β-lactam antibiotic concentrations during continuous renal replacement therapy

Abstract

IntroductionThe use of standard doses of β-lactam antibiotics during continuous renal replacement therapy (CRRT) may result in inadequate serum concentrations. The aim of this study was to evaluate the adequacy of unadjusted drug regimens (i.e., similar to those used in patients with normal renal function) in patients treated with CRRT and the influence of CRRT intensity on drug clearance.MethodsWe reviewed data from 50 consecutive adult patients admitted to our Department of Intensive Care in whom routine therapeutic drug monitoring (TDM) of broad-spectrum β-lactam antibiotics (ceftazidime or cefepime, CEF; piperacillin/tazobactam; TZP; meropenem, MEM) was performed using unadjusted β-lactam antibiotics regimens (CEF = 2 g q8h; TZP = 4 g q6h; MEM = 1 g q8h). Serum drug concentrations were measured twice during the elimination phase by high-performance liquid chromatography (HPLC-UV). We considered therapy was adequate when serum drug concentrations were between 4 and 8 times the minimal inhibitory concentration (MIC) of Pseudomonas aeruginosa during optimal periods of time for each drug (≥70% for CEF; ≥ 50% for TZP; ≥ 40% for MEM). Therapy was considered as early (ET) or late (LT) phase if TDM was performed within 48 hours of antibiotic initiation or later on, respectively.ResultsWe collected 73 serum samples from 50 patients (age 58 ± 13 years; Acute Physiology and Chronic Health Evaluation II (APACHE II) score on admission 21 (17–25)), 35 during ET and 38 during LT. Drug concentrations were above 4 times the MIC in 63 (90%), but above 8 times the MIC in 39 (53%) samples. The proportions of patients with adequate drug concentrations during ET and LT were quite similar. We found a weak but significant correlation between β-lactam antibiotics clearance and CRRT intensity.ConclusionsIn septic patients undergoing CRRT, doses of β-lactam antibiotics similar to those given to patients with normal renal function achieved drug levels above the target threshold in 90% of samples. Nevertheless, 53% of samples were associated with very high drug levels and daily drug regimens may need to be adapted accordingly.

Population pharmacokinetics and dosing simulations of cefepime in septic shock patients receiving continuous renal replacement therapy

“…In this study, data from two previously published PK studies were pooled, the details of which have been described elsewhere [11,12]. The first study was a PK study with blood sampling on multiple occasions [12].…”

“…The second study reviewed data that had been collected as part of routine treatment. Therefore, the ethics committee waived the need for informed consent because of its retrospective nature [11]. The inclusion criteria of the first study were as follows: age >18 years; diagnosis of severe sepsis or septic shock according to standard criteria; acute renal failure treated with CRRT; and receiving cefepime.…”

“…Anticoagulation was performed using systemic heparin or citrate within the circuit. The blood flow rate was set around 130-150 mL/min and the UFR was adjusted to provide ≥15-20 mL/kg/h [11,12]. CRRT intensity was calculated as dialysate flow rate (mL/kg/h) + UFR (mL/kg/h).…”

“…Extracorporeal circuits such as those used for continuous renal replacement therapy (CRRT) may further complicate pharmacokinetics. Indeed, recent studies showed a wide variability in antibiotic concentrations during CRRT, with many patients having low concentrations early in therapy and accumulation occurring in the following days [11][12][13]. Unfortunately, there is relatively little clinical data on drug removal by CRRT; moreover, it is unclear how the specific CRRT settings, such as ultrafiltration flow rate (UFR) and dialysis flow rate, influence drug concentrations.…”

“…Although not very common, toxicity from ␤-lactam antibiotics may occur and is associated with high concentrations [11]. Extracorporeal circuits such as those used for continuous renal replacement therapy (CRRT) may further complicate pharmacokinetics.…”