Cephalosporin Induced Myoclonus

Myoclonus - Unusual Cause

Drug Induced

Case No 1

• 50 year old female patient

• Referred from medical oncology for involuntary, jerky movements of all the four limbs since one day

• Patient was a case of neutropenic fever, following chemotherapy for malignancy

May 2007

Patient Assessed

• Patient was drowsy, easily arousable and obeyed commands

• Had multifocal myoclonus involving the limbs

• No weakness of limbs

• Plantars flexor

• No meningeal signs, BP – Normal

• Patient was on Cefepime 2gms IV BD for neutropenic fever for 5 days

• Investigations reviewed

Lab values

• CBC – severe neutropenia – TC 200, 10%N• LFT – Normal• Calcium – Normal• Electrolytes – Normal• Serum Creatinine – 2.8

• Advised• CT Brain Plain – Normal• EEG – Mild intermittent slowing, No triphasic

complexes or seizure discharges

Treatment

• Patient had received 800mg of IV Phenytoin before referral

• Was advised Inj Sodium Valproate 500mg IV BD

• Clonazepam 0.5 mg TID

• The Myoclonic Jerks Continued

Nephrologist Opinion

• Sepsis, ARF

• Creatinine – 2.8

• Patient not oliguric

• Potassium normal, no acidosis

• The Myoclonic jerks unlikely to be due to renal dysfunction ( since creat clearance was more than 15ml/min)

• The neurotoxicity and safety of treatment withcefepime in patients with renal failure, J. Sonck, G. Laureys and D. VerbeelenNDT Advance Access published online on January 5, 2008 Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm713

• In view of Myoclonic jerks, having started after cefipime was introduced, we started wondering if there was any cause and effect and relationship between cefepime and myoclonus

• Literature Survey…

Review of Literature

• Cefipime – 1:10,000 chance of producing neurotoxicity

• Cefipime withheld, patient dialysed for early clearance of the drug, as the patient had disabling myoclonus

• Antibiotic changed to Pipericillin/tazobactum

• Myoclonic jerks subsided totally after 2 sessions of HD

Case No 2

• 45 year old male patient• Type 2 Diabetes Mellitus• ESRD, initiated on HD at a creatinine of 13.5

• Neurologically, had no complains

• Admitted to the Dept of Nephrology at MSRMH with UTI

July 2007

Case Review

• Urosepsis

• Blood C/S and Urine C/S– Pseudomonas grown, sensitive to ceftazidime, amikacin, piperacillin, tazobactum

• Serum Creatinine – 8.8

• CBC, TC elevated, Hb – 9

• LFT, Electrolytes, ABG - Normal

• Started on Ceftazidime 1 gm IV OD, Amikacin 250mg IV OD

• HD Continued

• On 6th day of treatment, Patient started having severe, myoclonic jerks

• After 3 days, neurology reference was sought for because of persistent myoclonic jerks ispite of regular HD and the serum creatinine coming down

• Creat 7.2, ABG, Electrolytes, LFT, Calcium - Normal

• CT Brain Plain – Normal

• EEG – Bilateral slowing, no triphasic complexes or seizure discharges

• Patient was put on clonazepam and IV sodium valproate.

• No response to treatment

• Ceftazidime stopped on the next day, changed over to piperacillin/tazobactum

• 36 hours later, myoclonic jerks stopped totally

• Review of literature revealed 3:1000 incidence of neurotoxicity with ceftazidime

Case No 3

• 67 year old female patient

• Post op Ca endometrium

• On Chemo – Cisplatin, Cyclophosphamide

• Admitted with Neutropenic fever

• Earlier serum creatinine – 0.7

Aug 2008

Reports

• TC – 114

• Neutrophils – 8%

• Creatinine 1.5

• Started on Cefipime 2gms IV Q8h and Amikacin 500mg IV OD

• Cefipime later reduced to 2gms IV BD

• Day 2 of treatment, patient had severe myoclonic jerks involving the limbs

• LFT, ABG, Electrolytes, Calcium – Normal• CT Brain, EEG - Normal

• Impression – Cefipime Neurotoxicity• Advised to withhold cefipime, alternative drug

added

Nephro Opinion

• Creat 1.7, CIS/CYP induced ARF

• Not dialysed since patients myoclonic jerks had reduced and renal dysfunction was mild

• Managed conservatively, no recurrence of the same

Case No 4

• 60 year old female patient was being treated with Cefepime for urosepsis.

