Cefepime neurotoxicity despite renal adjusted dosing

Gangireddy, Venu Gopala Reddy; Mitchell, Lauren C.; Coleman, Teresa

doi:10.3109/00365548.2011.581308

Cited by 44 publications

(24 citation statements)

References 6 publications

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“…Still, cefepime neurotoxicity can occur despite dose adjustments [19] and in our study, of those with cefepime neurotoxicity, 28.9% (four of fourteen patients with known doses) developed neurologic symptoms despite a standard dose reduction based on CL Cr . It is also notable that neurotoxicity can occur despite concurrent hemodialysis [20], though one expects the neurologic symptoms to improve after a few days if the dose has been appropriately adjusted and if flow rates are adequate.…”

Section: Discussionmentioning

confidence: 60%

Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy

et al. 2013

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IntroductionCefepime, a broad spectrum antibiotic, is commonly prescribed in intensive care units (ICU) and may be an overlooked cause of neurologic symptoms such as encephalopathy, myoclonus, seizures, and coma. We aimed to characterize cefepime neurotoxicity in the ICU.MethodsWe performed a retrospective study of adult ICU patients treated with intravenous cefepime for at least 3 days between January 1, 2009 and December 31, 2011. The primary outcome was the development of cefepime neurotoxicity, with the likelihood of causality ascribed via a modified Delphi method.ResultsThis study included 100 patients. The mean age was 65.8 years (± 12.7 years). The median daily average dose of cefepime was 2.5 (IQR 2.0 to 3.5) grams. The median treatment duration was 6 (IQR 4 to 10) days. Renal failure in any form was present in 84 patients. Chronic kidney disease affected 40 patients, and 77 had acute kidney injury. Cefepime neurotoxicity occurred in 15 patients. Of these, seven were considered definite cases, three probable, and five possible. Neurotoxic symptoms included impaired consciousness (n = 13), myoclonus (n = 11), disorientation (n = 6), and nonconvulsive status epilepticus (n = 1). The dose of cefepime was appropriately adjusted for renal clearance in 64 patients (75.3%) without cefepime neurotoxicity and four patients (28.6%) with neurotoxicity (P = 0.001). Chronic kidney disease was present in 30 patients (35.3%) without neurotoxicity and in 10 (66.7%) of those with neurotoxicity (P = 0.04).ConclusionsCritically ill patients with chronic kidney disease are particularly susceptible to cefepime neurotoxicity. Myoclonus and impaired consciousness are the predominant clinical manifestations. Neurotoxic symptoms occur more often when the cefepime dose is not adjusted for renal function, but can still occur despite those modifications.

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Section: Discussionmentioning

confidence: 60%

Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy

et al. 2013

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“…Drug accumulation and excessive β-lactam antibiotic concentrations may lead to adverse events, including neurological toxicity. Hallucinations, confusion, and seizures have been reported as a consequence of high β-lactam antibiotic concentrations, mostly in patients with renal impairment [25,26], but also in patients with normal kidney function [27]. The mechanism of cerebral toxicity seems to be related to the drug interaction with the GABA-A receptor and is concentration-dependent [28].…”

Section: Discussionmentioning

confidence: 99%

β-lactam antibiotic concentrations during continuous renal replacement therapy

et al. 2014

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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.

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“…However, it must also be highlighted that blindly increasing the dose in all patients may give rise to needlessly high concentrations in some of them. Although ␤-lactams are not commonly toxic, toxicity is severe when it occurs, with seizures from high concentrations being reported previously (39)(40)(41). This wide pharmacokinetic variability suggests that the principle of one dose fits all is unlikely to be appropriate in this patient population (42).…”

Section: Discussionmentioning

confidence: 94%

A Simulation Study Reveals Lack of Pharmacokinetic/Pharmacodynamic Target Attainment in De-escalated Antibiotic Therapy in Critically Ill Patients

Carlier

Roberts

Stove

et al. 2015

Antimicrob Agents Chemother

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f De-escalation of empirical antibiotic therapy is often included in antimicrobial stewardship programs in critically ill patients, but differences in target attainment when antibiotics are switched are rarely considered. The primary objective of this study was to compare the fractional target attainments of contemporary dosing of empirical broad-spectrum ␤-lactam antibiotics and narrower-spectrum antibiotics for a number pathogens for which de-escalation may be considered. The secondary objective was to determine whether alternative dosing strategies improve target attainment. We performed a simulation study using published population pharmacokinetic (PK) studies in critically ill patients for a number of broad-spectrum ␤-lactam antibiotics and narrower-spectrum antibiotics. Simulations were undertaken using a data set obtained from critically ill patients with sepsis without absolute renal failure (n ‫؍‬ 49). The probability of target attainment of antibiotic therapy for different microorganisms for which de-escalation was applied was analyzed. EUCAST MIC distribution data were used to calculate fractional target attainment. The probability that therapeutic exposure will be achieved was lower for the narrower-spectrum antibiotics with conventional dosing than for the broad-spectrum alternatives and could drastically be improved with higher dosages and different modes of administrations. For a selection of microorganisms, the probability that therapeutic exposure will be achieved was overall lower for the narrower-spectrum antibiotics using conventional dosing than for the broad-spectrum antibiotics. P rovision of antibiotic therapy that is timely and of an appropriate spectrum is one of the mainstays of treatment (1, 2). This has led to the widespread use of broad-spectrum antibiotic therapy for the empirical treatment of infections. After identification of the causative microorganism, antibiotic therapy is typically adapted to the susceptibility profile of the microorganism, with a preference to change therapy to narrower-spectrum agents in order to decrease selective pressure for resistant pathogens. This process is called antibiotic de-escalation and is considered an important element in antibiotic stewardship programs (3-5).Although the timing and adequacy of the antibiotic therapy remain crucial, recent data hint at the importance of antibiotic dosing and exposure on clinical outcome (6). Changes in the physiology of the critically ill alter the pharmacokinetics (PKs) of ␤-lactam antibiotics, with many patients being at risk of being underdosed (7,8). Attainment of PK/pharmacodynamic (PD) targets associated with efficacy is also dependent on the susceptibility of the pathogen and varies across antibiotic classes, an element that is rarely considered (8).Although de-escalation of antibiotic therapy is a key element in many antibiotic stewardship programs, the possible change in PK/PD target attainment in de-escalation has not yet been considered. De-escalation has been associated with improved outcomes in ...

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Cefepime neurotoxicity despite renal adjusted dosing

Cited by 44 publications

References 6 publications

Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy

Cefepime neurotoxicity in the intensive care unit: a cause of severe, underappreciated encephalopathy

β-lactam antibiotic concentrations during continuous renal replacement therapy

A Simulation Study Reveals Lack of Pharmacokinetic/Pharmacodynamic Target Attainment in De-escalated Antibiotic Therapy in Critically Ill Patients

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