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Saudi Journal of Kidney Diseases and Transplantation
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CASE REPORT  
Year : 2020  |  Volume : 31  |  Issue : 6  |  Page : 1427-1431
Meropenem at recommended dose is a potential risk for seizure in hemodialysis patient


1 Department of Internal Medicine, Division of Nephrology, King Fahd Hospital of the University, Alkhobar; Department of Internal Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia
2 Diaverum Al-Majdoi Dialysis Center, Eastern Province, Saudi Arabia

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Date of Web Publication29-Jan-2021
 

   Abstract 


Dosage adjustment of meropenem is usually recommended in hemodialysis (HD) patients and about 30% of meropenem is cleared during regular HD sessions. However, most of the published trials excluded patients on regular HD. Little is known about the accurate dosage of meropenem needed to avoid central nervous system toxicity. Herein, we report a 65-year-old Saudi female, a known case of end-stage renal disease on regular HD, who was admitted because of pyelonephritis and started on meropenem in the recommended dose according to cultures and sensitivity. She developed tonic-clonic convulsions after the 7th dose. Seizures were completely aborted after discontinuation of the offending drug. The recommended dosage of 500 mg daily in HD patients may still be too high particularly in Asian patients owing to their relatively small body mass index.

How to cite this article:
Al-Hwiesh A, Alhwiesh A, Abdul-Rahman IS, Al-Harbi A, Mousa D, Skiker S, Abdulkhani A, Beheri H, Radi M, AlKhaldi D, Aldwaihi A, Alqahtani S. Meropenem at recommended dose is a potential risk for seizure in hemodialysis patient. Saudi J Kidney Dis Transpl 2020;31:1427-31

How to cite this URL:
Al-Hwiesh A, Alhwiesh A, Abdul-Rahman IS, Al-Harbi A, Mousa D, Skiker S, Abdulkhani A, Beheri H, Radi M, AlKhaldi D, Aldwaihi A, Alqahtani S. Meropenem at recommended dose is a potential risk for seizure in hemodialysis patient. Saudi J Kidney Dis Transpl [serial online] 2020 [cited 2021 Mar 4];31:1427-31. Available from: https://www.sjkdt.org/text.asp?2020/31/6/1427/308364



   Introduction Top


Seizures are episodes of transient neurologic changes due to hyper-excitation of brain neuronal activity. Seizures are divided into two types: provoked and unprovoked. Provoked seizures occur with a recognized cause and are Corresponding author not expected to recur in the absence of that particular cause, whereas unprovoked seizures usually occur without a recognized cause.[1] The incidence of provoked seizures in patients older than 60 years is estimated at 0.55–1 per 1000, with linear increase every decade after the age of 30. Drugs and drug withdrawal account for 10% of provoked seizures.[2] Acute stroke, intracranial lesions, metabolic ence-phalopathy, drugs, and alcohol are identifiable causes of provoked seizures.[3] A wide range of medications has been identified as a cause of provoked seizures in late-life such as opioids, methotrexate, carbapenems (imipenem, meropenem, etc.), penicillin, and hypoglycemic agents.[3],[4] Meropenem is a broad-spectrum antibiotic that works by inhibiting bacterial cell-wall synthesis through binding to penicillin-binding proteins. It is metabolized in the liver and excreted in urine. Its clinical adverse effects include nausea, diarrhea, constipation, seizure (≤1%), urticaria, and dysuria.[5] Elderly people are particularly susceptible to drug-induced seizure due to the high prevalence of impaired drug clearance and poly-pharmacy.[1],[3] Carbapenems, in general, have abroad spectrum antibacterial activity and are commonly reserved for serious and complicated bacterial infections.[4] Carbapenems have antibacterial activity mainly against Gram-negative pathogens. It is well tolerated by most patients, but an important adverse effect of their use is central nervous system (CNS) toxicity.[6] Initial trials reported seizures associated mainly with imipenem in high doses and particularly in elderly patients.[7] Practice Guidelines for the management of Infectious disease in the USA recommended meropenem over imipenem due to decreases risk of seizure with the former.[8] However, there is inconsistency in the literature regarding whether there is a difference in the seizure potential between the two carbapenems. In general, the frequency of seizure for imipenem and meropenem is 0.4% and 0.7%, respectively.[9],[10] Dosage adjustment of meropenem is usually recommended in hemodialysis (HD) patients and about 30% of meropenem is cleared during regular HD session.[11] However, most of the published trials excluded patients on regular HD. Little is known about the exact dosage of meropenem in this group of patients to avoid CNS toxicity. We hereby report a 65-year-old Saudi lady, known case of end-stage renal disease (ESRD) on regular HD, who was admitted because of pyelonephritis and was started on meropenem at a recommended dose. This patient developed tonic-clonic convulsions after the 7th meropenem dose. Seizures were completely aborted after discontinuation of the offending drug. The recommended dosage of 500 mg meropenem daily in HD patients maybe still too high in Asian patients, owing to thei rrelatively small body mass index.


