Severe sepsis and septic shock can alter the pharmacokinetics of broad-spectrum ␤-lactams (meropenem, ceftazidime/cefepime, and piperacillin-tazobactam), resulting in inappropriate serum concentrations. Obesity may further modify the pharmacokinetics of these agents. We reviewed our data on critically ill obese patients (body mass index of >30 kg/m 2 ) treated with a broadspectrum ␤-lactam in whom therapeutic drug monitoring was performed and compared the data to those obtained in critically nonobese patients (body mass index of <25 kg/m 2 ) to assess whether there were differences in reaching optimal drug concentrations for the treatment of nosocomial infections. Sixty-eight serum levels were obtained from 49 obese patients. There was considerable variability in ␤-lactam serum concentrations (coefficient of variation of 50% to 92% for the three drugs). Standard drug regimens of ␤-lactams resulted in insufficient serum concentrations in 32% of the patients and overdosed concentrations in 25%. Continuous renal replacement therapy was identified by multivariable analysis as a risk factor for overdosage and a protective factor for insufficient ␤-lactam serum concentrations. The serum drug levels from the obese cohort were well matched for age, gender, renal function, and sequential organ failure assessment (SOFA) score to 68 serum levels measured in 59 nonobese patients. The only difference observed between the two cohorts was in the subgroup of patients treated with meropenem and who were not receiving continuous renal replacement therapy: serum concentrations were lower in the obese cohort. No differences were observed in pharmacokinetic variables between the two groups. Routine therapeutic drug monitoring of ␤-lactams should be continued in obese critically ill patients.

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IntroductionThe use of standard doses of β-lactam antibiotics during continuous renal replacement therapy (CRRT) may result in inadequate serum concentrations. The aim of this study was to evaluate the adequacy of unadjusted drug regimens (i.e., similar to those used in patients with normal renal function) in patients treated with CRRT and the influence of CRRT intensity on drug clearance.MethodsWe reviewed data from 50 consecutive adult patients admitted to our Department of Intensive Care in whom routine therapeutic drug monitoring (TDM) of broad-spectrum β-lactam antibiotics (ceftazidime or cefepime, CEF; piperacillin/tazobactam; TZP; meropenem, MEM) was performed using unadjusted β-lactam antibiotics regimens (CEF = 2 g q8h; TZP = 4 g q6h; MEM = 1 g q8h). Serum drug concentrations were measured twice during the elimination phase by high-performance liquid chromatography (HPLC-UV). We considered therapy was adequate when serum drug concentrations were between 4 and 8 times the minimal inhibitory concentration (MIC) of Pseudomonas aeruginosa during optimal periods of time for each drug (≥70% for CEF; ≥ 50% for TZP; ≥ 40% for MEM). Therapy was considered as early (ET) or late (LT) phase if TDM was performed within 48 hours of antibiotic initiation or later on, respectively.ResultsWe collected 73 serum samples from 50 patients (age 58 ± 13 years; Acute Physiology and Chronic Health Evaluation II (APACHE II) score on admission 21 (17–25)), 35 during ET and 38 during LT. Drug concentrations were above 4 times the MIC in 63 (90%), but above 8 times the MIC in 39 (53%) samples. The proportions of patients with adequate drug concentrations during ET and LT were quite similar. We found a weak but significant correlation between β-lactam antibiotics clearance and CRRT intensity.ConclusionsIn septic patients undergoing CRRT, doses of β-lactam antibiotics similar to those given to patients with normal renal function achieved drug levels above the target threshold in 90% of samples. Nevertheless, 53% of samples were associated with very high drug levels and daily drug regimens may need to be adapted accordingly.

This new vancomycin regimen allowed the rapid achievement of target drug concentrations in the majority of patients. CRRT intensity had an influence on vancomycin clearance.