CRRT广谱抗生素剂量

This Provisional PDF corresponds to the article as it appeared upon acceptance. Copyedited and fully formatted PDF and full text (HTML) versions will be made available soon. Recommended beta-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy Critical Care 2011, 15:R137 doi:10.1186/cc10257 Lucie Seyler (l.seyler.96@cantab.net) Frederic Cotton (fcotton@ulb.ac.be) Fabio Silvio Taccone (ftaccone@ulb.ac.be) Daniel De Backer (ddebacke@ulb.ac.be) Pascale Macours (pmacours@ulb.ac.be) Jean-Louis Vincent (jlvincen@ulb.ac.be) Frederique Jacobs (fjacobs@ulb.ac.be) ISSN 1364-8535 Article type Research Submission date 16 March 2011 Acceptance date 7 June 2011 Publication date 7 June 2011 Article URL http://ccforum.com/content/15/3/R137 This peer-reviewed article was published immediately upon acceptance. It can be downloaded, printed and distributed freely for any purposes (see copyright notice below). 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This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 1 Recommended ββββ-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy Lucie Seyler1, Frédéric Cotton2, Fabio Silvio Taccone3, Daniel De Backer3, Pascale Macours2, Jean-Louis Vincent3 and Frédérique Jacobs1 1Department of Infectious Diseases, Erasme Hospital, Université Libre de Bruxelles, route de Lennik 808, 1070 Bruxelles, Belgium 2Department of Clinical Chemistry, Erasme Hospital, Université Libre de Bruxelles, route de Lennik 808, 1070 Bruxelles, Belgium 3Department of Intensive Care, Erasme Hospital, Université Libre de Bruxelles, route de Lennik 808, 1070 Bruxelles, Belgium Correspondence: Prof. Frédérique Jacobs email: fjacobs@ulb.ac.be 2 Abstract Introduction: Sepsis is responsible for important alterations in the pharmacokinetics (PK) of antibiotics. Continuous renal replacement therapy (CRRT), which is commonly used in septic patients, may further contribute to PK changes. Current recommendations for antibiotic doses during CRRT combine data obtained from heterogeneous patient populations in which different CRRT devices and techniques have been used. We studied whether these recommendations met optimal PK criteria for broad-spectrum antibiotic levels in septic shock patients undergoing CRRT. Methods: This open, prospective study enrolled consecutive patients treated with CRRT and receiving either meropenem (MEM), piperacillin-tazobactam (TZP), cefepime (FEP) or ceftazidime (CAZ). Serum concentrations of these antibiotics were determined by high- performance liquid chromatography (HPLC) from samples taken before (t=0) and 1, 2, 5, and 6 or 12 hours (depending on the β-lactam regimen) after the administration of each antibiotic. Series of measurements were separated into those taken during the early phase (<48 hours from the first dose) of therapy and those taken later (>48 hours). Results: A total of 69 series of serum samples were obtained in 53 patients (MEM, n=17; TZP, n=16; FEP, n=8; CAZ, n=12). Serum concentrations remained above 4 times the minimal inhibitory concentration (MIC) for Pseudomonas spp. for the recommended time, in 81% of patients treated with MEM, 71% with TZP, 53% with CAZ and 0% with FEP. Accumulation after 48h of treatment was significant only for MEM. Conclusions: In septic patients receiving CRRT, recommended doses of β-lactams for Pseudomonas aeruginosa are adequate for MEM but not for TZP, FEP and CAZ; for these latter drugs, higher doses and/or extended infusions should be used to optimize serum concentrations. 3 Introduction Severe sepsis and septic shock are major causes of morbidity and mortality in intensive care units (ICUs) [1-3]. Antibiotic treatment, if adequate and given early [4, 5], remains of paramount importance to optimize chances of survival [6]. Several studies have shown the crucial impact of the first 24 hours of treatment on outcome [7]. In addition to timing, the chosen antibiotic should target the potential pathogens involved, taking local susceptibility patterns into account. To be effective, the doses given should reach therapeutic concentrations in the blood and at the site of infection [8-10]. Sepsis can significantly alter the pharmacokinetics (PK) of antimicrobials and result in subtherapeutic drug concentrations [11, 12], potentially contributing to decreased bacterial killing, therapeutic failure and emergence of resistance. Acute renal failure is a common complication of sepsis. In septic patients, continuous renal replacement therapy (CRRT) is often preferred to conventional hemodialysis because it is better tolerated hemodynamically. However, CRRT can further alter the PK of antibiotics [13]. These changes depend on several variables, such as the ultrafiltrate and dialysate