Reduced subcutaneous tissue distribution of cefazolin in morbidly obese versus non-obese patients determined using clinical microdialysis.
OBJECTIVE
As morbidly obese patients are prone to surgical site infections, adequate blood and subcutaneous tissue concentrations of prophylactic antibiotic agents during surgery are imperative. In this study we evaluated cefazolin subcutaneous adipose tissue distribution in morbidly obese and non-obese patients, thereby quantifying the influence of morbid obesity on cefazolin pharmacokinetics and enabling Monte Carlo simulations for subsequent dose adjustments.


METHODS
Nine morbidly obese patients [body mass index (BMI) 47 ± 6 kg/m(2)], of whom eight were evaluable, and seven non-obese patients (BMI 28 ± 3 kg/m(2)) received cefazolin 2 g intravenously before surgery (NCT01309152). Using microdialysis, interstitial space fluid (ISF) samples of subcutaneous adipose tissue were collected together with total and unbound plasma cefazolin samples until 240 min after dosing. Using NONMEM, population pharmacokinetic modelling, covariate analysis and Monte Carlo simulations were performed.


RESULTS
The unbound (free) cefazolin ISF penetration ratio (fAUC(tissue)/fAUC(plasma)) was 0.70 (range 0.68-0.83) in morbidly obese patients versus 1.02 (range 0.85-1.41) in non-obese patients (P < 0.05). A two-compartment model with saturable protein binding was identified in which the central volume of distribution and cefazolin distribution from the central compartment to the ISF compartment proved dependent on body weight (P < 0.001 and P < 0.01, respectively). Monte Carlo simulations showed reduced probability of target attainment for morbidly obese versus non-obese patients for MIC values of 2 and 4 mg/L.


CONCLUSIONS
This study shows that cefazolin tissue distribution is lower in morbidly obese patients and reduces with increasing body weight, and that dose adjustments are required in this patient group.
Division of Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.
Margreke J E
MJ
Brill
Aletta P I
AP
Houwink
Stephan
S
Schmidt
Eric P A
EP
Van Dongen
Eric J
EJ
Hazebroek
Bert
B
van Ramshorst
Vera H
VH
Deneer
Johan W
JW
Mouton
Catherijne A J
CA
Knibbe
D061605:Administration, Intravenous; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D002437:Cefazolin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D005260:Female; D006801:Humans; D008297:Male; D017551:Microdialysis; D008875:Middle Aged; D015233:Models, Statistical; D009767:Obesity, Morbid; D010949:Plasma / Q000737:chemistry; D011446:Prospective Studies; D040521:Subcutaneous Tissue / Q000737:chemistry*
D000900:Anti-Bacterial Agents; D002437:Cefazolin
Monte Carlo simulations; population pharmacokinetics; subcutaneous ISF; surgical prophylaxis