Fleur Wolff

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.

Rapid quantification of six β-lactams to optimize dosage regimens in severely septic patients

A fast analytical procedure was developed for the simultaneous quantification of cefepime (CEF), meropenem (MEM), ceftazidime (CZA), cefuroxime (CFX), aztreonam (AZT), and piperacillin (PIP) in serum of intensive care patients. The β-lactam pharmacokinetic parameters can be altered in severe sepsis due to changes in the distribution, the metabolism and the elimination process. Therapeutic drug monitoring (TDM) of β-lactams is therefore recommended in critically ill patients. The plasma samples were spiked with cefoperazone as internal standard and proteins were precipitated with methanol. The different β-lactams were separated with high performance liquid chromatography within 18 min, and quantified by UV spectrophotometry with a diode array detector. The method was validated by means of the accuracy profile approach based on β expectation tolerance intervals. The acceptance limits were settled at ± 30% according to the regulatory requirements. Assay validation demonstrated good performance for all β-lactams analyzed in terms of trueness, repeatability, linearity and intermediate precision over the range of 2-200 μg/mL. The simple extraction procedure provides respective absolute and relative recoveries ranging from 70% to 86% and from 66% to 89% for all the β-lactams analyzed. Few interferences were observed and the method was easily applicable to TDM in intensive care patients. The quantification of β-lactams should allow for antibiotic regimen adjustment in critically ill patients.

Hepcidin-25: Measurement by LC-MS/MS in serum and urine, reference ranges and urinary fractional excretion.

A liquid chromatography tandem-mass spectrometry (LC-MS/MS) method was developed for reliably quantifying hepcidin-25 in human urine and serum. A 95% reference range was established for serum hepcidin-25 levels by standardizing the sampling time between 8:00am and 11:00am in 90 apparently healthy volunteers. The association between hepcidin-25 concentration and other biological parameters was studied using multivariable analysis and the coefficient of renal excretion of hepcidin-25 was calculated. Preanalytical variables were also investigated. The LC-MS/MS method was validated using a recent validation strategy based on accuracy profiles. Good results were obtained in terms of trueness, precision, and linearity in the following dosing ranges: from 0.77 to 200nmol/L for urine and from 0.48 to 100nmol/L for serum. The 95% reference range of serum hepcidin-25 concentration established after excluding known conditions that affect hepcidin-25 expression was 1.5 to 15.2nmol/L. A difference between genders was demonstrated with a median concentration of 5.5 versus 7.2nmol/L for women and men, respectively. Serum hepcidin-25 concentrations were strongly correlated with ferritin and, to a lesser extent, with iron levels. The coefficient of renal excretion ranged from 0.1 to 16.4%. Higher values of hepcidin-25 concentrations were observed on ethylene diamine tetraacetate tubes compared to serum or lithium-heparin devices.

Cystatin C for early detection of renal impairment in diabetes

OBJECTIVES Evaluation of glomerular filtration rate is of crucial importance in diabetes. Cystatin C, a cysteine protease inhibitor seems to be an interesting parameter. DESIGN AND METHODS 67 diabetic patients with normal creatinine are evaluated. Cystatin C is compared to renal markers, by reference to Cr EDTA clearance. RESULTS Significant correlations are found between cystatin C and creatinine (r=0.54). GFR MDRD (r=-0.47) and GFR Cr EDTA (r=-0.47). The AUC of the receiver operating curves is better for GFR MDRD (0.83) and cystatin C (0.75) than for creatinine (0.63) considering the cut off value of 80 mL/min for GFR EDTA. CONCLUSION Cystatin C seems to be a more sensitive parameter than creatinine for the detection of an incipient nephropathy in diabetes.

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).

Osteoprotegerin and Progression of Coronary and Aortic Calcifications in Chronic Kidney Disease

Vascular calcifications (VCs) are important predictors of cardiovascular mortality in patients with chronic kidney disease (CKD). We have shown previously that osteoprotegerin (OPG), a potential early biomarker for VC, was an independent predictor of mortality in CKD patients. The aim of our study was to follow longitudinally coronary and aortic VCs. VCs were measured using Siemens 16 detector CT in a group of predialysis and hemodialyzed patients before and after a follow-up of 4 years. Some of these patients were transplanted in the meantime. Renal function, calcium, phosphate, iPTH, hs-CRP (high sensitive protein C reactive), and OPG serum levels were also compared. VCs progressed in predialysis, hemodialyzed, and transplanted patients but the progression was not the same in all arterial beds. A progression of coronary calcifications was observed in predialysis and transplanted patients, while aortic calcifications worsened significantly only in hemodialyzed patients. OPG serum levels and hs-CRP were significantly lower among transplanted patients. We concluded that VC depends on the severity of the kidney disease. Transplanted patients are not protected from VC, yet their OPG serum levels were significantly lower, suggesting that there is no link between between OPG levels and severity of VC. Longer follow-up of these patients would be necessary to assess whether a decline in OPG correlates with better survival.

Assessment of the diagnostic performances of IgA heavy and light chain pairs in patients with IgA monoclonal gammopathy.

OBJECTIVES Preliminary results of the IgA Hevylite™ assay including the establishment of the 95% reference interval and assessment of the specificity and sensitivity in different populations are reported. DESIGN AND METHODS The concentrations of IgA heavy and light chains (HLC) enabling to determine an IgAκ/IgAλ ratio were quantified in 119 apparently healthy individuals to generate 95% reference intervals. The specificity of this assay was assessed in 48 patients with an isolated polyclonal IgA increase. In a retrospective analysis of 68 patients with a monoclonal component type IgA (MC-IgA) identified by serum immunofixation (IFE), IgA HLC ratio values were compared with known results for serum protein electrophoresis (SPE) and free light chain (FLC) ratios. RESULTS The 95% reference range obtained in 119 controls (0.91-2.04) was close to that quoted by the manufacturer (0.80-2.04). Eight of the 48 patients (16.7%) with a polyclonal IgA increase had an IgA HLC ratio above the upper limit of the 95% reference interval. The IgA HLC ratio identified 65 (95.6%) among 68 patients with MC-IgA identified on the basis of IFE. For 34 of these patients (50%), MC-IgA was not detected by SPE due to its co-migration with alpha-2 or beta-globulins. CONCLUSIONS Compared with serum IFE, the IgA HLC ratio has a sensitivity of 95.6%. Further studies are needed to assess the specificity of the IgA HLC ratio in patients with an isolated polyclonal increase of serum IgA.

Serum β‐lactam concentrations in critically ill patients with cirrhosis: a matched case‐control study

The pharmacokinetics of β‐lactam antibiotics have not been well defined in critically ill patients with cirrhosis.