Series of cases of Cephalosporin Induced Myoclonus, with detailed discussion on the possible Mechanisms

1. Myoclonus - Unusual
Cause
Drug Induced

2. May 2007
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

3. 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

4. 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

5. 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

6. 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

7. • 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…

8. 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

9. July 2007
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

10. 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

11. • 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

12. • 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

13. • 36 hours later, myoclonic jerks stopped totally
• Review of literature revealed 3:1000 incidence
of neurotoxicity with ceftazidime

14. Aug 2008
•
•
•
•
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

15. Reports
• TC – 114
• Neutrophils – 8%
• Creatinine 1.5
• Started on Cefipime 2gms IV Q8h and
Amikacin 500mg IV OD

16. • 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

17. 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

18. July 2009
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.

19. • 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.

20. Review of Literature
• 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

21. Review of Literature
• 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

23. Review of Literature
• 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

24. Serum creatinine, mean ± SD
(mg/dl)
8.3 ± 5.1
6.5 ± 3.7
0.33
9 (21)
5 (42)
0.26
5 (12)
4 (33)
0.69
4 (10)
0
0.56
Concurrent condition, no. (%)
Received regular dialysis
therapy
Acute renal failure
Transplant recipient (kidney,
lung)
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

25. Clinical features, no. (%)
Seizures
6 (14)
1 (8)
1.00
Confusion
39 (93)
11 (91)
1.00
Myoclonus
12 (29)
6 (50)
0.18
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
Electrophysiologic findings, no. (%)

26. Review of Literature
• 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

27. • 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

28. Review of Literature
• 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

30. • “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 blactam antibiotics have been related to the reduction of GABA
released from nerve terminals or to the inhibition of GABA
binding to its receptor sites”.

32. Authors conclusion
• “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.”

33. 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

34. • 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

35. • 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.

36. Review of Literature
• 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

37. • 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

38. • 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

39. 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

40. 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

42. Drugs known to cause
Seizures – More Common
• Antipsychotics
– Phenothiazines
– Clozapine
• Analgesics
• Drug Abuse
• Cocaine
• Amphetamines
• Alcohol
• Withdrawl
– Mepiridine
• Immusuppressants
– Cyclosporine
• Antibiotics
– Penicillins,
cephalosporins
• Benzodizepines
• Phenobarbitone
• Iodinated Contrast
• Flumazenil
Epilepsy, Special Issues, Neurology Clinics of North America, 1994;
Treatment of Epilepsy, Shorvon, 2005

43. Drugs known to cause
seizures – Less Common
•
•
•
•
•
•
•
•
Antidepressants
Butyrophenone
INH
Alkylating agents
Mefloquine
Theophylline
Zidovudine
General Anaesthetics
Epilepsy, Special Issues, Neurology Clinics of North America, 1994;
Treatment of Epilepsy, Shorvon, 2005

44. Drugs known to cause
seizures – Uncommon
•
•
•
•
•
•
Quinolones
Acyclovir
Lidocaine
Anticonvulsants
Beta blockers
Other antidepressants
Epilepsy, Special Issues, Neurology Clinics of North America, 1994;
Treatment of Epilepsy, Shorvon, 2005