Cefepime and continuous renal replacement therapy (CRRT): In vitro permeability of two CRRT membranes and pharmacokinetics in four critically ill patients

doi:10.1016/j.clinthera.2005.05.004

Clinical Therapeutics

Volume 27, Issue 5, May 2005, Pages 599-608

https://doi.org/10.1016/j.clinthera.2005.05.004 Get rights and content

Abstract

Background:

Cefepime is a fourth-generation cephalosporin with a broad spectrum of antimicrobial activity against gram-positive and gram-negative micro-organisms. It is a useful option for treating infections in critically ill patients in intensive care due to its high degree of activity and its tolerability.

Objective:

The aim of this study was to characterize in vitro the permeability to cefepime of 2 membranes frequently used in continuous renal replacement therapies (CRRTs). An in vivo study was also carried out to determine the pharmacokinetics of cefepime in critically ill patients undergoing CRRT.

Methods:

In vitro procedures were conducted in 3 different fluids using polyacrylonitrile (AN69) or polysulfone (PS) membranes. Continuous venovenous hemofiltration (CVVH) and continuous venovenous hemodialysis (CVVHD) were simulated. Four male patients undergoing CVVH or continuous venovenous hemodiafiltration, who received 2000 mg of cefepime intravenously every 8 hours, entered the in vivo study. Prefilter and ultrafiltrate samples were collected, and concentrations of cefepime were measured using high-performance liquid chromatography. The sieving coefficient (Sc), defined as the fraction of drug eliminated across the membrane, and the saturation coefficient (Sa), defined as the fraction of drug diffused through the membrane to the dialysate fluid, were analyzed. Pharmacokinetic parameters were determined according to a noncompartmental analysis.

Results:

The patients ranged in age from 18 to 75 years and weighed from 65 to 80 kg. By analyzing Sc and Sa values in the in vitro procedures, no differences were detected in the permeability of AN69 or PS membranes to cefepime in CVVH or CVVHD. Sc/Sa values were between 0.93 and 1.03 in Ringer's lactate and in bovine albumin-containing Ringer's lactate samples, but Sc/Sa values were lower in plasma samples (0.82–0.95). In the in vivo portion of the study, the patients' mean (SD) Sc/Sa value was 0.76 (0.21) and correlated well with the fraction unbound to proteins (0.79 [0.09]). Clearance by CRRT (mean [SD]) was 29.0 (16.8)% of the total clearance. Serum elimination t_1/2 was 4.6 (0.9) hours, and the volume of distribution at steady state was 0.6 (0.3) L/kg (mean [SD] values).

Conclusions:

Cefepime was significantly removed by CRRT. No significant differences were found in the Sc or Sa of cefepime between AN69 and PS membranes used in the CVVH or CVVHD procedures. The clearance of cefepime by CRRT must be considered when dosing critically ill patients.

