Incidence and Predictive Factors Associated with Beta-Lactam Neurotoxicity in the Critically Ill: A Retrospective Cohort Study

Haddad, Natalie; Schreier, Diana J.; Fugate, Jennifer E.; Gajic, Ognjen; Hocker, Sara E.; Ice, Calvin; Leung, Sarah; Mara, Kristin C.; Rabinstein, Alejandro A.; Rule, Andrew D.; Barreto, Erin F.

doi:10.1007/s12028-022-01442-1

Cited by 11 publications

(9 citation statements)

References 28 publications

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“…Similar to other trials which report rates of cefepime‐mediated neurological events of 4%–6%, our results indicate a low incidence of CRN (4.4%; n = 22) 19,20 . Conversely, CRN rates as high as 11–23% have been reported 3,21–23 . The variability seen in the incidence of CRN rates among studies is likely due to differences in the criteria utilized to define a neurotoxic case.…”

Section: Discussionsupporting

confidence: 86%

“…19,20 Conversely, CRN rates as high as 11-23% have been reported. 3,[21][22][23] The variability seen in the incidence of CRN rates among studies is likely due to differences in the criteria utilized to define a neurotoxic case. We attribute the lower incidence of CRN in our cohort to the use of stringent criteria for identification of neurotoxicity cases.…”

Section: Discussionmentioning

confidence: 99%

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Use of therapeutic drug monitoring to characterize cefepime‐related neurotoxicity

et al. 2022

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Study Objectives Data evaluating cefepime thresholds associated with neurotoxicity remain limited. The objectives of this study were to evaluate the incidence of cefepime‐related neurotoxicity (CRN) in patients with plasma cefepime concentrations, assess the relationship between cefepime exposure and CRN, investigate clinical factors associated with CRN, and describe electroencephalogram (EEG) abnormalities in CRN. Design This was a retrospective study of adult inpatients admitted between 2016 and 2018 who received cefepime therapeutic drug monitoring (TDM). Potential CRN cases were identified utilizing a standard definition. The primary outcomes of the study were to determine the incidence of CRN and evaluate the relationship between cefepime trough concentrations, the average daily AUC, and neurotoxicity. Bayesian posteriors were generated for each patient using a cefepime pharmacokinetic (PK) model, and the mean daily area under the concentration–time curve (AUC) was calculated. Multiple regression was performed to assess the association between CRN, cefepime PK, and clinical predictors of neurotoxicity. Main Results Four hundred eighty‐one patients with 503 hospital encounters received cefepime TDM and were included in the analysis. The incidence of CRN was 4.4% (22/503). Patients with CRN had a higher incidence of renal dysfunction, hypertension, and diabetes mellitus compared to patients without CRN (non‐NT). The mean cefepime trough concentration was significantly greater in the CRN patients than in the non‐NT group (61.8 ± 33.7 vs. 30 ± 27.7 mg/L, respectively, p = 0.0002). Cefepime trough concentration and renal dysfunction were independently associated with increased risk of CRN in the adjusted multiple regression model. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CRN. Delaying cefepime TDM greater than 72 h after the initiation of cefepime was associated with a 3‐fold increased risk of CRN. Conclusion Cefepime should be used cautiously in hospitalized patients with renal dysfunction due to the risk of neurotoxicity. Dose optimization utilizing TDM early in cefepime treatment may minimize adverse effects and improve patient safety.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Use of therapeutic drug monitoring to characterize cefepime‐related neurotoxicity

et al. 2022

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“…In patients treated with cefepime, piperacillin/tazobactam or meropenem, up to 15% experienced signs of neurotoxicity [ 13 ]. Nevertheless, in a recent retrospective cohort study, the overall incidence was found to be between 2.1% and 2.6% [ 80 ]. The greatest potential for inducing seizures was described in cefazolin and cefepime, followed by penicillin G and imipenem [ 79 ].…”