rates, dialysate concentrations and the type of membrane used; each of these introducing additional variability in expected drug concentrations [14]. A recent systematic review [15] addressed the importance of all these factors for antibiotic prescription, however the most recent recommendations on antibiotic dosing during CRRT [16] were established using evidence from studies that included a limited number of patients, with varying inclusion/exclusion criteria and receiving different types of CRRT [17-20]. Serum measurements were usually performed at steady state, which also limits the extrapolation of results to the early phase of sepsis, during which patients are often hemodynamically unstable. Finally, these recommendations have never been validated in a septic ICU population suffering from multiple organ failure. The objective of our study was to evaluate whether the recommended doses of broad- spectrum β-lactams [16] result in appropriate serum concentrations in ICU patients with severe sepsis and septic shock receiving CRRT. 4 Materials and methods Study design, patients and inclusion criteria This observational, prospective study was conducted between January 2008 and May 2009, in a 35-bed medico-surgical intensive care unit (ICU) at Erasme Hospital, Brussels (Belgium). The study was approved by the local Ethics Committee (Comité d'Ethique Hospitalo- Facultaire Erasme-ULB, reference number: OM021) and informed consent was obtained from each patient or their closest relative. The study was conducted in compliance with the Helsinki Declaration for human research. Inclusion criteria were as follows: Age > 18 years; diagnosis of severe sepsis or septic shock according to standard criteria [1]; acute renal failure treated with CRRT; receiving at least one of: meropenem (MEM), piperacillin-tazobactam (TZP), cefepime (FEP) or ceftazidime (CAZ). All patients fulfilling these criteria were included consecutively. Exclusion criteria were: pregnancy, burns and cystic fibrosis. Patients receiving different study drugs successively were included more than once. Antibiotic treatment and serum samples The choice of antibiotic was at the discretion of the clinicians and based on local guidelines. All patients included received a first dose (loading dose) of 1g of MEM, 4.0/0.5 g of TZP, 2g of FEP or CAZ. The highest daily dose was taken from published recommendations (16) for patients on CRRT, whether on continuous veno-venous hemofiltration (CVVH) or hemodiafiltration (CVVHDF): 1g bid for MEM and 2g bid for FEP and CAZ; for TZP the daily dose were adapted to the European format, i.e., 4.0/0.5 g qid. Each antibiotic dose was administered as a 30-min infusion. Blood samples for drug assays (3-4 mL of blood) were drawn from the arterial line on the day of inclusion, and then every second day during CRRT treatment when possible. On each sampling day, a series of blood samples was drawn to obtain a PK curve for each dose: immediately before the antibiotic administration (0 h) then 1 h, 2 h, 5 h, and 6 h or 12 h (depending on the antibiotic) after the start of the infusion. The exact sampling times were recorded. Blood was collected in plain tubes and centrifuged at 3000 rpm at 4°C for 10 minutes; the supernatant was separated immediately and kept at -80°C until analyses were performed. Sample series were grouped according to the day of sampling relative to the start of the antibiotic treatment, i.e., into early (<48 hours from the first dose) or late (>48 hours). 5 CRRT Continuous renal replacement therapy was performed through a double-lumen catheter inserted into a large vein. CVVH or CVVHDF was performed using a Prisma or PrismaFlex machine (Hospal, Meyzieu, France), with an AN69 hemofilter (Gambro Lundia AB, Lund, Sweden). Characteristics of the CRRT were recorded for each patient at each blood sampling time. Serum antibiotic analyses Serum concentrations of all antibiotics were measured in the clinical chemistry department by high-performance liquid chromatography connected to UV spectrophotometry (HPLC-UV). Briefly, 1 mL of methanol was added to 500 µL of serum in order to precipitate proteins. The supernatant was separated and evaporated, and the residue was solubilized in phosphate buffer 50 mmol/L, pH 3.8. Thirty microliters were injected in an Agilent 1200 series chromatograph (Agilent, Diegem, Belgium) equipped with a YMC ODS AQ column (YMC GmbH, Dinslaken, Germany). Antibiotics were separated within 60 min in an acetonitrile-phosphate buffer gradient. UV absorbance was monitored at 204 nm for tazobactam and MEM and at 240 nm for piperacillin, FEP and CAZ. Cefoperazone was used as internal standard. The limit of quantification was 0.2 µg/mL for tazobactam and 2.0 µg/mL for