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Body weight was limited to 40 kg as a minimum to assume all patients were adults. It was assumed that all simulated patients are anuric as most critically ill patients receiving CRRT with cefepime or ceftazidime therapy were anuric [21,22,24,25,27-30]. Four conventional cefepime and ceftazidime dosing regimens were simulated: 2-g loading dose (LD) infused over 0.5 h, followed by 1 or 2-g every 8 or 12 h with a 4-h extended-infusion.
This study aimed to determine optimal extended-infusion dosing regimens for cefepime and ceftazidime in critically ill patients receiving continuous renal replacement therapy using Monte Carlo Simulations (MCS).
Pharmacokinetic models were built using published pharmacokinetic/demographic data to predict drug disposition in 5000 virtual critically ill patients receiving continuous venovenous hemofiltration (CVVH) with the standard (20–30 mL/kg/h) and a higher (40 mL/kg/h) effluent rates. MCS was performed to assess the probability of target attainment (PTA) of four cefepime and ceftazidime doses administered over 4-h with the target of ≥60% fT > 4×MIC. The lowest dose attaining PTA ≥90% during the first 48-h was considered optimal. Additionally, risk of drug toxicity was assessed at 48-h using suggested neurotoxicity thresholds.
Cefepime 2 g loading dose (LD), then extended-infusion of 2 g q8hr was optimal in CVVH at 20 mL/kg/h and the same ceftazidime dose was optimal in CVVH at 20–30 mL/kg/h. Higher cefepime and ceftazidime doses were required to be optimal at higher effluent rates. This optimal dose particularly for cefepime likely increases neurotoxicity risk in most virtual patients with all CVVH settings.
Cefepime and ceftazidime 2 g LD, followed by extended-infusion 2 g q8hr may be optimal in CVVH with standard effluent rates.
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Fig. 1 (flow chart) displays reference selection process, main results of which are shown in Tables 1 and 2. Table 1 summarises 42 studies performed in ICU patients not focusing on RRT [30–73], while Table 2 presents data on patients under RRT from 28 studies [10,74–100]. Vd and Cl variability data were reported for 5 penicillins (amoxicillin, ampicillin, flucloxacillin, piperacillin and temocillin), 3 beta-lactamase inhibitors (clavulanic acid, sulbactam, tazobactam), 6 cephalosporins (cefazolin, cefepime, cefpirome, ceftazidime, ceftriaxone and cefuroxime) and 4 carbapenems (doripenem, ertapenem, imipenem and meropenem).
The use of antibacterial drugs is very common in critically ill patients and beta-lactam agents are widely used in this context. Critically ill patients show several characteristics (e.g., sepsis, renal impairment or conversely augmented renal clearance, renal replacement therapy) that may alter beta-lactam pharmacokinetics (PK) in comparison with non-critically ill patients. This narrative literature review aims to identify recent studies quantifying the variability of beta-lactams volume of distribution and clearance and to determine its main determinants. Seventy studies published between 2000 and 2018 were retained. Data on volume of distribution and clearance variability were reported for 5 penicillins, 3 beta-lactamase inhibitors, 6 cephalosporins and 4 carbapenems. Data confirm specific changes in PK parameters and important variability of beta-lactam PK in critically ill patients. Renal function, body weight and use of renal replacement therapy are the principal factors influencing PK parameters described in this population. Few studies have directly compared beta-lactam PK in critically ill versus non-critically ill patients. Conclusions are also limited by small study size and sparse PK data in several studies. These results suggest approaches to assess this PK variability in clinical practice. Beta-lactam therapeutic drug monitoring seems to be the best way to deal with this issue.
Antibiotic Dosing in Continuous Renal Replacement Therapy
2017, Advances in Chronic Kidney Disease
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The MCS model integrated relevant input parameters to construct a virtual patient population. Body weight was derived from a large renal replacement therapy study8 and pharmacokinetic data were gathered from published cefepime,35-41 ceftazidime,42-48 levofloxacin,49-52 meropenem,53-59 piperacillin,10,60-65 and tazobactam10,60,61 studies in critically ill patients receiving renal replacement therapy. Antibiotics in this study were chosen based on whether (1) known pharmacokinetic data in CRRT exists, (2) pharmacodynamic target data associated with patient outcomes have been identified, and (3) routine therapeutic drug monitoring are unavailable at most hospitals.
Appropriate antibiotic dosing is critical to improve outcomes in critically ill patients with sepsis. The addition of continuous renal replacement therapy makes achieving appropriate antibiotic dosing more difficult. The lack of continuous renal replacement therapy standardization results in treatment variability between patients and may influence whether appropriate antibiotic exposure is achieved. The aim of this study was to determine if continuous renal replacement therapy effluent flow rate impacts attaining appropriate antibiotic concentrations when conventional continuous renal replacement therapy antibiotic doses were used. This study used Monte Carlo simulations to evaluate the effect of effluent flow rate variance on pharmacodynamic target attainment for cefepime, ceftazidime, levofloxacin, meropenem, piperacillin, and tazobactam. Published demographic and pharmacokinetic parameters for each antibiotic were used to develop a pharmacokinetic model. Monte Carlo simulations of 5000 patients were evaluated for each antibiotic dosing regimen at the extremes of Kidney Disease: Improving Global Outcomes guidelines recommended effluent flow rates (20 and 35 mL/kg/h). The probability of target attainment was calculated using antibiotic-specific pharmacodynamic targets assessed over the first 72 hours of therapy. Most conventional published antibiotic dosing recommendations, except for levofloxacin, reach acceptable probability of target attainment rates when effluent rates of 20 or 35 mL/kg/h are used.
Severe cefepime-induced status epilepticus treated with haemofiltration
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Neurotoxicity caused by cefepime may occur predominantly in patients with impaired renal function. A case of a cefepime-induced non-convulsive status epilepticus (NCSE) is presented. A 65-year-old woman suffered a severe NCSE due to cefepime in the presence of acute renal failure, requiring coma induction with sodium thiopental. A serious interaction between valproic acid (VPA) and meropenem was also produced after changing cefepime to meropenem. Continuous veno-venous haemofiltration was employed to improve cefepime clearance, and the patient progressively regained her previous mental condition. In conclusion, the cefepime dose must be adjusted according to renal function in order to avoid toxicity in patients with renal failure. Electroencephalogram should be considered in cases of acute confusional state in patients receiving cefepime, to achieve early detection of NCSE. Continuous renal replacement therapy may be successfully employed in severe cases in order to accelerate cefepime removal. Likewise, meropenem should not be used concomitantly with VPA.
La neurotoxicidad por cefepime puede producirse principalmente en pacientes con insuficiencia renal. Presentamos un caso de status epiléptico no convulsivo producido por cefepime. Una mujer de 65 años con fracaso renal agudo en tratamiento con cefepime sufrió un episodio grave de status epiléptico no convulsivo que requirió inducción de coma barbitúrico con tiopental sódico. Tras el cambio de cefepime a meropenem se produjo también una interacción grave entre meropenem y ácido valproico. Se utilizó hemofiltración venovenosa continua para acelerar el aclaramiento de cefepime y la paciente recuperó progresivamente su situación neurológica previa. En conclusión, la dosis de cefepime debe ser ajustada a la función renal para evitar toxicidad en pacientes con insuficiencia renal. Debería considerarse la utilización del electroencefalograma en casos de estado confusional agudo en pacientes en tratamiento con cefepime para un diagnóstico precoz del status epiléptico no convulsivo. La terapia continua de reemplazo renal puede ser empleada en casos graves para acelerar la eliminación de cefepime. Además el meropenem no debe de utilizarse concomitantemente con el ácido valproico.
Simultaneous determination of seven β-lactam antibiotics in human plasma for therapeutic drug monitoring and pharmacokinetic studies
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On the other hand clearance may be unchanged [17] or decreased [4,18] and in the presence of organ dysfunction such acute kidney injury, diminished clearance may lead to massive accumulation and toxicity [25–27]. In patients with renal dysfunction, optimization antibiotic dosing is further complicated by the use of renal replacement therapy which provides significant and variable extracorporeal clearance for several β-lactams [28–34]. These pharmacokinetic challenges would mean that empiric fixed dose strategy is unlikely to ensure sufficient antibiotic exposure and as well empiric dose optimization is unrealistic due the little data available to guide clinicians.
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Pseudomonas es un patógeno frecuente en las unidades de pacientes críticos y puede ser causa de shock séptico y de fallo renal. Es fundamental en estos pacientes instaurar un tratamiento antibiótico precoz y a dosis adecuadas. La disfunción renal aguda es también habitual en pacientes críticos. En aquellos que necesitan depuración extrarenal, las técnicas continuas de depuración extrarenal (TCDE) son una alternativa a la hemodiálisis intermitente y es necesario tener en cuenta que muchos antibióticos se eliminan de forma sustancial por las TCDE.
El objetivo de esta revisión es analizar la evidencia clínica disponible sobre el comportamiento farmacocinético y las recomendaciones posológicas de los principales grupos de antibióticos empleados en el tratamiento de infecciones por Pseudomonas spp. en pacientes críticos sometidos a técnicas continuas de depuración extrarenal.
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Original ResearchCefepime and continuous renal replacement therapy (CRRT): In vitro permeability of two CRRT membranes and pharmacokinetics in four critically ill patients

