Pilot Study of the Pharmacokinetics of Cefotaxime in Critically Ill Patients with Acute Kidney Injury Treated with Continuous Renal Replacement Therapy

Abstract

h The objective of this study was to describe the pharmacokinetics of cefotaxime (CTX) in critically ill patients with acute kidney injury (AKI) when treated with continuous renal replacement therapy (CRRT) in the intensive care unit (ICU). This single-center prospective observational pilot study was performed among ICU-patients with AKI receiving >48 h concomitant CRRT and CTX. CTX was administered intravenously 1,000 mg (bolus) every 6 h for 4 days. CRRT was performed as continuous venovenous hemofiltration (CVVH). Plasma concentrations of CTX and its active metabolite desacetylcefotaxime (DAC) were measured during CVVH treatment. CTX plasma levels and patient data were used to construct concentration-time curves. By using this data, the duration of plasma levels above 4 mg/liter (four times the MIC) was calculated and analyzed. Twenty-seven patients were included. The median CTX peak level was 55 mg/liter (range, 19 to 98 mg/liter), the median CTX trough level was 12 mg/liter (range, 0.8 to 37 mg/liter), and the median DAC plasma level was 15 mg/liter (range, 1.5 to 48 mg/liter). Five patients (19%) had CTX plasma levels below 4 mg/liter at certain time points during treatment. In at least 83% of the time any patient was treated with CTX, the CTX plasma level stayed above 4 mg/liter. A dosing regimen of 1,000 mg of CTX given four times daily is likely to achieve adequate plasma levels in patients with AKI treated with CVVH. Dose reduction might be a risk for suboptimal treatment. Nosocomial infections are frequently acquired in the intensive care unit (ICU), leading to an increase in morbidity and mortality in patients (1). Systemic antibiotics are used to treat these infections. Also in our ICU, patients are treated to prevent colonization and subsequent infections by selective decontamination of the digestive tract (SDD) (2-4). Widely used systemic agents are broad-spectrum parenteral cephalosporins such as cefotaxime (CTX). CTX is a ␤-lactam antibiotic that has antimicrobial activity against potential pathogenic microorganisms such as Staphylococcus aureus, Streptococcus pneumoniae, and Enterobacteriaceae (5). After administration, CTX undergoes hydrolysis by esterases available in plasma and the liver to form its active metabolite, desacetylcefotaxime (DAC), which is further metabolized into inactive compounds (6). CTX and DAC have half-lives of 1.1 and 1.3 h, respectively, and are mainly excreted in the urine (7).Since CTX is mainly cleared by the kidneys, acute kidney injury (AKI) may alter its excretion and pharmacokinetic parameters (8). Subsequently, supporting a patients impaired renal function with renal replacement therapy can again significantly alter the elimination of the drugs. Continuous renal replacement therapy (CRRT) substitutes for renal function by effectively removing solutes from the blood. The extracorporeal clearance is especially relevant for drugs with a dominant renal clearance and results in unpredictable pharmacokinetics (8). Dose modifications of CTX might therefore be required...

Population pharmacokinetics of cefotaxime in intensive care patients

“…However, higher total V of 26–32 L has been reported for patients with liver disease in different disease stages [ 23 ]. Koedjik et al [ 24 ] showed a median total V in ICU patients on renal replacement therapy of 22.5 L, results that are in line with this current investigation. High V in ICU patients can be attributed to fluid leakage into the interstitial space and the use of resuscitation fluids [ 4 ], an effect that could be further pronounced by the high proportion of burn patients (35%) in this study.…”

Dose optimization of cefotaxime as pre‐emptive treatment in critically ill adult patients: A population pharmacokinetic study

“…In children and neonates targets ranged from 75 to 100% 36 . In adults, targets of 100% of total or free concentration above or 4–5 times above the (actual measured) MIC have also been used in the critically ill 11,27,37,38 . In concordance with Aardema et al .…”

“…MIC have also been used in the critically ill. 11,27,37,38 In concordance with Aardema et al we used 100% fT> MIC ECOFF. The MIC ECOFF was used to account for variability in MIC testing and natural variability within isolates.…”

Cefotaxime Loaded Polycaprolactone Based Polymeric Nanoparticles with Antifouling Properties for In-Vitro Drug Release Applications

“…Cefotaxime is effectively used against various microbial strains responsible for skin, lower respiratory, urinary tract, intra-abdominal, bone and joint, and CNS infections [ 15 , 16 ]. Thus, it is considered to be an effective antifouling agent for nanoencapsulation with a high in vitro activity, favorable pharmacokinetics, and a moderate molecular weight [ 17 ].…”