Marjorie Beumier

Case-Control Study of Drug Monitoring of β-Lactams in Obese Critically Ill Patients

ABSTRACT Severe sepsis and septic shock can alter the pharmacokinetics of broad-spectrum β-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/m2) treated with a broad-spectrum β-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/m2) 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 β-lactam serum concentrations (coefficient of variation of 50% to 92% for the three drugs). Standard drug regimens of β-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 β-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 β-lactams should be continued in obese critically ill patients.

A new regimen for continuous infusion of vancomycin during continuous renal replacement therapy

INTRODUCTION Continuous infusion (CI) of high-dose vancomycin is often used to treat life-threatening infections caused by less-susceptible Gram-positive bacteria. However, this approach has not been well studied in patients on continuous renal replacement therapy (CRRT). The aim of this study was to evaluate the adequacy of a new CI vancomycin regimen in septic patients undergoing CRRT. METHODS In this prospective study we measured vancomycin concentrations obtained with a new CI regimen for CRRT, which included a loading dose of 35 mg/kg given over a 4 h period followed by a daily dose of 14 mg/kg. Vancomycin concentrations were measured: at the end of the loading dose (T1); 12 h after the onset of therapy (T2); and 24 h after the onset of therapy (T3). Drug concentrations (at T2 and T3) were considered adequate if between 20 and 30 mg/L. CRRT intensity was calculated as: dialysate rate (mL/kg/h) + ultrafiltration rate (mL/kg/h). Vancomycin population pharmacokinetics were calculated using non-linear mixed-effects modelling. RESULTS We studied 32 patients who received median (IQR) loading and daily vancomycin doses of 2750 mg (2250-3150) and 1100 mg (975-1270), respectively. Drug concentrations were: T1, 44 mg/L (38-58); T2, 27 mg/L (24-31); and T3, 23 mg/L (19-31). Vancomycin concentrations were adequate in 22/32 patients (69%) at T2 and in 20/32 (63%) at T3. The two relevant covariates that significantly affected drug concentrations were body weight and CRRT intensity. CONCLUSIONS 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.

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.

Diagnostic and prognostic markers in sepsis

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.

Continuous infusion of vancomycin in septic patients receiving continuous renal replacement therapy.

Vancomycin is frequently administered as a continuous infusion to treat severe infections caused by Gram-positive bacteria. Previous studies have suggested a loading dose of 15 mg/kg followed by continuous infusion of 30 mg/kg in patients with normal renal function; however, there are no dosing recommendations in patients with renal failure undergoing continuous renal replacement therapy (CRRT). Data from all adult septic patients admitted to a Department of Intensive Care over a 3-year period in whom vancomycin was given as a continuous infusion were reviewed. Patients were included if they received vancomycin for ≥48h during CRRT. Vancomycin levels were obtained daily. During the study period, 85 patients (56 male; mean age 65±15 years; weight 85±24kg) met the inclusion criteria. Median (interquartile range) APACHE II and SOFA scores were 24 (20-29) and 11 (7-14), respectively, and the overall mortality rate was 59%. Mean vancomycin doses were 16.4±6.4 (loading dose), 23.5±8.1 (Day 1), 23.2±7.4 (Day 2) and 23.3±11.0 (Day 3) mg/kg, resulting in blood concentrations of 24.7±9.0 (Day 1), 26.0±8.1 (Day 2) and 27.7±9.3 (Day 3) μg/mL. On Day 1, 43 patients (51%) had adequate drug concentrations (20-30 μg/mL), 17 (20%) had levels >30 μg/mL and 25 (29%) had levels <20 μg/mL. Most patients with adequate drug concentrations received a daily dose of 16-35 mg/kg. The intensity of CRRT directly influenced vancomycin concentrations on Day 1 of therapy.

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.

Can changes in renal function predict variations in β-lactam concentrations in septic patients?