Background:

Objective:

Methods:

Results:

Conclusions:

J Pharm Sci

Am J Kidney Dis

Am J Surg

Diagn Microbiol Infect Dis

Medicina Intensiva

Cefepime. A review of its antibacterial activity, pharmacokinetic profile and therapeutic use

Drugs

Factors involved in the enhanced efficacy against gram-negative bacteria of fourth generation cephalosporins

J Antimicrob Chemother

Evaluation of several dosing regimens of cefepime, with various simulations of renal function, against clinical isolates of Pseudomonas aeruginosa in a pharmacodynamic infection model

Antimicrob Agents Chemother

Pharmacokinetics of cefepime during continuous renal replacement therapy in critically ill patients

Antimicrob Agents Chemother

Low plasma cefepime levels in critically ill septic patients: Pharmacokinetic modeling indicates improved troughs with revised dosing

Antimicrob Agents Chemother

Pharmacokinetics of cefepime: A review

J Antimicrob Chemother

Pharmacokinetics of cefepime during continuous venovenous hemodiafiltration

Antimicrob Agents Chemother

Reevaluation of formulas for predicting creatinine clearance in adults and children, using compensated creatinine methods

Clin Chem

Bioanalytical method validation—a revisit with a decade of progress

Pharm Res

Guidance for Industry: Bioanalytical Methods Validation for Human Studies

Drug removal during continuous arteriovenous hemofiltration: Theory and clinical observations

Int J Artif Organs

Drug therapy in patients undergoing hemodialysis: Clinical pharmacokinetic considerations

Clin Pharm

Drug administration in critically ill patients with acute renal failure

New Horiz

Original Research
Cefepime and continuous renal replacement therapy (CRRT): In vitro permeability of two CRRT membranes and pharmacokinetics in four critically ill patients