• diabetic nephropathy, serum creatinine was 5

• 1gm of Cefepime per day.

• 6th day of treatment, she developed severe multifocal myoclonus of the face and limbs, not responding to sodium valproate or clonazepam.

July 2009

• The myoclonus was thought to be due to Cefepime, since all the metabolic parameters were normal.

• Cefepime was withheld and she was put on peritoneal dialysis.

• She also had a complete cessation of the myoclonic jerks at the end of 36 hours.


• Neurotoxicity in Cephalosporins, especially for cefepime and ceftazidime

• Spectrum of manifestations in neurotoxicity

• What makes these two molecules more neurotoxic when compared to other cephalosporins

• Mechanism of neurotoxicity

• Management of neurotoxicity













Serum creatinine, mean ± SD (mg/dl)

8.3 ± 5.1 6.5 ± 3.7 0.33

Concurrent condition, no. (%)

Received regular dialysis therapy

9 (21) 5 (42) 0.26

Acute renal failure 5 (12) 4 (33) 0.69

Transplant recipient (kidney, lung)

4 (10) 0 0.56

Retrospective Review of Neurotoxicity Induced by Cefepime and Ceftazidime Kai Ming Chow, M.D., Cheuk Chun Szeto, M.D., Andrew Che-Fai Hui, M.D., Teresa Yuk-Hwa Wong, M.D., Philip Kam-Tao Li, M.D., FRCP, FACP Published: 04/18/2003Pharmacotherapy. 2003;23(3) © 2003

Clinical features, no. (%)

Seizures 6 (14) 1 (8) 1.00

Confusion 39 (93) 11 (91) 1.00

Myoclonus 12 (29) 6 (50) 0.18

Electrophysiologic findings, no. (%)

Encephalopathy 21 (50) 2 (25) --

Nonconvulsive status epilepticus 15 (35) 6 (75) 0.17

Generalized seizures 6 (14) 0 --

Length of drug therapy before symptom onset, median (interquartile range) days

5 (4-10) 6.5 (4-11) 0.36

Time lag between symptom onset and diagnosis, median (interquartile range) days

5 (4-6) 3 (2-4) 0.005







• Compounds with two heterocyclic rings at both position 3 and position 7 of the cephalosporin molecule, for example ceftriaxone, cefoperazone, and ceftazidime, and cefepime were even more epileptogenic than benzylpenicillin, while others, with only one heterocyclic ring at position 7, for example cefotaxime and cefonicid, were less potent. Cefazolin, a tetrazole derivative, similar to the convulsant phenyltetrazole, was most potent.

• Meyler’s Side Effects of Drugs, The Encyclopedia of Adverse Drug Reactions and Interactions, 2006, Elsevier Publications







• “This leads to the suggestion that the b-lactam antibiotics may bind different sites which may or may not be responsible for epileptogenic activity in the brain”

• “We emphasize that b-lactam antibiotics could exert their convulsant effects by more than a simple interaction with the GABA receptor complex. In fact, the convulsant actions of b-lactam antibiotics have been related to the reduction of GABA released from nerve terminals or to the inhibition of GABA binding to its receptor sites”.

• “These results clearly demonstrate that the mechanism of cephalosporin-induced convulsions is mediated predominantly through the inhibition of GABA(A)-R function and not through NMDA receptor modulation.”

