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Original article

Higher than expected rates of seizures associated with the use of ertapenem in older hospitalized patients

Han Yee Neo, MD

a, * , Keng Teng Tan, BSc b , Yew Yoong Ding, MD a a

Department of Geriatric Medicine, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore

b Department of Pharmacy, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433, Singapore article info

Article history:

Received 31 October 2011

Received in revised form

12 September 2012

Accepted 26 September 2012

Keywords:

Aged

Carbapenems

Drug toxicity

Seizuresabstract

Background:Use of carbapenems is expected to increase with rising prevalence of multidrug-resistant

bacteria. Available literature indicates that the incidence of seizure with ertapenem use ranges from

0.2% to 0.5% in adults. However, anecdotal clinical experience suggests that the frequency of seizures in

frail geriatric patients could be higher.

Aim:We sought to estimate the rate of seizures with the use of ertapenem in older hospitalized patients

and to identify possible predisposing factors for their occurrence.

Methods:We performed a retrospective chart review for hospital episodes of patients who were admitted

to the department of geriatric medicine of an acute care hospital and received at least one dose of ertapenem between October 2009 and September 2010. Results:Chart reviews for 116 patients were conducted. The mean age of the study population was 82.9 years [standard deviation (SD)¼8.1] and 69% of the patients were female. The mean number of

comorbidities was 8.6 (SD¼3.7) and the mean number of assisted or dependent activities of daily living

out of 5 was 3.5 (SD¼2.0). Seizures occurred in six (5.17%) hospitalized patients. The Naranjo Adverse

Drug Reaction Probability Scale revealed a causality relationship graded as"possible"in two episodes and"probable"in the remaining four episodes. Patients who experienced seizures were significantly

younger (mean age: 75.7 vs. 83.3 years,p¼0.023) and had fewer comorbidities (5.5 vs. 8.8,p¼0.033).

Seizure occurrence had statistically nonsignificant associations with a history of central nervous system

disorders and previous seizures. Conclusion:We found a higher rate of seizures amongst older hospitalized patients who were using ertapenem than reported in existing literature. Further studies should include a wider population of older hospitalized patients and compare seizure incidence with the use of carbapenem alternatives.

Copyright?2012, Asia Pacific League of Clinical Gerontology & Geriatrics. Published by Elsevier Taiwan1. Introduction

The rising incidence rates of extended spectrum

b-lactamase (ESBL) resistance amongst nosocomial microbial colonization and infection, coupled with limited antibiotic options against these ESBL producing organisms, and convenient once-daily dosing of ertapenem, 1,2 have led to a steady increase in the use of ertapenem in acute care hospitals. However, carbapenems are potentially neurotoxic compounds that have been associated with seizures. 3e5

Seizures associated with carbapenem use is not thought to bea class-related phenomenon. Rather, it is dependent on specific

molecules in individual compounds, which bind to and competi- tivelyinhibit the gamma-aminobutyric acid receptor in the brain.3,6 Although seizures occurred in less than 2% of patients who received imipenem and meropenem, 7e14
data on seizures associated with ertapenem use are scarce. At present, this serious adverse reaction is considered to be an infrequent event. 15 To date, 16 studies of adults receiving ertapenem have been published.

2,16e27

Of these,14 are randomized controlled trials with

active comparator arms, while two included open-label experi- ences in treating ventilator-associated pneumonia. 28,29

Of the

nearly 3000 patients who received a single dose of 1 g or more of ertapenem, only three drug-related seizures were reported.16,21,22 Several other case reports show an incidence rate of up to 0.5% in adults. 30e35
History of central nervous system (CNS) disorders, *Corresponding author. Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng,

Singapore 308433, Singapore.

E-mail address:han_yee_neo@ttsh.com.sg(H.Y. Neo).

