IntroductionIncreasingly, derived estimates of glomerular filtration, such as the modification of diet in renal disease (MDRD) equation and Cockcroft-Gault (CG) formula are being employed in the intensive care unit (ICU). To date, these estimates have not been rigorously validated in those with augmented clearances, resulting in potentially inaccurate drug prescription.MethodsPost-hoc analysis of prospectively collected data in two tertiary level ICU's in Australia and Portugal. Patients with normal serum creatinine concentrations manifesting augmented renal clearance (ARC) (measured creatinine clearance (CLCR) > 130 ml/min/1.73 m2) were identified by chart review. Comparison between measured values and MDRD and CG estimates were then undertaken. Spearman correlation coefficients (rs) were calculated to determine goodness of fit, and precision and bias were assessed using Bland-Altman plots.ResultsEighty-six patients were included in analysis. The median [IQR] measured CLCR was 162 [145-190] ml/min/1.73 m2, as compared to 135 [116-171], 93 [83-110], 124[102-154], and 108 [87-135] ml/min/1.73 m2 estimated by CG, modified CG, 4-variable MDRD and 6-variable MDRD formulae. All of the equations significantly under-estimated the measured value, with CG displaying the smallest bias (39 ml/min/1.73 m2). Although a moderate correlation was noted between CLCR and CG (rs = 0.26, P = 0.017) and 4-variable MDRD (rs = 0.22, P = 0.047), neither had acceptable precision for clinical application in this setting. CG estimates had the highest sensitivity for correctly identifying patients with ARC (62%).ConclusionsDerived estimates of GFR are inaccurate in the setting of ARC, and should be interpreted with caution by the physician. A measured CLCR should be performed to accurately guide drug dosing.

a b s t r a c tThe aim of this study was to evaluate the effect of augmented renal clearance (ARC) on vancomycin serum concentrations in critically ill patients. This prospective, single-centre, observational, cohort study included 93 consecutive, critically ill septic patients who started treatment that included vancomycin by continuous infusion, admitted over a 2-year period (March 2006 to February 2008. ARC was defined as 24-h creatinine clearance (CL Cr ) > 130 mL/min/1.73 m 2 . Two groups were analysed: Group A, 56 patients with a CL Cr ≤ 130 mL/min/1.73 m 2 ; and Group B, 37 patients with a CL Cr > 130 mL/min/1.73 m 2 . Vancomycin therapeutic levels were assessed on the first 3 days of treatment (D 1 , D 2 and D 3 ). Serum vancomycin levels on D 1 , D 2 and D 3 , respectively, were 13.1, 16.6 and 18.6 mol/L for Group A and 9.7, 11.7 and 13.8 mol/L for Group B (P < 0.05 per day). The correlation between CL Cr and serum vancomycin on D 1 was −0.57 (P < 0.001). ARC was strongly associated with subtherapeutic vancomycin serum concentrations on the first 3 days of treatment.

Augmented renal clearance appears to be a common finding in this patient group, with sustained elevation of creatinine clearance throughout the first week in ICU. Future studies should focus on the implications for accurate dosing of renally eliminated pharmaceuticals in patients with augmented renal clearance, in addition to the potential impact on individual clinical outcomes.

Estimates of GFR using CG, CKD-EPI and MDRD formulae are flawed in the critically ill with normal sCr, significantly underestimating renal function in those with ARC and overestimating it in those with normal or decreased 8h-CLCR. Globally, the population exhibited ARC on more than half of the ICU admission days.

Background The optimal dosing of antibiotics in critically ill patients receiving renal replacement therapy (RRT) remains unclear. In this study, we describe the variability in RRT techniques and antibiotic dosing in critically ill patients receiving RRT and relate observed trough antibiotic concentrations to optimal targets. Methods We performed a prospective, observational, multinational, pharmacokinetic study in 29 intensive care units from 14 countries. We collected demographic, clinical, and RRT data. We measured trough antibiotic concentrations of meropenem, piperacillin-tazobactam, and vancomycin and related them to high- and low-target trough concentrations. Results We studied 381 patients and obtained 508 trough antibiotic concentrations. There was wide variability (4–8-fold) in antibiotic dosing regimens, RRT prescription, and estimated endogenous renal function. The overall median estimated total renal clearance (eTRCL) was 50 mL/minute (interquartile range [IQR], 35–65) and higher eTRCL was associated with lower trough concentrations for all antibiotics (P &lt; .05). The median (IQR) trough concentration for meropenem was 12.1 mg/L (7.9–18.8), piperacillin was 78.6 mg/L (49.5–127.3), tazobactam was 9.5 mg/L (6.3–14.2), and vancomycin was 14.3 mg/L (11.6–21.8). Trough concentrations failed to meet optimal higher limits in 26%, 36%, and 72% and optimal lower limits in 4%, 4%, and 55% of patients for meropenem, piperacillin, and vancomycin, respectively. Conclusions In critically ill patients treated with RRT, antibiotic dosing regimens, RRT prescription, and eTRCL varied markedly and resulted in highly variable antibiotic concentrations that failed to meet therapeutic targets in many patients.

