title: Pharmacokinetics and tissue penetration of cefoxitin in obesity: implications for risk of surgical site infection.
abstract: BACKGROUND
  Obesity is a significant risk factor for surgical site infections (SSIs), for poorly understood reasons. SSIs are a major cause of morbidity, prolonged hospitalization, and increased health care cost. Drug disposition in general is frequently altered in the obese. Preoperative antibiotic administration, achieving adequate tissue concentrations at the time of incision, is an essential strategy to prevent SSIs. Nonetheless, there is little information regarding antibiotic concentrations in obese surgical patients. This investigation tested the hypothesis that the prophylactic antibiotic cefoxitin may have delayed and/or diminished tissue penetration in the obese.
  
  
  METHODS
  Plasma and tissue concentrations of cefoxitin were determined in obese patients undergoing abdominal and pelvic surgery (body mass index 43 ± 10 kg/m(2), n = 14, 2 g cefoxitin) and in normal-weight patients and healthy volunteers (body mass index 20 ± 2 kg/m(2), n = 13, 1 g cefoxitin). Tissue concentrations were measured using a microdialysis probe in the subcutaneous layer of the abdomen, and in adipose tissue excised at the time of incision and wound closure.
  
  
  RESULTS
  Plasma concentrations and area under the concentration-time curve (AUC) were approximately 2-fold higher in the obese patients because of the 2-fold-higher dose. Dose-normalized concentrations were higher, although AUCs were not significantly different. Measured and dose-normalized subcutaneous cefoxitin concentrations and AUCs in the obese patients were significantly lower than in the normal-weight subjects. There was an inverse relationship between cefoxitin tissue penetration (AUC(tissue)/AUC(plasma) ratio) and body mass index. Tissue penetration was substantially lower in the obese patients (0.08 ± 0.07 vs 0.37 ± 0.26, P < 0.05). Adipose tissue cefoxitin concentrations in obese patients were only 7.8 ± 7.3 and 2.7 ± 1.4 μg/g, respectively, at incision and closure, below the minimum inhibitory concentration of 8 and 16 μg/mL, respectively, for aerobic and anaerobic microorganisms.
  
  
  CONCLUSIONS
  Obese surgical patients have impaired tissue penetration of the prophylactic antibiotic cefoxitin, and inadequate tissue concentrations despite increased clinical dose (2 g). Inadequate tissue antibiotic concentrations may be a factor in the increased risk of SSIs in obese surgical patients. Additional studies are needed to define doses achieving adequate tissue concentrations.
authors.affiliation: Department of Anesthesiology, Division of Clinical and Translational Research, Washington University, St. Louis, MO, USA.
authors.forename: Octavian
authors.initials: O
authors.lastname: Toma
authors.forename: Patty
authors.initials: P
authors.lastname: Suntrup
authors.forename: Andrei
authors.initials: A
authors.lastname: Stefanescu
authors.forename: Amy
authors.initials: A
authors.lastname: London
authors.forename: Matthew
authors.initials: M
authors.lastname: Mutch
authors.forename: Evan
authors.initials: E
authors.lastname: Kharasch
mesh_terms: D000005:Abdomen / Q000601:surgery; D000273:Adipose Tissue / Q000378:metabolism / Q000601:surgery; D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D019072:Antibiotic Prophylaxis; D019540:Area Under Curve; D015992:Body Mass Index; D016022:Case-Control Studies; D002440:Cefoxitin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D017551:Microdialysis; D008875:Middle Aged; D008923:Missouri; D009765:Obesity / Q000150:complications* / Q000175:diagnosis / Q000378:metabolism; D010388:Pelvis / Q000601:surgery; D018570:Risk Assessment; D012307:Risk Factors; D013514:Surgical Procedures, Operative / Q000009:adverse effects*; D013530:Surgical Wound Infection / Q000209:etiology / Q000378:metabolism / Q000517:prevention & control*; D014018:Tissue Distribution; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000900:Anti-Bacterial Agents; D002440:Cefoxitin