the other antibiotics. Between-day imprecision was less than 6.5%. As the PK of piperacillin and tazobactam are highly correlated (21) and tazobactam serum concentration curves followed those of piperacillin in our study, only the latter were used in the analysis. The validation of the analytical method was performed daily, according to the published acceptance criteria for specificity, linearity, accuracy, precision (intra-day (repeatability), inter-day (intermediate precision)) and sensitivity (limit of detection (LOD) [22]. Under the described chromatographic conditions, MEM, TZP, FEP and CAZ were identified by sharp and well resolved peaks. The stability of plasma samples is at least 1 month at -80°C. Pharmacokinetic (PK) analysis To determine mean concentrations, each series of time points from each patient was linearized using a logarithmic transformation. Each curve was then reconstructed using fixed time points and mean concentrations were calculated. The peak concentration was the concentration measured 1 h after the start of the 30-minute antibiotic infusion. The area under the curve (AUC) for a given drug was calculated from the mean AUCs for each series for a given drug, using the raw concentrations. AUC was calculated using the trapezoidal rule. Also, AUCs 6 were used to estimate differences in drug exposure between measurements made <48 h and >48 h from the onset of antibiotic therapy. The volume of distribution (Vd) for a given drug was the mean of all Vds from the series taken under that drug, using the following formula applied to the linearized series: Vd=dose/ C0 (C0 being the concentration at the start of the infusion), and ln C = -ke.t + ln C0 (C being the concentration at time=t and ke = -slope). The clearance (CL) and the elimination half-life (T1/2 b) were calculated with the formulae: ke = CL/Vd and T1/2 b = 0.693/ke. No PK/PD profile was measured for loading doses. Pharmacodynamic (PD) analysis In the pharmacodynamic analyses, we considered the minimal inhibitory concentrations (MICs) defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) as the clinical breakpoints for the pathogens most frequently encountered in nosocomial or ICU infections [23]. As Pseudomonas aeruginosa is the most frequent, serious pathogen in the ICU and causes infection associated with the highest mortality rates [24], we used the clinical breakpoint of this pathogen as the target MIC. Sensitivity MIC thresholds for this pathogen are: ≤ 2 µg/mL (MEM), ≤ 16 µg/mL (TZP) and ≤ 8 µg/mL (CAZ and FEP). Some clinical data suggest that maximal killing of bacteria by β-lactams occurs when serum concentrations are maintained above the MIC of the causative pathogens for extended periods [25-28]. Achievement of maximal bactericidal effect requires 40%, 50% and 60-70% coverage of the dose interval for carbapenems, penicillins and cephalosporines, respectively [29]. To achieve optimal bactericidal activity, the adequacy of β-lactam therapy in our study was assessed by measuring the time the concentration was above more than four times the target MIC (T > 4 x MIC). The optimal Time > 4 x MIC for each drug was considered as ≥ 40% (MEM), ≥ 50% (TZP), or ≥ 70% (FEP, CAZ ) of the time interval between two doses [29]. We classified each patient as having an ‘adequate’ or ‘inadequate’ PK/PD-profile according to the percentage of time during which serum drug concentrations remained above 4 times the clinical breakpoint for P. aeruginosa (% T > 4 x MIC), i.e., ≥ 8 µg/mL for MEM; ≥ 64 µg/mL for TZP; ≥ 32 µg/mL for FEP and CAZ. Finally, using the concentrations obtained in our population, we calculated the probability of achieving targets of T > 4 x MIC for other MICs found in ICU-isolated Gram-negative bacteria. Statistical analysis Descriptive statistics were performed for all study variables. Discrete variables were expressed as counts (percentage) and continuous variables as means ± SD or median [25th– 7 75th percentiles]. Differences between groups (early vs. late) were assessed using Student’s t- test. A P < 0.05 was considered as statistically significant. Results Patients and series of samples We included 53 patients whose demographic and clinical characteristics are presented in Table 1. MEM was given in 17 patients, TZP in 16 patients, FEP in 8 patients and CAZ in 12 patients. Sixty-nine series of samples were obtained: MEM, n = 22; TZP, n =21; FEP, n = 11; CAZ, n = 15. Nineteen patients were treated with CVVHD, 34 with CVVHDF. The mean blood flow rate was 150 ± 24 mL/min. The mean ultrafiltration rate was 22 ± 12 mL/kg.hr. Twenty- two of the 53 patients had a fluid removal; in those patients, removal rate was 158 ± 140 mL/hr. The mean dialysate rate was 23 ± 9 mL/kg.hr. Pharmacokinetic