Risk factors associated with the development of seizures among adult patients treated with ertapenem: A matched case-control study

RESEARCH ARTICLE Risk factors associated with the development of seizures among adult patients treated with ertapenem: A matched case-control study Yi-Chien Lee1,2☯‡, Yun-Jhong Huang3☯‡, Miao-Chiu Hung4, Sheng-Che Hung5,6, ChihYen Hsiao1,7, Hui-Ling Cho8, Li-Fen Lai8, Show-Hwa Tong9, Jann-Tay Wang10* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Department of Internal Medicine, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan, 2 Department of Sports Management, Chia Nan University of Pharmacy and Science, Tainan, Taiwan, 3 Department of Colorectal Surgery, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan, 4 Department of Pediatrics, Taipei Veterans General Hospital, Taipei, Taiwan, 5 Department of Radiology, Taipei Veterans General Hospital, Taipei, Taiwan, 6 School of Medicine, National Yang-Ming University, Taipei, Taiwan, 7 Department of Hospital and Health Care Administration, Chia Nan University of Pharmacy and Science, Tainan, Taiwan, 8 Department of Nursing, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan, 9 Department of Pharmacy, Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chia-Yi, Taiwan, 10 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan ☯ These authors contributed equally to this work. ‡ These authors are first authors on this work. * OPEN ACCESS Citation: Lee Y-C, Huang Y-J, Hung M-C, Hung SC, Hsiao C-Y, Cho H-L, et al. (2017) Risk factors associated with the development of seizures among adult patients treated with ertapenem: A matched case-control study. PLoS ONE 12(7): e0182046. https://doi.org/10.1371/journal. pone.0182046 Editor: Gilles van Luijtelaar, Radboud Universiteit, NETHERLANDS Received: January 11, 2017 Accepted: July 11, 2017 Published: July 31, 2017 Copyright: © 2017 Lee et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: The authors received no specific funding for this work. Competing interests: The authors have declared that no competing interests exist. Abstract Objective The purpose of this study is to compare the characteristics of those ertapenem-treated adult patients with and without development of seizures, and identify the associated factors for the development of seizures. Methods This retrospective study was conducted at Chia-Yi Christian Hospital from January 2012 to December 2014. Patients developing seizures during their ertapenem treatment course were identified as case patients. Those without seizures who had received ertapenem for at least five days were considered as the pool of control patients. For each case patient, four matched patients from the control pool were randomly selected as the final control group, based on age, gender, and the date of ertapenem prescription. Results A total of 1706 ertapenem-treated patients were identified, 33 (1.9%) individuals developed seizures with the enrollment of 132 matched control patients. Among these 33 patients, the average age was 79.3 ± 7.5 years, and 20 (60.6%) were male. The mean Charlson co-morbidity score was 4.5 ± 2.4, and the first episode of seizure happened 3.3 ± 2.6 days after receiving ertapenem. In multivariate logistic regression analysis, the independent predictors associated with the development of ertapenem-associated seizures were old stroke (OR, 14.36; 95% CI, 4.38–47.02; p < 0.0001), undergoing brain images within one year prior to PLOS ONE | https://doi.org/10.1371/journal.pone.0182046 July 31, 2017 1 / 13 Factors for ertapenem-associated seizures the admission (OR, 5.73; 95% CI, 1.78–18.43; p = 0.0034), low hemoglobin level (OR, 3.88; 95% CI, 1.28–12.75; p = 0.0165) and low platelet count (OR, 4,94; 95% CI, 1.56–15.68; p = 0.0067) at presentations, and protective factors against the development of seizures were heart failure (OR, 0.04; 95% CI, 0.00–0.63; p = 0.0222), concomitant use of steroids (OR, 0.19; 95% CI, 0.05–0.77; p = 0.0201), or antiplatelet agents (OR, 0.12; 95% CI, 0.02–0.63, p = 0.0123) with ertapenem. Conclusions The development of ertapenem-associated seizures may occur more frequently and much earlier due to its widespread use in treating drug-resistant pathogens, especially when these pathogens emerged worldwide.Our study would help physician to estimate the risk of developing seizure among patients receiving ertapenem. Introduction Carbapenems possess greatest broad-spectrum activity against gram-positive and gram-negative aerobic and anaerobic bacteria. Among them, imipenem, meropenem, ertapenem, and doripenem have been approved for clinical use in various countries, including Taiwan [1]. They have been proven to be effective against serious infections, including bloodstream infections, nosocomial pneumonia, intra-abdominal infections, and complicated urinary tract infections [2–5]. Although good tolerability has been observed, the most common side effects of carbapenems were gastrointestinal tract upset with an estimated incidence of around 1% to 5% [6–9]. In addition, seizures (abnormal excessive or synchronous electrical discharge in the brain with clinical presentations of involuntary motor movements) have been associated with all carbapenems [6–9]. The mechanism of carbapenem-associated seizures has been thought to be directly associated with the resemblance of the β-lactam ring with the conformation of the γ-aminobutyric acid (GABA) neurotransmitter and antagonism at the receptor site [10,11]. Although such an adverse reaction happens rarely, uncontrolled seizures could lead to major injury or even increased mortality due to impaired level of consciousness or loss of motor control [12]. In general, the incidence of seizures associated with carbapenems is as follows, in order of decreasing frequency: Meropenem (0.7%) [6], ertapenem (0.5%) [7], and imipenem (0.4%) [8], according to FDA-approved labeling; but compared to other carbapenems, the highest seizure rate has occurred with the use of imipenem (3.8%), in clinical trials [13]. However, in a meta-analysis study directly comparing imipenem and meropenem, no difference existed in the rate of seizures in pooled OR analyses [14]. Among those imipenem-treated patients, important risk factors for seizures identified were high dose therapy (> 25 mg/kg), renal impairment, and preexisting neurologic disorders [15]. Nevertheless, only a few case reports or case series discussing the association between ertapenem use and seizures have been published [16–18,19–23]. Thus, we designed a case-control study to investigate the factors associated with seizures in those adult patients receiving ertapenem therapy to provide much safer prescript (...truncated)