Case Report Annals of Short Reports Published: 30 Sep, 2019

Meropenem at Recommended Dose Can Cause Potential Risk for Seizure in Hemodialysis Patient

Abdullah Al-Hwiesh1*, Amani Alhwiesh1, Eman Fathi2, Fadwa Mohamed2, Manar Elsayed2, Jamielou Almazan2, Abdullah Alrashidi2, Fatimah Aldehiam2, Azeeza Aldwaihi2, Saad Alqhtani2, Hussin Alsharani2 and Nadia Aluauda3 1Department of Nephrology, King Fahd Hospital of the University, Saudi Arabia

2Department of Nephrology, Security Force Hospital Damam, Saudi Arabia

3Department of Nephrology, Damman Central Hospital, Saudi Arabia

Abstract Dosage adjustment of meropenem is usually recommended in hemodialysis patient and about 30% of meropenem is cleared during regular hemodialysis session. However, most of published trials excluded patients on regular hemodialysis. Little is known about the exact dosage of meropenem to ovoid central nervous system toxicity. Here we report a 65 year old Saudi lady known case of end stage renal failure on regular hemodialysis was admitted due to pyelonephritis and was started on meropenem as recommended dose, developed tonic clonic convulsion after seventh dose of meropenem and the seizure completely aborted after discontinuation the offending drug. The recommended dosage of 500 mg daily in hemodialysis patients may be still too high in particularly Asians patient, owing to their relative small body mass index. Keywords: Meropenem; Seizure; ESRD; Hemodialysis

Introduction Seizures are episode of transient neurologic change due to hyper excitation of neuronal activity in the brain. Seizures are divided into two types: provoked and unprovoked seizure. Provoked seizure occurs with a recognized cause and is not expected to recur in the absence of that particular cause, OPEN ACCESS whereas unprovoked seizure occurs without a recognized cause [1]. The incidence of provoked *Correspondence: seizures in patients older than age 60 years is estimated at 0.55 to 1 per 1000, with linear increases Abdullah Al-Hwiesh, Department of every decade after age 30 years. Acute stroke, intracranial lesions, metabolic encephalopathy, drugs Nephrology, King Fahd Hospital of the and alcohol are identifiable causes of provoked seizures [2]. Drugs and drug withdrawal account for University, Al-Khobar, 40246, Saudi 10% of provoked seizures [3]. A rang of medications have been identified as a cause of provoked Arabia, seizures in late life such as: opioids, methotrexate, carbepenems (imipenem, meropenem), penicillin E-mail: [email protected] and hypoglycemic agents [3,4]. Meropenem is a broad spectrum antibiotic, works by inhibiting Received Date: 26 Aug 2019 bacterial cell-wall synthesis by binding to penicillin-binding proteins. It metabolized in liver and Accepted Date: 25 Sep 2019 excreted in urine. Its clinical adverse effects including nausea, diarrhea, constipation, seizure (≤ Published Date: 30 Sep 2019 1%), urticaria and dysuria [5]. Elderly people are particularly susceptible to drug induce seizure due to high prevalence of impaired drug clearance and poly-pharmacy [1,3]. Carbapenem in general Citation: had abroad spectrum antibacterial and commonly used in serous complicated bacterial infections Al-Hwiesh A, Alhwiesh A, Fathi E, [4,6]. Carbapenems have antibacterial activity against mainly gram-negative pathogens. It is well Mohamed F, Elsayed M, Almazan J, et tolerated by most patients, but an important adverse effect of their use is the Central Nervous System al. Meropenem at Recommended Dose (CNS) toxicity [7]. Initial trials reported seizure associated mainly with imipenem in particularly in Can Cause Potential Risk for Seizure high dose and elderly patients [8]. Infectious disease of America recommended meropenem over in Hemodialysis Patient. Ann Short imipenem due to decreases risk of seizure with meropenem [9]. However, there is inconsistency Reports. 2019; 2: 1043. in literature regarding whether there is a difference in the seizure potential between the two Copyright © 2019 Abdullah Al- Carbapenem. In general the frequency of seizure for imipenem and meropenem is 0.4% and 0.7% Hwiesh. This is an open access respectively [10,11]. Dosage adjustment of meropenem is usually recommended in hemodialysis article distributed under the Creative patient and about 30% of meropenem is cleared during regular hemodialysis session [12]. However, Commons Attribution License, which most of published trials excluded patients on regular hemodialysis. Little is known about the exact permits unrestricted use, distribution, dosage of meropenem to ovoid (CNS) toxicity. Here we report a 65 year old Saudi lady known and reproduction in any medium, case of end stage renal failure on regular hemodialysis was admitted due to pyelonephritis and was provided the original work is properly started on meropenem as recommended dose, developed tonic clonic convulsion after seventh dose cited. of meropenem and the seizure completely aborted after discontinuation the offending drug. The