Section: Beta-lactam Toxicitymentioning

confidence: 99%

Update on Therapeutic Drug Monitoring of Beta-Lactam Antibiotics in Critically Ill Patients—A Narrative Review

et al. 2023

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Beta-lactam antibiotics remain one of the most preferred groups of antibiotics in critical care due to their excellent safety profiles and their activity against a wide spectrum of pathogens. The cornerstone of appropriate therapy with beta-lactams is to achieve an adequate plasmatic concentration of a given antibiotic, which is derived primarily from the minimum inhibitory concentration (MIC) of the specific pathogen. In a critically ill patient, the plasmatic levels of drugs could be affected by many significant changes in the patient’s physiology, such as hypoalbuminemia, endothelial dysfunction with the leakage of intravascular fluid into interstitial space and acute kidney injury. Predicting antibiotic concentration from models based on non-critically ill populations may be misleading. Therapeutic drug monitoring (TDM) has been shown to be effective in achieving adequate concentrations of many drugs, including beta-lactam antibiotics. Reliable methods, such as high-performance liquid chromatography, provide the accurate testing of a wide range of beta-lactam antibiotics. Long turnaround times remain the main drawback limiting their widespread use, although progress has been made recently in the implementation of different novel methods of antibiotic testing. However, whether the TDM approach can effectively improve clinically relevant patient outcomes must be proved in future clinical trials.

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“…Published guidelines and consensus statements favor the use of BL TDM broadly to individualize therapy for critically ill patients 4,9,10 ; yet there are both clinical and practical reasons which hinder this approach. At Mayo Clinic, the decision was made to prioritize phased deployment in select patients 2,27–32 for the three broad‐spectrum BL antibiotics with highest use in the critical care setting: cefepime, piperacillin/tazobactam, and meropenem. The Mayo Clinic BL TDM patient candidacy guidelines were influenced by several factors.…”

Section: Establishing Clinical Workflowsmentioning

confidence: 99%

“How to” guide for pharmacist‐led implementation of beta‐lactam therapeutic drug monitoring in the critically ill

Ausman

Moreland‐Head

Saleh

et al. 2023

J Am Coll Clin Pharm

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Beta‐lactam therapeutic drug monitoring (TDM) can improve precision dosing and clinical outcomes in critically ill patients, but has not been implemented widely in the United States. Mayo Clinic recently implemented a beta‐lactam TDM program. This single‐center experience forms the basis of the manuscript which outlines practical considerations involved with beta‐lactam TDM implementation, including the pharmacist's role as a leader. Our implementation effort focused on three primary domains. First, we aimed to ensure a supportive organizational infrastructure. Early leadership engagement by the pharmacist‐led core team facilitated advocacy for the clinical need, allocation of resources, and assay development. Second, core clinical workflows were developed that addressed the preferred patient population for use, desirable pharmacokinetic and pharmacodynamic targets, and the preferred sampling strategy. Clinical tools to guide pharmacists in interpreting the results (e.g., pharmacokinetics calculator) and documenting decisions were developed. Third, stakeholders were offered repeated exposure to evidence and expertise to facilitate understanding and application of the new practice. This act of ‘individual internalization’ seems to be uniquely important to beta‐lactam TDM implementation compared with the implementation of other antimicrobial TDM programs. Educational strategies and supportive materials that were developed were focused on providing substantive and varied information tailored to the stakeholders' role in the process. For pharmacists, this included both clinical and operational considerations. A continuous improvement plan to support management of the process was instituted to address necessary updates and changes that inevitably emerged. In summary, the described approach to implementation of a pharmacist‐led beta‐lactam TDM program could be used as a roadmap to aid other institutions that aim to develop such a program.

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Incidence and Predictive Factors Associated with Beta-Lactam Neurotoxicity in the Critically Ill: A Retrospective Cohort Study

Cited by 11 publications

References 28 publications

Use of therapeutic drug monitoring to characterize cefepime‐related neurotoxicity

Use of therapeutic drug monitoring to characterize cefepime‐related neurotoxicity

Update on Therapeutic Drug Monitoring of Beta-Lactam Antibiotics in Critically Ill Patients—A Narrative Review

“How to” guide for pharmacist‐led implementation of beta‐lactam therapeutic drug monitoring in the critically ill

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