   Case Report Top


Informed consent was obtained from the patient’s relatives for the publication of this case report.

A 65-year-old Saudi lady, a known case of type-2 diabetes mellitus with diabetic retinopathy, neuropathy, and ESRD was on regular HD at Diaverum Dialysis Center through right permicath for over two years. She also had other co-morbid conditions namely hypertension, ischemic heart disease (status post-stent implantation), and cerebrovascular disease. She was maintained on insulin, amlodipine, calcium carbonate, one alpha, and folic acid. Her blood sugar and blood pressure were well controlled. She was admitted because of pyelonephritis and was started on meropenem 500 mg daily since her urine grew Klebsiellapneumoniae. On day 7 of antibiotic treatment, she started to be confused and agitated with incoherent speech. She was disoriented with visual hallucination following which she had recurrent attacks of generalized tonic-clonic seizure that lasted for approximately 1 min each. In response, she was loaded with phenytoin 100 mg every 8 h. Despite that, she continued with more episodes of tonic-clonic seizures, hence valproic acid was added. Computerized tomography (CT) scan of the brain showed multiple scattered hypodense areas seen more on the left occipital region and the right frontal area, which demonstrated diffuse periventricular white matter hypodensities. No mass effect or mid-line shift, no hemorrhagic lesions, intra-or extra-axial collection or evidence of recent stroke as seen [Figure 1]. Electroencephalogram (EEG) showed back-ground alpha rhythm symmetrical attenuation with eye-opening. Intermittent photonic stimulation and hyper-ventilation produced no abnormality. No epileptiform discharges were recorded [Figure 2]. The nonspecific CT brain, nonspecific EEG changes, and the absence of electrolyte disturbances or other concomitant medications that may explain her cognitive dysfunction and recurrent uncontrolled seizures raised the possibility of meropenem as being the offender. Therefore, meropenemwas discontinued and replaced with ciprofloxacin 250 mg daily. On the 7th day after stopping meropenem and intensifying her dialysis session with high flux biocompatible filter and increasing dialysis duration to 4.5 h, she started to be more oriented with no further seizure episodes. All anti-epileptic medications were gradually weaned off. She was then followed up for four months with no further seizures. She was reported to be fully oriented to time, place, and person with no signs of focal neurological deficit.
Figure 1: Multiple scattered hypodense areas seen more at the left occipital regin, right high frontal region, at the medial aspect of the right cerebellar hemisphere, and the vermis. Left aspect of the midbrain and left aspect of the pons tiny spots of hypodensity.diffuse periventricular white matter hypodenisties. No mass effect or midline shift. No hemorrhagic lesion. No intra- or extra-axial collection.

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Figure 2: Background alpha rhythm symmetrical attenuation with eye-opening, Intermittent photonic stimulation and hyperventilation produced no abnormality. No epileptiform discharges were recorded. Muscular and movement artifact were recorded.

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On examination upon admission, she looked ill and was oriented to time place and person. Blood pressure was 120/70 mmHg, heart rate 110 beats/min, temperature 37°C, weight 47 kg, height 148 cm, body mass index 21.5, and oxygen saturation 97 at room air. Cardiac examination was significant only for tachycardia, and pulmonary and abdominal examinations were normal. There was no lower limb edema and the peripheral pulses were intact. She had sensory peripheral neuropathy in the form of gloves and socks distribution and back ground diabetic retinopathy; otherwise, no significant neurological deficit was noted.