IntroductionAchievement of optimal vancomycin exposure is crucial to improve the management of patients with life-threatening infections caused by susceptible Gram-positive bacteria and is of particular concern in patients with augmented renal clearance (ARC). The aim of this study was to develop a dosing nomogram for the administration of vancomycin by continuous infusion for the first 24 hours of therapy based on the measured urinary creatinine clearance (8 h CLCR).MethodsThis single-center study included all critically ill patients treated with vancomycin over a 13-month period (group 1), in which we retrospectively assessed the correlation between vancomycin clearance and 8 h CLCR. This data was used to develop a formula for optimised drug dosing. The efficiency of this formula was prospectively evaluated in a second cohort of 25 consecutive critically ill patients (group 2). Vancomycin serum concentrations between 20 to 30 mg/L were considered adequate. ARC was defined as 8 h CLCR more than 130 ml/min/1.73 m2.ResultsThe incidence of ARC was 36% (n = 29/79) and 40% (10/25) in group 1 (n = 79) and 2 (n = 25), respectively. The mean serum vancomycin concentration on day 1 was 21.5 (6.4) and 24.5 (5.2) mg/L, for both groups respectively. On the treatment day, vancomycin plasma clearance was 5.12 (1.9) L/h in group 1 and correlated significantly with the 8 h CLCR (r2 = 0.66; P <0.001). The achievement of adequate vancomycin serum concentrations in group 2 was 84% (n = 21/25) versus 51% (n = 40/79) – P <0.005.ConclusionsThis new vancomycin nomogram enabled the achievement of adequate serum concentrations in 84% of the patients on the first day of treatment.

Background: Critically ill patients show a high, albeit variable, prevalence of augmented renal clearance (ARC). This condition has relevant consequences on the elimination of hydrophilic drugs. Knowledge of risk factors for ARC helps in the early identification of ARC. The aims of this study were evaluation of (1) risk factors for ARC and (2) the prevalence of ARC in critically ill patients over a period of 1 year. Methods: A retrospective cohort study was performed for all consecutive patients admitted to our intensive care unit (ICU). Augmented renal clearance was defined by a creatinine clearance ≥130 mL/min/1.73 m2. “Patient with ARC” was defined as a patient with a median of creatinine clearance ≥130 mL/min/1.73 m2 over the period of admission. Four variables were tested, Simplified Acute Physiology Score II (SAPS II), male gender, age, and trauma as cause for ICU admission. An analysis (patient based and clearance based) was performed with logistic regression. Results: Of 475 patients, 446 were included in this study, contributing to 454 ICU admissions and 5586 8-hour creatinine clearance (8h-CLCR). Overall, the prevalence of patients with ARC was 24.9% (n = 113). In a subset of patients with normal serum creatinine levels, the prevalence was 43.0% (n = 104). Of the set of all 8h-CLCR measurements, 25.4% (1418) showed ARC. In the patient-based analysis, the adjusted odds ratio was: 2.0 (confidence interval [CI]:1.1-3.7; P < .05), 0.93 (CI: 0.91-0.94; P < .01), 2.7 (CI: 1.4-5.3; P < .01), and 0.98 (CI: 0.96 -1.01; P = .15), respectively, for trauma, age, male sex, and SAPS II. In the clearance-based analysis, the adjusted odds ratio were 1.7 (CI: 1.4-1.9; P < .01), 0.94 (CI: 0.932-0.942; P < .01), and 2.9 (CI: 2.4-3.4; P < .01), respectively, for trauma, age, and male sex. Conclusions: Trauma, young age, and male sex were independent risk factors for ARC. This condition occurs in a considerable proportion of critical care patients, which was particularly prevalent in patients without evidence of renal dysfunction.

Antibiotic therapy (AT) is the cornerstone of the management of severe community-acquired pneumonia (CAP). However, the best treatment strategy is far from being established. To evaluate the impact of different aspects of AT on the outcome of critically ill patients with CAP, we performed a post hoc analysis of all CAP patients enrolled in a prospective, observational, multicentre study. Of the 502 patients included, 76% received combination therapy, mainly a β-lactam with a macrolide (80%). AT was inappropriate in 16% of all microbiologically documented CAP (n=177). Hospital and 6months mortality were 34% and 35%. In adjusted multivariate logistic regression analysis, combination AT with a macrolide was independently associated with a reduction in hospital (OR 0.17, 95%CI 0.06-0.51) and 6months (OR 0.21, 95%CI 0.07-0.57) mortality. Prolonged AT (>7days) was associated with a longer ICU (14 vs. 7days; p<0.001) and hospital length of stay (LOS) (25 vs. 17days; p<0.001). Combination AT with a macrolide may be the most suitable AT strategy to improve both short and long term outcome of severe CAP patients. AT >7days had no survival benefit and was associated with a longer LOS.