data and pharmacodynamic analysis Pharmacokinetic data are shown in Table 2. There was a marked inter-individual variation in all PK parameters; Vd was increased for all four drugs when compared with healthy volunteers, with consequently a lower Cmax. There was no significant impact of the technique (CVVHD vs. CVVHDF) on the PKs of the studied drugs (data not shown). Figures 1, 2, 3 and 4 show the concentrations of MEM, TZP, FEP and CAZ over time, separated into early (<48 h) and later (>48 h) phases of treatment. MEM concentrations were significantly higher in the late (>48 h) than in the early (<48 h) phases (Student’s T-test, P = 0.018). Although serum concentrations of TZP, FEP and CAZ were higher after 48 h of treatment, there was no statistically significant difference between early and later concentrations of these antibiotics. Pharmacodynamic analyses for each antibiotic against Pseudomonas aeruginosa clinical breakpoints are summarized in Table 3. The PK/PD target was reached in 81% of patients treated with MEM, 71% with TZP, 53% with CAZ but in none of the patients receiving FEP. We calculated the probability of target T > 4x MIC attainment for several MIC values (Table 4): MEM concentrations would reach the target T > 4 x MIC in > 90% of cases with pathogens with MICs of 1 or less; TZP with MICs of 8 or less; FEP and CAZ with MICs of 2 or less. 8 Discussion In this population of patients with severe sepsis and septic shock treated with CRRT, we showed that the recommended doses for broad spectrum β-lactams are generally insufficient to maintain therapeutic serum concentrations greater than 4 times the MIC of P. aeruginosa. In the first 48 h of treatment, 29, 34, 100 and 62% of our patients treated with MEM, TZP, FEP and CAZ, respectively, never reached the PK target. After 48 h of treatment, the drug concentrations obtained were higher (significantly different only for MEM), but they remained insufficient in many patients. Despite the prolonged elimination half-time, we did not find significant drug accumulation for TZP, FEP and CAZ over time. This finding could be due to several concomitant factors that may affect drug concentrations, such as changes in CRRT settings, modification in filter efficacy, renal recovery with additional drug clearance, fluids and vasoactive agents administration with related changes in drug Vd (15). Also, the smaller number of patients evaluated for these three drugs could have limited this analysis and larger studies are warranted to address this question. If we apply our results to other MICs, the observed concentrations for all antibiotics were adequate in 90% of patients only for MICs lower than the clinical breakpoint of Pseudomonas spp, which correspond to MICs of sensitive Enterobacteriacea. Reaching high target concentrations early in the course of treatment seems particularly important in severely ill patients [30], especially given the heterogeneous nature of these patients [31]. In such patients, the PK is altered both in terms of distribution (sepsis itself can modify the volume of distribution; resuscitation measures; nutritional factors) and of elimination (drains; altered metabolism; clearance changes). The higher Vd in the initial phase of sepsis has been previously described in studies on aminoglycosides [32, 33] and vancomycin [34]. We recently demonstrated an increased Vd and an high variability of serum antibiotic concentrations in ICU patients with severe sepsis and septic shock [14]. Effective cure of infection in ICU patients can be compromised for other reasons. First, ICU patients are frequently immunosuppressed because of underlying diseases, treatments, or other medical interventions [28]. Impairments in neutrophil and monocyte/macrophage functions are common in critically ill patients and may play a role in the increased risk of developing sepsis and in the severity of the infection. Secondly, bacterial loads can be particularly high, for example in ventilator-associated pneumonia, intra-abdominal abscesses or peritonitis. Finally, resistant bacteria can be selected by prior antimicrobial treatment or through 9 nosocomial transmission. For the above reasons, high concentration targets may be preferable in difficult-to-treat infections such as those caused by Pseudomonas spp,, which are associated with the highest mortality rates. β-lactam antibiotics have long been known to have ‘time-dependent’ anti-bacterial activity [35]. Time above the MIC of the infecting organism is the best parameter to reflect the efficacy of β-lactams [36]. In vitro killing curve studies have shown that β-lactams killing activity was rapidly saturated at concentrations corresponding to 4 times the MIC, so that gr