The initial investigation showed RBS 150 mg/dL, serum creatinine 6 mg/dL, blood urea nitrogen 65 mg/dL, sodium 131 mmol/L, potassium 3.5 mmol/L, chloride 97 mmol/L, CO2 28 mEq/L and anion gap 8 mEq/L. Hb: 9.7 g/dL hematocrit 29.7%, mean corpuscular volume 74.9, platelets: 239, white blood cell: 8.20/μL of blood. Liver function tests were within normal limits, serum calcium 8.9 mg/dL, phosphorus 3.2 mg/dL, magnesium 1.8 mg/dL, uric acid 5 mg/dL, urine analysis was consistent with urinary tract infection and three blood cultures were negative. The serum lactate was 9.7mg/dL and Hb-A1c was 8.0. The arterial blood gas: pH: 7.42, PCO2: 34 mm Hg, HCO3: 26 mEq/L, cardiac enzyme, and isoenzyme and ECG were all within normal limits. Hepatitis profile and HIV were negative, prothrombin time, partial thromboplastin time, echocardiograph, chest X-ray and bilateral carotid ultrasound were normal. Renal ultrasound showed bilateral small kidneys.


   Discussion Top


Carbapenems in general have broad-spectrum antibacterial activity and are commonly used in serious and complicated bacterial infections.[12] Carbapenems have anti-bacterial activity mainly against Gram-negative pathogens. It is well tolerated by most patients, but an important adverse effect of their use is CNS toxicity.[6] Initial trials reported seizure associated mainly with imipenem in high doses and particularly in elderly patients.[12] Practice Guidelines for the Management of Infectious Disease in the USA recommended meropenem over imipenem due to decreased risk of seizure with the former.[8] However, there is inconsistency in the literature regarding whether there is any difference in seizure potential between the two carbapenems. The frequency of seizure for imipenem and meropenem was reported to be 0.4% and 0.7%, respectively.[7],[8] In a recent meta-analysis by Cannon et al,[13] the odds ratio (ORs) for risk of seizures from imipenem, meropenem, ertapenem, and dori-penem compared with other antibiotics were 3.50 [95% confidence interval (CI) 2.23, 5.49], 1.04 (95% CI 0.61, 1.77), 1.32 (95% CI 0.22, 7.74), and 0.44 (95% CI 0.13, 1.53), respectively. In that study, there was no difference in epileptogenicity in either risk difference or pooled OR analyses.[13]

It is worth noting, that the main risk factors for carbapenem-induced seizures are higher dose and renal impairment since they are eliminated mainly by the kidney. However, there still conflicting results in the literature regarding other risk factors (previous CNS injury, or history of seizure and concomitant medications known to decrease seizure threshold.[14],[15]

The pool safety studies for carbapenems have identified the frequency of seizure of 0.4% and 0.2% for meropenem and ertapenem, respectively. The absolute risk of seizure with carba-penem compared to non-carbapenem antibiotic is still low. However, most of meropenem trials associated with CNS toxicity have excluded patients on regular HD.[11] Little is known about the exact dosage of meropenem to avoid CNS toxicity. The molecular weight of meropenem is 383.5 g/mol and the plasma half-life is approximately 1 h in adults with normal renal function. The plasma half-life is increased and clearance of the drug is decreased in patients with renal impairment; about 30% of meropenem is cleared during regular HD sessions.[16] Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response and signs of adverse reactions due to drug accumulation.[14] The mechanism of seizure provocation by carbapenems is multifactorial; it is related to the drug’s ability to reduce inhibition of epileptic discharges by blocking the gamma aminobutyric acid A (GABA) receptors; to its action on amino-3-hydroxy-5-methyl-isoxazolepropionate (AMPA) and N-methyl-D-aspartate receptor complexes (which may be secondary to the drug’s action on GABA receptors); or to its penicillin-like activity.[17]

Common CNS symptoms of carbapenem toxicity include disorientation, incoherent speech, agitation, restlessness, and visual hallucinations.[15] The high protein binding, high volume of distribution and increased permeability of blood-brain barrier of meropenem may hinder rapid tissue elimination after CNS toxicity.[1618]

Our patient was anuric and had a small bodyweight which may have led to accumulation of meropenem at the recommended dose leading to classical CNS toxicity that completely disappeared after removing the offending drug. Our case showed that the recommended dose of 500 mg meropenem on daily basis for conventional HD patient may be still too high particularly in the anuric patients with small body mass index. We think that healthcare providers’ awareness about meropenem CNS toxicity would avoid unnecessary extensive investigation, hospitalization, and potential devastating complications.