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Figure 1: Multiple scattered hypodense areas seen more at the left occipital Figure 2: Showed background alpha rhythm symmetrical attenuation with regin, right high frontal region, at the medial aspect of right cerebelluar eye opening .Intermittent photonic stimulation and hyperventilation produced hemisphere and the vermis. Left aspect of midbrain and left aspect of no abnormality. No epiletiform discharges were recorded. Muscular and the pons tiny spots of hypodenisty.diffuse periventricular white matter movement artifact were recorded. hypodenisties .No mass effect or midline shift. No hemorrhagic lesion. No intra or extra axial collection. rate 110 beats per minute, temperature 37°C, weight 50 Kg height 146 recommended dosage of 500 mg meropenem daily in hemodialysis cm, and oxygen saturation 97 at room air. Cardiac examination was patients may be still too high in particular Asians patient, owing to significant only for tachycardia, and the pulmonary and abdominal their relative small body mass Index. examination were normal. No lower limb edema and the peripheral pulses were intact. She had sensory peripheral neuropathy inform of Case Presentation gloves and socks distribution and back ground diabetes retinopathy A 65 years old Saudi lady known case of diabetes mellitus since otherwise no significant neurological deficit. more than 20 years with diabetic retinopathy, neuropathy and Initial investigation: RBS 150 mg/dl, creatinine 6 mg/dl urea nephropathy end stage renal failure on regular hemodialysis three 65 mg/dl, sodium 131 mmol/l, potassium 3.5 mmol/l, chloride 97 time per week, four hour duration through right premicath for 2 year. mmol/l. CO2 28 mEq/l and anion gap 8 mEq/l. Hb: 9.7 gm/dl HCT Also known case of hypertension, coronary heart disease status post 29.7, MCV 74.9, PLT: 239, WBC 8.20 L × 10 L. Liver function tests stent and cerebrovascular disease old right cerebral artery stroke. were within normal, calcium 8.9 mg/dl, phosphorus 3.2 mg/dl, She was maintained on insulin, amlodipine, calcium carbonate, one magnesium 1.8 mg/dl, uric acid 5 mg/dl, urine analysis consistent alpha and folic acid. Her blood sugar and blood pressure was well with urinary tract infection and three blood culture were negative. controlled. She was admitted to our hospital due to pyelonephritis Serum lactate 9.7 mg/dl. HA1c 8. and was started on meropenem 500 mg daily as her urine culture th grew klebsella pneumonia. On 7 day of antibiotic patient started to Arterial blood gas: PH: 7.42, PCO2: 34, HCO3: 26, cardiac enzyme be confused, agitated with incoherent speech, disoriented with visual and isoenzyme, ECG were within normal, Hepatitis profile and HIV hallucination and she developed recurrent attack of generalized tonic negative, PT, PTT, Eco cardiograph, chest X-ray and bilateral carotid clonic seizure that lasted for about 1 min each. Due to that, she was ultrasound were within normal limit and renal ultrasound showed loaded with phenytoin then 100 mg every 8 h and her condition bilateral small shrunk kidney. deteriorated with more episodes of tonic clonic seizure, so valoropic Discussion acid was added. CT brain showed multiple scattered hypodense areas seen more on the left occipital region, right frontal region showed Carbapenem in general had abroad spectrum antibacterial diffuse peri-ventricular white matter hypodensities, no mass effect or and commonly used in serous complicated bacterial infections midline shift. No hemorrhagic lesion, no intra or extra axial collection [6]. Carbapenems have antibacterial activity against mainly gram- or evidence of recent stroke Figure 1. EEG Showed background alpha negative pathogens. It is well tolerated by most patients, but rhythm symmetrical attenuation with eye opening. Intermittent an important adverse effect of their use is the CNS toxicity [7]. photonic stimulation and hyperventilation produced no abnormality. Initial trials reported seizure associated mainly with imipenem in No epileti form discharges were recorded Figure 2. Due to recurrent particularly in high dose and elderly patients [6]. Infectious disease of attack of seizure, nonspecific CT brain, nonspecific EEG changes, America recommended meropenem over imipenem due to decreases no electrolyte disturbance or other concomitant medication explain risk of seizure with meropenem [9]. However, there is inconsistency her cognitive dysfunction and recurrent uncontrolled seizures, in literature regarding whether there is a difference in the seizure the possibility of meropenem induce seizure was raised. Therefore potential between the two carbapenem. In general the frequency of meropenem was discontinued and ciprofloxacin 250 mg daily was seizure for imipenem and meropenem is 0.4% and 0.7% respectively started. On the 7th day after holding meropenem and intensifying her [8,9]. In recent meta-analysis by Joan et al. [13] the ORs for risk of dialysis session with high flux biocompatible filter and increase dialysis seizures from imipenem, meropenem, ertapenem and doripenem duration to four and half hour, she started to be more oriented and no compared with other antibiotics were 3.50 (95% CI 2.23, 5.49), 1.04 more convulsion episodes, so all anti-epileptic medications gradually (95% CI 0.61, 1.77), 1.32 (95% CI 0.22, 7.74) and 0.44 (95% CI 0.13, weaned off. Follow up two months after discharge at dialysis unit with 1.53), respectively. In studies directly comparing imipenem and no more seizure and she was fully oriented to time, place and person meropenem, there was no difference in epileptogenicity in either risk with no signs of focal neurological deficit. difference or pooled OR analyses [13]. On examination: upon admission she looked ill and was oriented It is worth noting, that the main risk factors for carbapenem to time place and person. Blood pressure 120 mmHg/70 mmHg, heart induce seizure are higher dose and renal impairment as meropenem

