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.

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Sepsis is a common and serious complication in intensive care unit patients. An important factor in optimizing survival rates in septic patients is the ability to start treatment early in the course of disease; there is, therefore, a need for accurate diagnostic tests. In recent years, there has been a move away from the rather vague and nonspecific signs that were previously used to diagnose sepsis towards the possible adjunctive role of biomarkers. Many biomarkers have been proposed and assessed clinically, but none alone is specific enough to definitively determine diagnosis. The future direction of research is most likely a greater focus on the use of panels or combinations of markers with clinical signs. Some biomarkers may also be useful for prognosis and guiding therapy. Here, the authors will review our changing approaches to sepsis diagnosis and discuss some of the markers that seem most relevant at the present time.

Vancomycin remains a primary treatment for infections caused by Gram-positive bacteria resistant to ␤-lactam antibiotics, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and ampicillin-resistant enterococci (1). Despite extensive clinical use of vancomycin over recent years, the optimal dosing strategy for rapid achievement of therapeutic concentrations still remains a challenge for physicians. This is of particular interest for patients with septic shock, who require adequate antibiotic therapy, especially in terms of drug concentrations, from the early phase of treatment (2, 3). To rapidly achieve optimal vancomycin concentrations in such patients, a loading dose followed by a continuous drug infusion (CI) has been proposed (4).Although CI of vancomycin is increasingly used, especially in the intensive care unit (ICU), there is still a controversy as to whether this mode of administration provides better results than standard intermittent drug administration (II). Several studies have shown no differences in clinical efficacy or mortality between the two therapeutic strategies in infections with Gram-positive bacteria (4-6). However, Wysocki et al. (5) demonstrated that CI allowed faster achievement of target concentrations, presented less variability in drug concentrations, and resulted in reduced costs of therapy. Furthermore, a recent meta-analysis showed that CI was associated with a significantly lower risk of drug-related nephrotoxicity than II, despite the use of similar daily doses (6).Nevertheless, because of significant changes in vancomycin pharmacokinetics (PK) during critical illness, such as increased volume of distribution (V) and augmented clearance, the standard CI regimen (e.g., a loading dose of 15 mg/kg of body weight, followed by 30 mg/kg over 24 h for patients with normal renal function) (5) has been associated with inadequate drug concentrations in a high proportion of septic patients in the first 2 days of therapy (7). As such, Roberts et al. (8), using a population PK analysis, suggested that a vancomycin loading dose of 35 mg/kg, followed by daily doses adjusted to creatinine clearance (CrCL, ranging from 7 to 45 mg/kg/day), would rapidly achieve adequate drug concentrations in critically ill patients. Nevertheless, this approach has not been prospectively validated yet.Another important issue concerning vancomycin is that clinical efficacy is best predicted when the ratio between the area under the curve of drug concentrations over 24 h (AUC 0 -24 ) and the MIC for the pathogen isolated (AUC 0 -24 /MIC) exceeds 400 (9-12). To ensure optimal AUC 0 -24 /MIC ratios, several studies have proposed target serum drug concentrations between 15 and 30 mg/liter during CI of vancomycin (5, 13-15). Nevertheless, no study has evaluated the correlation between vancomycin concentrations and the achievement of an AUC 0 -24 /MIC ratio of Ն400 in critically ill patients, in particular during the first day of therapy.The aim of thi...

IntroductionThe aim of this study was to describe the population pharmacokinetics of vancomycin in critically ill patients treated with and without extracorporeal membrane oxygenation (ECMO).MethodsWe retrospectively reviewed data from critically ill patients treated with ECMO and matched controls who received a continuous infusion of vancomycin (35 mg/kg loading dose over 4 hours followed by a daily infusion adapted to creatinine clearance, CrCl)). The pharmacokinetics of vancomycin were described using non-linear mixed effects modeling.ResultsWe compared 11 patients treated with ECMO with 11 well-matched controls. Drug dosing was similar between groups. The median interquartile range (IQR) vancomycin concentrations in ECMO and non-ECMO patients were 51 (28 to 71) versus 45 (37 to 71) mg/L at 4 hours; 23 (16 to 38) versus 29 (21 to 35) mg/L at 12 hours; 20 (12 to 36) versus 23 (17–28) mg/L at 24 hours (ANOVA, P =0.53). Median (ranges) volume of distribution (Vd) was 99.3 (49.1 to 212.3) and 92.3 (22.4 to 149.4) L in ECMO and non-ECMO patients, respectively, and clearance 2.4 (1.7 to 4.9) versus 2.3 (1.8 to 3.6) L/h (not significant). Insufficient drug concentrations (that is drug levels <20 mg/dL) were more common in the ECMO group. The pharmacokinetic model (non-linear mixed effects modeling) was prospectively validated in five additional ECMO-treated patients over a 6-month period. Linear regression analysis comparing the observed concentrations and those predicted using the model showed good correlation (r2 of 0.67; P <0.001).ConclusionsVancomycin concentrations were similar between ECMO and non-ECMO patients in the early phase of therapy. ECMO treatment was not associated with significant changes in Vd and drug clearance compared with the control patients.