   Acknowledgments Top


The authors are pleased to express their great thanks and appreciation to the staff nurses at Diaverum A-lMajdoi dialysis center for their great efforts and high standard care to our patient and to the intensive care unit and the female medical ward at King Fahd University Hospital, Al-Khobar for their valuable support during the patient’s hospitalization.

Conflict of interest: None declared.



 
   References Top

1.
Shih T. Seizures and Epilepsy in Older Adults: Etiology, Clinical Presentation, and Diagnosis. Top. 2223., Ver. 33.0. UpToDate; 2019.  Back to cited text no. 1
    
2.
Loiseau J, Loiseau P, Duché B, Guyot M, Dartigues JF, Aublet B. A survey of epileptic disorders in southwest France: Seizures in elderly patients. Ann Neurol 1990;27:232-7.  Back to cited text no. 2
    
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Pesola GR, Avasarala J. Bupropion seizure proportion among new-onset generalized seizures and drug related seizures presenting to an emergency department. J Emerg Med 2002;22:235-9.  Back to cited text no. 3
    
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Reichert C, Reichert P, Monnet-Tschudi F, Kupferschmidt H, Ceschi A, Rauber-Lüthy C. Seizures after single-agent overdose with pharmaceutical drugs: Analysis of cases reported to a poison center. ClinToxicol (Phila) 2014;52:629-34.  Back to cited text no. 4
    
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Meropenem: Drug Information. Top. 9613., Ver. 220.0. UpToDate; 2019.  Back to cited text no. 5
    
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Calandra GB, Brown KR, Grad LC, Ahonkhai VI, Wang C, Aziz MA. Review of adverse experiences and tolerability in the first 2,516 patients treated with imipenem/cilastatin. Am J Med 1985;78:73-8.  Back to cited text no. 6
    
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Wong VK, Wright HT Jr., Ross LA, Mason WH, Inderlied CB, Kim KS. Imipenem/cilastatin treatment of bacterial meningitis in children. Pediatr Infect Dis J 1991;10:122-5.  Back to cited text no. 7
    
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Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39:1267-84.  Back to cited text no. 8
    
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Primaxin. Whitehouse Station, NJ: Merck & Co., Inc.; 2012.  Back to cited text no. 9
    
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Merrem. Wilmington, DE: Astra Zeneca; 2010.  Back to cited text no. 10
    
11.
Linden P. Safety profile of meropenem: an updated review of over 6,000 patients treated with meropenem. Drug Saf 2007;30:657-68.  Back to cited text no. 11
    
12.
Clark NM, Patterson J, Lynch JP 3rd. Antimicrobial resistance among gram-negative organisms in the intensive care unit. CurrOpinCrit Care 2003;9:413-23.  Back to cited text no. 12
    
13.
Cannon JP, Lee TA, Clark NM, Setlak P, Grim SA. The risk of seizures among the carba-penems: A meta-analysis. J AntimicrobChemother 2014;69:2043-55.  Back to cited text no. 13
    
14.
Majumdar AK, Musson DG, Birk KL, et al. Pharmacokinetics of ertapenem in healthy young volunteers. Antimicrob Agents Chemother 2002;46:3506-11.  Back to cited text no. 14
    
15.
Chow KM, Szeto CC, Hui AC, Li PK. Mechanisms of antibiotic neurotoxicity in renal failure. Int J Antimicrob Agents 2004;23:213-7.  Back to cited text no. 15
    
16.
Lee KH, Ueng YF, Wu CW, Chou YC, Ng YY, Yang WC. The recommended dose of ertapenem poses a potential risk for central nervoussystem toxicity in hemodialysis patients – Case reports and literature reviews. J Clin Pharm Ther 2015;40:240-4.  Back to cited text no. 16
    
17.
Miller AD. Epileptogenic potential of carbapenem agents: Mechanism of action, seizure rates, and clinical considerations. Pharmacotherapy 2011;31:408-23.  Back to cited text no. 17
    
18.
Schmidt S, Röck K, Sahre M, Burkhardt O, Brunner M, Lobmeyer MT, et al. Effect of protein binding on the pharmacological activity of highly bound antibiotics. Antimicrob Agents Chemother 2008;52:3994-4000.  Back to cited text no. 18
    

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Correspondence Address:
Abdullah Al-Hwiesh
Department of Internal Medicine, Division of Nephrology, King Fahd Hospital of the University, Alkhobar
Saudi Arabia
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DOI: 10.4103/1319-2442.308364

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