Stefano Cristallini

Vancomycin population pharmacokinetics during extracorporeal membrane oxygenation therapy: a matched cohort study

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.

β-Lactam pharmacokinetics during extracorporeal membrane oxygenation therapy: A case-control study

Most adult patients receiving extracorporeal membrane oxygenation (ECMO) require antibiotic therapy, however the pharmacokinetics of β-lactams have not been well studied in these conditions. In this study, data from all patients receiving ECMO support and meropenem (MEM) or piperacillin/tazobactam (TZP) were reviewed. Drug concentrations were measured 2h after the start of a 30-min infusion and just before the subsequent dose. Therapeutic drug monitoring (TDM) results in ECMO patients were matched with those in non-ECMO patients for (i) drug regimen, (ii) renal function, (iii) total body weight, (iv) severity of organ dysfunction and (v) age. Drug concentrations were considered adequate if they remained 4-8× the clinical MIC breakpoint for Pseudomonas aeruginosa for 50% (TZP) or 40% (MEM) of the dosing interval. A total of 41 TDM results (27 MEM; 14 TZP) were obtained in 26 ECMO patients, with 41 matched controls. There were no significant differences in serum concentrations or pharmacokinetic parameters between ECMO and non-ECMO patients, including Vd [0.38 (0.27-0.68) vs. 0.46 (0.33-0.79)L/kg; P=0.37], half-life [2.6 (1.8-4.4) vs. 2.9 (1.7-3.7)h; P=0.96] and clearance [132 (66-200) vs. 141 (93-197)mL/min; P=0.52]. The proportion of insufficient (13/41 vs. 12/41), adequate (15/41 vs. 19/41) and excessive (13/41 vs. 10/41) drug concentrations was similar in ECMO and non-ECMO patients. Achievement of target concentrations of these β-lactams was poor in ECMO and non-ECMO patients. The influence of ECMO on MEM and TZP pharmacokinetics does not appear to be significant.

Strongyloides disseminated infection successfully treated with parenteral ivermectin: case report with drug concentration measurements and review of the literature

We report the case of an immunosuppressed patient with Strongyloides disseminated infection who was successfully treated with the veterinary parenteral form of ivermectin. A kidney transplant recipient developed disseminated infection with Strongyloides stercoralis. Because oral treatment with ivermectin was not possible, subcutaneous ivermectin (75 µg/kg/day, then 200 µg/kg/day) was given for 9 days, with clinical improvement and disappearance of all larvae. Serum ivermectin concentrations were between 15.6 ng/mL and 19.7 ng/mL during the 9 days of therapy; however, drug accumulation (plasma levels >40 ng/mL) 48 h after discontinuation of therapy was associated with the development with encephalopathy. We also review all cases of human disseminated Strongyloides infection treated with parenteral ivermectin.

New Regimen for Continuous Infusion of Vancomycin in Critically Ill Patients

ABSTRACT Despite the development of new agents with activity against Gram-positive bacteria, vancomycin remains one of the primary antibiotics for critically ill septic patients. Because sepsis can alter antimicrobial pharmacokinetics, the development of an appropriate dosing strategy to provide adequate concentrations is crucial. The aim of this study was to prospectively validate a new dosing regimen of vancomycin given by continuous infusion (CI) to septic patients. We included all adult septic patients admitted to a mixed intensive care unit (ICU) between January 2012 and May 2013, who were treated with a new vancomycin CI regimen consisting of a loading dose of 35 mg/kg of body weight given as a 4-h infusion, followed by a daily CI dose adapted to creatinine clearance (CrCL), as estimated by the Cockcroft-Gault formula (median dose, 2,112 [1,500 to 2,838] mg). Vancomycin concentrations were measured at the end of the loading dose (T1), at 12 h (T2), at 24 h (T3), and the day after the start of therapy (T4). Vancomycin concentrations of 20 to 30 mg/liter at T2, T3, and T4 were considered adequate. A total of 107 patients (72% male) were included. Median age, weight, and CrCL were 59 (interquartile range [IQR], 48 to 71) years, 75 (IQR, 65 to 85) kg, and 94 (IQR, 56 to 140) ml/min, respectively. Vancomycin concentrations were 44 (IQR, 37 to 49), 25 (IQR, 21 to 32), 22 (IQR, 19 to 28), and 26 (IQR, 22 to 29) mg/liter at T1, T2, T3, and T4, respectively. Concentrations were adequate in 56% (60/107) of patients at T2, in 54% (57/105) at T3, and in 73% (41/56) at T4. This vancomycin regimen permitted rapid attainment of target concentrations in serum for most patients. Concentrations were insufficient in only 16% of patients at 12 h of treatment.

Vancomycin Pharmacokinetics During Extracorporeal Membrane Oxygenation: A Case-Control Study

Introduction: Antibiotics are often administered in patients treated by extracorporeal membrane oxygenation (ECMO) but pharmacokinetics (PKs) of antibiotics during ECMO have not been well defined.Hypothesis: To evaluate vancomycin concentrations in critically ill patients treated with ECMO.Methods: We reviewed all patients who received a continuous infusion (CI) of vancomycin when on ECMO support from January 2011 to May 2012. Vancomycin was given as a 35 mg/kg loading dose in 4-hr, and the infusion doses were adapted to creatinine clearance, CrCL). Drug concentrations were measured at 4 (T1), 12 (T2) and in the first 24 hours (T3) after the onset of therapy. Using a database reporting all patients having this vancomycin regimen, ECMO patients were matched (1:1) with non-ECMO patients according to four criteria: 1) renal function (i.e. same CrCL or both on continuous renal replacement therapy, CRRT); 2) total body weight; 3) Sequential Organ Failure Assessment (SOFA) score; 4) age. Vancomycin concentrations between 20 and 30 [micro]g/ml were considered as adequate.Results: We compared 11 patients treated with ECMO and 11 well matched controls. Mean vancomycin loading (2500 [1610-2975] mg vs. 2450 [1645-3500] mg) and daily doses (1125 [750-3000] vs. 1200 [750-2500] mg) were similar in the two groups. Drug concentrations in ECMO and non-ECMO patients were: 51 [28-71] mcg/mL vs. 45 [37-71] mcg/mL on T1; 23 [16-38] vs. 29 [21-35] mcg/mL on T2; 20 [12-36] vs. 23 [17-28] mcg/mL on T3 (ANOVA, p=0.53). The number of patients with insufficient drug concentrations in ECMO group was 2 on T2 and 4 on T3 when compared to 0 and 1, respectively, in the control group.Conclusions: Vancomycin concentrations in the early phase of therapy were quite similar in patients treated or not with ECMO. Nevertheless, more patients in the ECMO group tended to have insufficient drug concentrations, so that vancomycin doses should be probably increased somewhay in these patients.