Remedy Publications LLC. 2 2019 | Volume 2 | Article 1043 Abdullah Al-Hwiesh, et al., Annals of Short Reports - Nephrology mainly excreted by kidney. However, there is conflicting result 3. Pesola GR, Avasarala J. Bupropion seizure proportion among new‐onset in literature regarding other risk factors (previous CNS injury, or generalized seizures and drug related seizures presenting to an emergency history of seizure and concomitant medication known to decrease department. J Emerg Med. 2002;22(3):235-9. seizure threshold) [14,15]. 4. Reichert C, Reichert P, Monnet-Tschudi F, Kupferschmidt H, Ceschi A, Rauber-Lüthy C. Seizures after single‐agent overdose with pharmaceutical The pool safety studies for carbapenem have identified the drugs: Analysis of cases reported to a poison center. Clin Toxicol. frequency of seizure of 0.4% and 0.2% for meropenem and 2014;52(6):629-34. etrapenem respectively. The absolute risk of seizure with carbapenem 5. Meropenem: Drug information. Uptodate. 2019;9613. compared to non carbapenem antibiotic is still low. However most of meropenem trials associated with CNS toxicity have excluded 6. Clark NM, Patterson J, Lynch JP. Antimicrobial resistance among gram- patients on regular hemodialysis [16]. Little is known about the exact negative organisms in the intensive care unit. Curr Opin Crit Care. dosage of meropenem to ovoid central nervous system toxicity. The 2003;9(5):413-23. molecular weight of meropenem is 383.5 g/mol, the plasma half-life is 7. Calandra GB, Brown KR, Grad LC, Ahonkhai VI, Wang C, Aziz MA. approximately 1 h in adults with normal renal function. Plasma half- Review of adverse experiences and tolerability in the first 2,516 patients life is increased and clearance of the drug is decreased in patients with treated with imipenem/cilastatin. Am J Med. 1985;78(6A):73-8. renal impairment, about 30% of meropenem is cleared during regular 8. Wong VK, Wright HT, Ross LA, Mason WH, Inderlied CB, Kim KS. hemodialysis session [17]. Drug clearance is highly dependent on the Imipenem/cilastatin treatment of bacterial meningitis in children. Pediatr method of renal replacement, filter type, and flow rate. Appropriate Infect Dis J. 1991;10(2):122-5. dosing requires close monitoring of pharmacologic response, signs of 9. Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM, adverse reactions due to drug accumulation [14]. The mechanism of et al. Practice guidelines for the management of bacterial meningitis. Clin seizure provocation by carbapenem is multifactorial; it’s related to the Infect Dis. 2004;39(9):1267-84. drug’s ability to reduce inhibition of epileptic discharges by blocking 10. Primaxin. Whitehouse Station, NJ: Merck & Co., Inc., 2012. the amino butyric