Recommended β-lactam regimens are inadequate in septic patients treated with continuous renal replacement therapy

Abstract

IntroductionSepsis is responsible for important alterations in the pharmacokinetics of antibiotics. Continuous renal replacement therapy (CRRT), which is commonly used in septic patients, may further contribute to pharmacokinetic 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 pharmacokinetic criteria for broad-spectrum antibiotic levels in septic shock patients undergoing CRRT.MethodsThis 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 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).ResultsA 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 four times the minimal inhibitory concentration for Pseudomonas spp. for the recommended time in 81% of patients treated with MEM, in 71% with TZP, in 53% with CAZ and in 0% with FEP. Accumulation after 48 hours of treatment was significant only for MEM.ConclusionsIn 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 optimise serum concentrations.

Pharmacokinetics and Pharmacodynamics of Piperacillin-Tazobactam in 42 Patients Treated with Concomitant CRRT

“…Our PD data resembled the data of others, suggesting that the probability of target attainment (probability of reaching fT.MIC564 mg/ml>50%) was not 100% (10,19,20).…”

“…PK parameters for piperacillin in our study resembled those parameters reported in the work by Seyler et al (10), and they are notably differ from those parameters published in a commonly used prescribing guide ("The Green Book") (16). Protein binding was lower, volume of distribution was higher, and half-life was longer than described in this prescribing guide (16).…”

“…This study population is relatively obese compared with studies from Europe and Asia (10,13). The majority of patients were severely oligoanuric (median=38 ml/24 h, IQR=157 ml).…”

“…The percent of time that the free piperacillin plasma level was above the minimum inhibitory concentration (MIC) during the dosing interval (%T.MIC) was calculated for MIC of 16 and 64 mcg/ml using previously reported methods (8,9). A pharmacodynamic (PD) target for piperacillin of .50%T.MIC64 mcg/ml was selected as the parameter of interest based on prior publications and proportion with target achievement calculated (10). The equations used to calculate the PK and PD parameters are listed in Supplemental Material.…”

Adding to the Armamentarium

“…Consequently, many of the antibiotic doses that seemed to be appropriate for patients receiving RRTs in the ICU in the past are probably insufficient today (32,33). Pharmacokinetic and pharmacodynamic studies like the one by Lorenzen et al (7) need to continue to be conducted for all types RRT, to begin to reduce the infectious mortality rate in this vulnerable patient population.…”