Contents lists available atSciVerse ScienceDirect

Journal of Clinical Gerontology & Geriatrics

journal homepage: www.e-jcgg.com2210-8335 Copyright?2012, Asia Pacific League of Clinical Gerontology & Geriatrics. Published by Elsevier Taiwan LLC.

http://dx.doi.org/10.1016/j.jcgg.2012.09.004 Journal of Clinical Gerontology & Geriatrics 4 (2013) 17e21

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impaired creatinine clearance, and a history of seizures were identified as possible predispositions. However, the frequency of seizures in frail older hospitalized patients who received intrave- nous ertapenem appears to be higher in our clinical practice. The objectives of this study were to (1) evaluate the rate of seizures with the use of ertapenem in older hospitalized patients, (2) measure the mortality risk in relation to ertapenem-related seizures, and (3) to investigate the relationship between the rate of seizure occurrence with ertapenem administration and risk factors identifieda priori, including age, comorbidity, functional disability, pre-existing CNS disorders, and a history of seizures.

2. Methods

2.1. Participants

This is a retrospective cohort study conducted at a 1000-bed acute care hospital in Singapore. All patients who were admitted to the department of geriatric medicine and given at least one dose of intravenous ertapenem between October 1, 2009 and September

31, 2010 were enrolled.

Patients selected for inclusion in the study cohort were identi- fied using the hospital pharmacy dispensing database (iPharm). Using the patients'unique identification card number, we identi- fied the patients and their specific admissions for which ertapenem was administered and retrieved the relevant inpatient admission notes for data collection from the hospital's medical records office. Data collectionwas carried out from December 2010 to March 2011. Inpatient admission notes that were not available for review during the data collection period were excluded from the study. This study was initiated as part of a department's internal audit toward quality improvement. Approval was obtained from the Head of Department, Geriatric Medicine, Tan Tock Seng Hospital.

2.2. Data collection

Based on literature review that yielded several case reports and case series, a number of factors postulated to be associated with increased predisposition to seizures with ertapenem use were identifieda priori, and their association with seizures was assessed. These included age, comorbidity, functional disability, history of CNS disorders, history of seizures, renal impairment (estimates of creatinine clearance), and electrolyte abnormalities. We reviewed the inpatient admission notes of all included patients and collected demographic data such as age, gender, ethnicity, and duration of hospital stay. Dosage and duration of ertapenem administration were also obtained by reviewing the inpatient admission notes and the electronic inpatient medication records. Data on the risk factors identifieda prioriduring literature review, including age, number of diseases, functional disability in terms of number of dependent or assisted activities of daily living (ADLs), history of CNS disorders, history of seizures, renal impair- ment (estimates of creatinine clearance), and electrolyte abnor- malities were collected. Prognosticating measures such as age, comorbidity, and functional disability aid in indicating complex needs and, perhaps, frailty in the study population. In instances where patients were admitted two or more times during the study period, only data from the earliest admission are analyzed.

2.3. Identification and description of seizures

The primary study outcome was defined as occurrence of seizures during the period of hospitalization after the administra- tion of ertapenem. Seizures were considered to be possibly related

to ertapenem use if it occurred after at least one dose of ertapenemwas administered. By reviewing inpatient charts, evidence of

seizure activity including information on the phenotypic presen- tation, frequency, and timing of seizures, as well as the presence or absence of an electroencephalogram was collected. In-hospital mortality information was also collected as a secondary outcome using chart review. In order to evaluate the strength of the causality relationship between ertapenem use and seizure occurrence, the Naranjo

Adverse Drug Reaction Probability Scale (NADRPS)

36,37
was applied to all identified seizures events that occurred after ertapenem administration. This is an objective ten-item weighted scale that has gained wide applicability in establishing causality relationship between administered drugs and adverse events. Probability is assigned as definite, probable, possible, or doubtful on the basis of the score obtained. Previous case studies and case series examining ertapenem-related seizures have also used NADRPS as a measure of causality. 30e35

2.4. Statistical analyses

All data analyses were performed using IBM SPSS Statistics version 19. Two-sidedpvalues less than 0.05 were taken to indicate statistical significance. Demographic features of the study pop- ulation were described. The proportion of patients who had seizures after ertapenem administration was determined. The independentttest and the Chi-square test were used to analyze possible associations between seizures and continuous and cate- gorical variables, respectively. These include age,gender, number of comorbidities, pill burden, history of CNS disorders, history of seizures, renal impairment (estimates of creatinine clearance), and electrolytic abnormalities. The Kruskal eWallis test was used for analyzing the median length of hospital stay and the Fisher exact test was used for analyzing the in-hospital mortality in view of expected low mortality.