This study investigated whether variations in creatinine clearance (CLCr) are correlated with changes in β-lactam concentrations or pharmacokinetics in septic patients. Data for 56 adult patients admitted to the ICU in whom routine therapeutic drug monitoring (TDM) of broad-spectrum β-lactams (ceftazidime, cefepime, piperacillin or meropenem) was performed were reviewed. Patients were included if they had at least two TDM during their ICU stay for the same antibiotic and were not concomitantly treated with any extracorporeal replacement therapy. Serum drug concentrations were measured by HPLC-UV. Antibiotic pharmacokinetics were calculated using a one-compartment model and the percentage of time spent above four times the MIC (%T>4×MIC) for Pseudomonas aeruginosa and the antibiotic clearance (ATB-CL) were obtained. CLCr was measured on the same day as the TDM using 24-h urine collection. The %T>4×MIC and ATB-CL were significantly correlated with CLCr at the first (r=-0.41, P=0.002; r=0.56, P<0.001, respectively) and second (r=-0.61, P<0.001; r=0.63, P<0.001, respectively) TDM. However, changes in ATB-CL were only weakly correlated with changes in CLCr (r=0.34, P=0.01). The proportion of patients with insufficient β-lactam concentrations at the first and second TDM were 39% and 30%, respectively, and increased proportionally to CLCr. Although CLCr was significantly correlated with concentrations and clearance of broad-spectrum β-lactams, changes in CLCr did not reliably predict variations in drug pharmacokinetics/pharmacodynamics. Routine TDM should be considered to adapt β-lactam doses in this setting.

Broad-spectrum β-lactams in obese non-critically ill patients

Objectives:Obesity may alter the pharmacokinetics of β-lactams. The goal of this study was to evaluate if and why serum concentrations are inadequate when standard β-lactam regimens are administered to obese, non-critically ill patients.Subjects and methods:During first year, we consecutively included infected, obese patients (body mass index (BMI) ⩾30 kg m−2) who received meropenem (MEM), piperacillin-tazobactam (TZP) or cefepime/ceftazidime (CEF). Patients with severe sepsis or septic shock, or those hospitalized in the intensive care unit were excluded. Serum drug concentrations were measured twice during the elimination phase by high-performance liquid chromatography. We evaluated whether free or total drug concentrations were >1 time (fT>minimal inhibition concentration (MIC)) or >4 times (T>4MIC) the clinical breakpoints for Pseudomonas aeruginosa during optimal periods of time: ⩾40% for MEM, ⩾50% for TZP and ⩾70% for CEF.Results:We included 56 patients (median BMI: 36 kg m−2): 14 received MEM, 31 TZP and 11 CEF. The percentage of patients who attained target fT>MIC and T>4MIC were 93% and 21% for MEM, 68% and 19% for TZP, and 73% and 18% for CEF, respectively. High creatinine clearance (107 (range: 6–398) ml min−1) was the only risk factor in univariate and multivariate analyses to predict insufficient serum concentrations.Conclusions:In obese, non-critically ill patients, standard drug regimens of TZP and CEF resulted in insufficient drug concentrations to treat infections due to less susceptible bacteria. Augmented renal clearance was responsible for these low serum concentrations. New dosage regimens need to be explored in this patient population (EUDRA-CT: 2011-004239-29).

Appropriate Antibiotic Dosage Levels in the Treatment of Severe Sepsis and Septic Shock

Antibiotic treatment of critically ill patients remains a significant challenge. Optimal antibacterial strategy should achieve therapeutic drug concentration in the blood as well as the infected site. Achieving therapeutic drug concentrations is particularly difficult when infections are caused by some pathogens, such as Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus (MRSA) and Gram-negative rods, because of their low susceptibility to antimicrobials. In sepsis, pharmacokinetics (PKs) of antibiotics are profoundly altered and may result in inadequate drug concentrations, even when recommended regimens are used, which potentially contribute to increased mortality and spread of resistance. The wide inter-individual PK variability observed in septic patients strongly limits the a priori prediction of the optimal dose that should be administered. Higher than standard dosages are necessary for the drugs, such as β-lactams, aminoglycosides, and glycopeptides, that are commonly used as first-line therapy in these patients to maximize their antibacterial activity. However, the benefit of reaching adequate drug concentrations on clinical outcome needs to be further determined.

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.