acid (GABA). A receptor; to its action on -Amino- 3-Hydroxy-5-Methyl- iso xazole Propionate (AMPA) and N-Methyl- 11. Merrem. Wilmington, DE: Astra Zeneca, 2010. D-Aspartate (NMDA) receptor complexes (which may be secondary 12. Linden P. Safety profile of meropenem: an updated review of over 6,000 to the drug’s action on GABA receptors); or to its penicillin-like patients treated with meropenem. Drug Saf. 2007;30(8):657-68. activity [18]. 13. Cannon JP, Lee TA, Clark NM, Setlak P, Grim SA. The risk of seizures Common (CNS) symptoms of carbapenem toxicity including among the carbapenems: a meta-analysis. J Antimicrob Chemother. 2014;69(8):2043-55. disorientation, incoherent speech, agitation, restlessness and visual hallucination [15]. The high protein binding, high volume 14. Majumdar AK, Musson DG, Birk KL, Kitchen CJ, Holland S, McCrea of distribution and increase permeability of blood brain barrier of J, et al. Pharmacokinetics of ertapenem in healthy young volunteers. Antimicrob Agents Chemother. 2002;46(11):3506-11. meropenem may hinder rapid tissue elimination after CNS toxicity [16,17]. 15. Chow KM, Szeto CC, Hui AC, Li PK. Mechanisms of antibiotic neurotoxicity in renal failure. Int J Antimicrob Agents. 2004;23(3):213-7. Our patient is un-uric and has small bodyweight which lead to accumulation of meropenem recommended dose leading to 16. Schmidt S, Röck K, Sahre M, Burkhardt O, Brunner M, Lobmeyer MT, et al. Effect of protein binding on the pharmacological activity of highly classical CNS toxicity that completely disappeared after removing bound antibiotics. Antimicrob Agents Chemother. 2008;52(11):3994- the offending drug. Therefore, our case report highlighted that 4000. the recommended dose of 500 mg meropenem on daily basis for conventional hemodialysis patient may be still too high in 17. Lee KH, Ueng YF, Wu CW, Chou YC, Ng YY, Yang WC. The recommended dose of ertapenem poses a potential risk for central nervous system toxicity particularly un-uric with small body weight, so heath care providers in hemodialysis patients - case reports and literature reviews. J Clin Pharm awareness about meropenem CNS toxicity would avoid unnecessarily Ther. 2015;40(2):240-4. extensive investigation, hospitalization and potential devastation complications. 18. Miller AD, Ball AM, Bookstaver PB, Dornblaser EK, Bennett CL. Epileptogenic Potential of Carbapenem Agents: Mechanism of References Action, Seizure Rates, and Clinical Considerations. Pharmacotherapy. 2011;31(4):408-23. 1. Tina S. Seizures and epilepsy in older adults: Etiology, clinical presentation, and diagnosis. Uptodate. 2019. 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(3):232-7.

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