3. Results

A total of 118 patients met the inclusion criteria and were therefore included in the study. The charts of two patients were unavailable for examination, and thus they were excluded from analyses. The mean age was 82.9 years [standard deviation (SD)¼8.1]. Majority of the participants were women (62%). The mean number of comorbidities per patient was 8.6 (SD¼3.7), while the mean number of assisted or dependent ADLs was 3.5 (SD¼2.0) (Table 1). For 66.7% of hospital episodes, ertapenem was prescribed for urinary tract infections, as well as for bacteremia in 11.6% of the episodes. In the remaining 21.7% it was prescribed for various combinations of urinary tract infection, bacteremia, and other concurrent infections. Seizures occurred in six (5.17%) of the 116 hospitalized patients. All seizures were clinically diagnosed focal or generalized tonice clonic convulsions. With the exception of one case where the seizure occurred on the 2nd day of ertapenem administration, all the other patients had seizures on or after the 4th day of antibiotic administration. Recurrent seizures were seen in three patients. Characteristics of these patients and their seizures are summarized inTable 2. By applying the NADRPS to these six seizure episodes, we found a causality relationship graded as"possible"in two patients with seizures and"probable"in the other four (Table 3). Two patients with seizures passed away during the same period of admission. One passed away on the day of seizure onset, while the other passed away 4 days after seizure onset. The cause of death of thefirst patient was attributed to urinary tract infection and pneumonia, while that of the second patient was reported as sacral H.Y. Neo et al. / Journal of Clinical Gerontology & Geriatrics 4 (2013) 17e2118 osteomyelitis with subcutaneous abscesses. In-hospital mortality was higher in the seizure group than in the nonseizure group (33.3% vs. 9.1%; relative risk¼3.66), although this was not statis- tically significant. Patients in the seizure group were significantly younger (mean age:75.7 vs. 83.3 years,p¼0.023) and had fewercomorbidities (5.5 vs. 8.8,p¼0.033), compared with those without seizures. All patients in the seizure group had a history of CNS disorders such as cerebral gliosis, previous cerebrovascular thrombosis, and hemor- rhage, compared with 80.9% among those without seizures. The high rate of CNS disorders amongst these elderly patients is largely accounted for by the presence of lacunar infarcts and micro- hemorrhages noted on previous neuroimaging studies. A higher proportion of patients with seizures had a history of antiepileptic drug use and seizures before admission than those without seizures, although these differences did not reach statistically significant levels (Table 1).

4. Discussion

To the best of our knowledge, this is thefirst retrospective cohort study investigating the relationship between ertapenem use and seizures in the elderly, many of whom are more complex and may be frail. In previous researches on seizures and ertape- nem use that included several case reports and one case series, seizure incidence was reported to be between 0.2% and 0.5% among adults. 30
e35

A manufacturer review of the influence of age

(>65 vs.<65 years) on the occurrence of adverse drug events didnot identify age-related differences in seizure rates.