Authors conclusion

Why these two molecules

• Both cefepime and ceftazidime, because they are not very lipophilic, traverse cell membranes poorly and enter the cerebrospinal fluid slowly, by way of paracellular pathways.

• In the CSF they get concentrated since they are not lipophilic

– Lutsar I, Friedland IR. Pharmacokinetics and pharmacodynamics of cephalosporins in cerebrospinal fluid. Clin Pharmacokinet 2000;39:335-43

• However, active transport of cephalosporins from cerebrospinal fluid to blood might be impaired due to competitive inhibition by accumulated toxic organic acids in patients with renal failure.

» Martínez-Rodríguez JE, Barriga FJ, Santamaria J, et al. Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure. Am J Med 2001;111:115-19.

» The neurotoxicity and safety of treatment withcefepime in patients with renal failure, J. Sonck, G. Laureys and D. VerbeelenNDT Advance Access published online on January 5, 2008 Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfm713

• This may account for the susceptibility of patients with renal failure and those receiving dialysis to both cefepime and ceftazidime neurotoxicity.

» Manian FA, Stone WJ, Alford RH. Adverse antibiotic effects associated with renal insufficiency. Rev Infect Dis 2008;12:236-49.







• Withhold the drug– t½ of cefepime – 120 minutes

– t½ of ceftazidime – 108 minutes

– Kinetics are such that 50% reduction of GFR increases the t½ by four times

• Retrospective Review of Neurotoxicity Induced by Cefepime and Ceftazidime Kai Ming Chow, M.D., Cheuk Chun Szeto, M.D., Andrew Che-Fai Hui, M.D., Teresa Yuk-Hwa Wong, M.D., Philip Kam-Tao Li, M.D., FRCP, FACP Published: 04/18/2003 Pharmacotherapy. 2003;23(3) © 2003

• Hemodialysis – for rapid improvement of disabling symptoms– Cefepime – 68 to 100 percent dialyzable

– Ceftazidime – 50 to 100 percent dialyzable

• Barbhaiya RH, Knupp CA, Forgue ST, et al. Pharmacokinetics of cefepime in subjects with renal insufficiency. Clin Pharmacol Ther (1990) 48:268–76

• Clin Nephrol. 1985 Sep;24(3):142-6. Effect of hemodialysis on ceftazidime pharmacokinetics; Nikolaidis P, Tourkantonis

To summarize…

• Neurotoxicity of Cephalosporins – May not be very uncommon

• Awareness is not widespread

• Median time to diagnosis in published data is 3-5 days

• Should be considered as a d/d, especially in the elderly, with compromised renal function, or with no other explaination

Some drugs known to cause myoclonus….

• Amantadine

• Antineoplastic agents

• Bismuth

• Bromocriptine

• Carbamazepine

• Carvedilol

• Contrast agents

• Cyclosporine

• Dopamine agonists

Etomidate Gatifloxacin•Lamotrigine

•Lithium

•Mefloquine •Phenytoin •Propofol

•Salbutamol •Tramadol •Vigabatrin

Drugs known to cause Seizures – More Common

• Antipsychotics– Phenothiazines

– Clozapine

• Analgesics– Mepiridine

• Immusuppressants– Cyclosporine

• Antibiotics– Penicillins,

cephalosporins

• Drug Abuse• Cocaine

• Amphetamines

• Alcohol

• Withdrawl• Benzodizepines

• Phenobarbitone

• Iodinated Contrast

• Flumazenil

Epilepsy, Special Issues, Neurology Clinics of North America, 1994; Treatment of Epilepsy, Shorvon, 2005

Drugs known to cause seizures – Less Common

• Antidepressants

• Butyrophenone

• INH

• Alkylating agents

• Mefloquine

• Theophylline

• Zidovudine

• General Anaesthetics


Drugs known to cause seizures – Uncommon

• Quinolones

• Acyclovir

• Lidocaine

• Anticonvulsants

• Beta blockers

• Other antidepressants


Health & Medicine

Cephalosporin Induced Myoclonus