacterial Agents; D000077725:Piperacillin, Tazobactam Drug Combination; D010397:Penicillanic Acid; D010878:Piperacillin