38,39

Pharma-

cokinetic analysis of ertapenem use in elderly patients demon- strated only mild, nonsignificant increases in area under the concentrationetime curve and decreases in clearance compared with those parameters in healthy adult volunteers, with no need for dosage adjustment. 40,41
However, ourfindings indicate that the rates of seizures with the use of ertapenem in older hospitalized patients who were likely to be frail far exceeded what was previously reported in adults (5.17% vs. 0.5%). The true risk of seizures may even be higher given that from anecdotal observations, attending physicians tended to avoid prescribing ertapenem in older patients deemed to be at higher risk of seizures. Of the six patients who were identified with seizure episodes, four were classified as having"probable"and two having"possible" causality relationship with ertapenem use (NADRPS score range:

3e7). This magnitude of causal association is comparable if not

superior to existing case series and case reports (NADRPS score range: 3e5). Our study revealed a higher hospital mortality amongst patients with ertapenem-related seizures (33.3% vs. 9.1%,p¼0.117), although this difference in mortality was not statistically significant given the small number of patients admitted with seizure episodes. Although seizures may increase mortality risk due to the elevated risks of cere- bral insults, hypoxemia, and aspiration pneumonia, it is quite possible that the higher mortality observed could also reflectconcurrentand severe illness associated with both seizure occurrence and death. Because of the retrospective design of this study, we are unable to

Table 2

Characteristics of patients with seizures and concurrent ertapenem use.

Patient no. 1 2 3 4 5 6

Gender, age in years F, 75 F, 68 F, 81 M, 75 F, 79 M, 76

Indication for

ertapenem useESBLþKlebsiellaUTI ESBLþEscherichia coliUTI, sacral sore, pneumoniaESBLþE. coliUTIESBLþE. coli bacteremiaESBLþE. coli bacteremiaESBLþE. coliUTI History of CNS disorder Yes, ischemic stroke Yes, ischemic stroke, gliosis Yes, brain tumorYes, gliosis, ischemicstroke,encephalomalaciaYes, ischemic stroke Yes, ischemic stroke

History of seizure NilNilNilYesNilNil

Use of AEDNilNilNilPhenytoinNilNil

Creatinine (

mmol/L) 10041394911194

In-hospital death NoYesNoNoYesNo

Type of seizuresFocal X1, GTC X1 Facial twitchingGTC X1 Focal X2GTC X4GTC X1

Number of days

until seizures2 (second episodeon Day 10)13511 (second episodeon Day 13)10 (four episodeson Day 10)5 AED¼anti-epileptic drug; CNS¼central nervous system; ESBLþ¼extended spectrum b-lactamase producing; GTC¼generalized toniceclonic seizures; UTI¼urinary tract infection.

Table 1

Baseline characteristics of the study population.

Study population

(n¼116)Seizure (n¼6) No seizure (n¼110)p(for differences between seizure and nonseizure groups) Mean age, years (SD)82.9 (8.1)75.7 (4.5)83.3 (8.3)0.023

Female gender,n(%)80 (69)4 (66.6)76 (69.0)0.607

Ethnicity,n(%)

Chinese105 (90.5)4 (66.7)101 (91.8)

Malay6 (5.2)1 (16.7)5 (4.5)

Indian4 (3.4)0 (0)4 (3.6)d

Others1 (0.8)1 (16.7)0 (0)

Mean number of assisted or dependant ADLs,n(SD) 3.5 (2.0)3.8 (1.9)3.5 (2.1)0.692 Mean number of medications,n(SD)7.8 (3.6)6.0 (4.0)7.9 (3.5)0.215 Mean number of comorbid conditions,n(SD)8.6 (3.7)5.5 (2.1)8.8 (3.7)0.033 History of seizures,n(%)6 (5.2)1 (16.7)5 (4.5)0.278 Use of antiepileptic agents,n(%)15 (12.9%)1 (16.7)14 (12.7)0.573 History of CNS disease,n(%)95 (81.9)6 (100)89 (80.9)0.293 Median length of hospital stay, days (IQR)21 (13e37)40 (20e47)21 (13e35) 0.157 In-hospital death,n(%)12 (10.3)2 (33.3)10 (9.1)0.117

ADLs¼activities of daily living; CNS¼central nervous system; IQR¼interquartile range; SD¼standard deviation.

