ImportanceBlack patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients.ObjectiveTo compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM.DesignCross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance.ExposurePresence of DCM.Main Outcomes and MeasuresVariants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic).ResultsA total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, −0.09 [95% CI, −0.14 to −0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, −0.06 [95% CI, −0.11 to −0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, −0.07 [95% CI, −0.22 to 0.09]) due to a larger number of non-TTN non–predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001).Conclusion and RelevancePatients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.
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.
Background: The incidence of cefepime-induced neurotoxicity (CIN) in hospitalized patients is highly variable. Although greater cefepime exposures incite neurotoxicity, data evaluating trough thresholds associated with CIN remains limited. The objectives of this study were to evaluate the incidence of CIN, assess the relationship between cefepime trough concentrations and CIN, investigate clinical factors associated with CIN, and describe electroencephalogram (EEG) abnormalities in CIN. Methods: This was a retrospective study of adult patients who had received ≥ 5 days of cefepime with ≥ 1 trough concentration > 25 mg/L. Potential CIN cases were identified utilizing neurological symptoms, neurologist assessments, EEG findings and improvement of neurotoxicity after cefepime discontinuation. Results: One-hundred and forty-two patients were included. The incidence of CIN was 13% (18/142). The mean cefepime trough concentration in CIN patients was significantly greater than the non-neurotoxicity group (74.2 mg/L ± 41.1 vs. 46.6 mg/L {plus minus} 23, p=0.015). Lower renal function (creatinine clearance < 30 ml/min), greater time to therapeutic drug monitoring (TDM) (≥72 hours), and each 1 mg/mL rise in cefepime trough were independently associated with increased risk of CIN. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CIN.Conclusion: Cefepime should be used cautiously in hospitalized patients due to the risk of neurotoxicity. Patients with greater renal function and those who had early cefepime TDM (≤ 72 hours) had lower risk of CIN.
BackgroundBased on prior studies, elderly patients and those with renal dysfunction are prone to cefepime (CFP) toxicity. The toxicokinetics and toxicodynamics for CFP are not well established. Lamoth et al. reported a 50% probability of CFP neurotoxicity at a serum trough concentration of ≥22 mg/L, whereas Huwyler et al. observed CFP neurotoxicity when concentrations exceeded 35 mg/L. The objectives of this study were to quantify the incidence of CFP neurotoxicity and to assess the association between CFP concentrations and neurotoxicity.MethodsWe conducted a retrospective review between March 2016 and May 2018, of adult patients with serum CFP trough concentrations ≥25 mg/L. To be considered a CFP neurotoxicity case, patients were required to fulfill at least two of the NCI criteria for neurological toxicity such as, presence of new-onset confusion, delirium, or drowsiness. Following this, cases were classified as (1) high likelihood of toxicity (HLT) if they either had a neurology consult or EEG findings consistent with CFP toxicity and if their symptoms improved after discontinuation of CFP, (2) possible toxicity (PT) if neurology consult or EEG was absent or if we were unable to assess improvement after CFP was discontinued, or (3) nontoxicity (NT). Cases were independently reviewed by an ID pharmacist and physician. Additional data such as comorbidities, renal function, and use of anti-epileptics were collected.ResultsOne hundred and forty-two patients were included in the analysis. Neurotoxicity (HLT+PT) related to CFP occurred in 18/142 (13%) patients; 67% (12/18) were considered HLT. The median age in the HLT cohort was 68 years (interquartile range [IQR], 57–74), with toxicity occurring a median of 6 days (IQR, 5–8) after starting CFP. At the time of neurotoxicity, HLT patients had diminished renal function with a median SCr of 1.6 mg/dL (IQR, 1.2–2.4) and a corresponding CrCl of 35.8 mL/minute (IQR, 19.2–50.9). The median CFP trough concentration in the HLT patients was 62 mg/L (IQR, 50–73) vs. 70mg/L (IQR, 41–115) in the PT and 42 mg/L (IQR, 31–61) in the NT groups.ConclusionOur data emphasize the need for careful dosing in older patients with renal insufficiency. Interestingly, our study reveals higher cefepime troughs (~3-fold higher) associated with neurotoxicity than previously reported.Disclosures All authors: No reported disclosures.
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