pvalue less than 0.05 are in bold to highlight statistical significance. H.Y. Neo et al. / Journal of Clinical Gerontology & Geriatrics 4 (2013) 17e2119 obtain clinical indices of disease severity amongst enlisted patients to enableadjustmentfortheinfluenceofdiseaseseverityonmortality.As such, despite the positive association with mortality in our study, we areunabletodrawadefinitive conclusion that ertapenem-related seizures lead to increased mortality. Future prospective studies with large sample sizes where disease severity is measured as a confound- ing variable would be helpful to ascertain this issue. One might have expected that age and comorbidity burden would be associated with the risks of ertapenem-induced seizures. However, the opposite was observed in our study population. The reason for this surprisingfinding is not clear from our data. Because of the retrospective study design, data on specific risk factors for seizures identifieda priori, such as electrolyte abnormalities and creatinine clearance, were not available due to incomplete docu- mentation or testing. Incomplete data collection on creatinine clearance further precluded the analysis of appropriate drug dosing with the rates of seizure occurrence. Similarly, plasma antiepileptic drug levels, as well as changes in dosing regimen of these drugs during the course of antibiotic administration, could not be evaluated. Lack of this set of important information and the small number of seizure events precluded the performance of meaningful regression analyses to address poten- tial confounding variables. Nevertheless, we postulate that physi- cians may have tended to prescribe ertapenem less cautiously in younger patients, patients with less comorbidity, and others who were considered to be at lower risk for adverse events. Further and larger studies are needed to examine the relationship between seizures and these risk factors more closely. We acknowledge that the limitations of this study include its relatively small sample size, the absence of a comparison group not exposed to ertapenem, and unavailability of data on several important variables as discussed. The study population is confined to the more complex hospitalized older patients typically seen in geriatric medicine departments. Therefore, our results cannot be extrapolated to younger and less complex patients. Furthermore, as geriatricians may have avoided the use of carbapenems in patients who were more frail and sick, and thus deemed to be at higher seizure risk, this may have undermined our attempt to estimate the true risk of ertapenem-induced seizures in older patients. Never- theless, this study contributes to the literature by highlighting the higher seizure incidence amongst older and more complex hospi- talized patients who received ertapenem, and thus sets the stage for future studies to be performed over a wider patient spectrum and across different carbapenems.5. Conclusion We have found that the rates of seizures with the use of erta- penem in older and more complex hospitalized patients far exceededthose previouslyreportedinadults. Itis likelythat theuse of ertapenem lowers the seizure threshold in elderly patients with predisposing risk factors. Usage of carbapenems is expected to increase with the rising prevalence of multiresistant bacteria. Therefore, it is important for clinicians to be aware that older patients may be more susceptible to this potentially neurotoxic adverse effect of ertapenem and exercise due vigilance and care when prescribing this antibiotic.

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Table 3

Application of the Naranjo Adverse Drug Reaction Probability Scale to patients with seizures.

QuestionScore assigned to answer

Y N Do not know

Patient with seizure123456

Are there previousconclusivereports on this reaction?þ100þ1þ1þ1þ1þ1þ1

Did the adverse event occur after the suspected drug was administered?þ2?10þ2þ2þ2þ2þ2þ2

Did the adverse reaction improve when the drug was discontinued or aspecificantagonist was administered?þ1000þ1þ1þ10þ1 Did the adverse reaction reappear when the drug was readministered?þ2?10þ2?10þ20?1 Are there alternative causes (other than the drug) that could have on their own caused the reaction??1þ20?1?1þ2?1?1þ2 Did the reaction reappear when a placebo was given??1þ10000000 Was the drug level detected in the blood (or otherfluids) in concentrations known to be toxic?þ1 00000000 Was the reaction more severe when the dose was increased or less severe when the dose was decreased?þ100000000 Did the patient have a similar reaction to the same or similar drugs inanyprevious exposure?þ1 00000000

Was the adverse event con

firmed by any objective evidence?þ100þ1þ1þ1þ1þ1þ1

Total Score537636

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