Cefepime: FDA Drug Safety Communication on Non-Convulsive Status Epilepticus Risk
Special Feature
Cefepime: FDA Drug Safety Communication on Non-Convulsive Status Epilepticus Risk
By Jessica C. Song, M.A., Pharm.D, Clinical Supervisor of Pharmacy and Therapeutics, Ambulatory Care, and Mental Health at Santa Clara Valley Medical Center, San Jose, CA, is Associate Editor for Infectious Disease Alert.
Dr. Song reports no financial relationships relevant to this field of study.
The U.S. Food and Drug Administration (FDA) recently issued an alert on the potential risk of non-convulsive status epilepticus associated with the use of cefepime, a broad spectrum fourth generation cephalosporin.1 The FDA Adverse Event Reporting System database yielded 59 cases of non-convulsive status epilepticus that occurred during cefepime administration from 1996 through February 2012. Approximately two thirds of the cases involved females and over half of the cases involved older patients (>65 years). Of note, with the exception of 1 patient (renal function unknown), all patients had varying degrees of renal impairment. In 56 of 59 patients, prescribers failed to comply with dose adjustments for renal function as recommended in the cefepime label.
Cefepime provides broad-spectrum coverage for numerous infections, including skin, soft tissue, lower respiratory tract, complicated intraabdominal, urinary tract infections, and for suspected febrile neutropenia.2 This agent, along with ceftazidime, a third-generation cephalosporin, are distinguished by providing bactericidal activity against a wide array of organisms, including Pseudomonas aeruginosa.2,3
Cefepime is primarily cleared from the body by renal excretion, with 85% of the drug recovered unchanged in the urine.2 The half-life of cefepime in adults with normal renal function approaches 2 hours. In patients with renal dysfunction, the increase in elimination half-life and the reduction in total body clearance are proportional to the decline in renal function. Cefepime is dialyzable; 68% of a dose may be removed during a 3-hour hemodialysis session.2 Because of its pharmacokinetic properties, adjustment in cefepime dosage is imperative for patients with renal insufficiency. Table 1 summarizes manufacturer recommended dosing of cefepime in patients with normal and impaired renal function.2 It should be noted that, at least for patients with normal renal functions, their recommended dose may be inadequate for treatment of infection due to organisms such a P. aeruginosa.
Table 1. Manufacturer's FDA-Approved Recommended Adult Dosing Regimens for Cefepime Based on Renal Function
Manufacturer's Recommended Dosing Schedule Based on Indication |
||||
Creatinine Clearance (mL/min) |
UTIa |
UTIa, Pneumoniab |
Pneumoniab, UTIc, |
Febrile Neutropeniaf |
> 60 |
500 mg IV Q 12 h |
1 g IV Q 12h |
2 g IV Q 12h |
2 g IV Q 8h |
30-60 |
500 mg IV Q 24h |
1 g IV Q 24h |
2 g IV Q 24h |
2 g IV Q 12h |
11-29 |
500 mg IV Q 24h |
500 mg IV Q 24h |
1 g IV Q 24h |
2 g IV Q 24h |
<11 |
250 mg IV Q 24h |
250 mg IV Q 24h |
500 mg IV Q 24h |
1 g IV Q 24h |
CAPD |
500 mg IV Q 48h |
1 g IV Q 48h |
2 g IV Q 48h |
2 g IV Q 48h |
Hemodialysis (post-dialysis on dialysis day) |
1 g on day 1, then |
1 g on day 1, then |
1 g on day 1, then |
1 g IV Q 24h |
UTI = urinary tract infection; SSSI = skin and skin structure infection; CAPD = continuous ambulatory peritoneal dialysis
aFor mild-to-moderate uncomplicated or complicated UTIs, including pyelonephritis
bFor moderate-to-severe pneumonia
cFor severe uncomplicated or complicated UTIs, including pyelonephritis
dFor complicated intra-abdominal infections when used concurrently with metronidazole
eFor moderate-to-severe uncomplicated skin and skin structure infections
fEmpiric treatment for febrile neutropenia
Penicillins, cefepime, third generation cephalosporins (ceftazidime, cefotaxime, ceftriaxone), carbapenems, and quinolones have been reported to be associated with non-convulsive status epilepticus.3 Predisposing factors for antibiotic-induced seizures include history of seizures, renal impairment, meningitis or central nervous system infections which lead to opening of blood brain barrier, extremes of age, low serum albumin resulting in higher free drug concentration, and co-administration of other seizure-provoking medications.3
The mechanism of non-convulsive status epilepticus provocation is not sufficiently established, but the most likely explanation arises from competitive inhibition of the inhibitory neurotransmitter g-aminobutyric acid (GABA), resulting in decreased suppression of epileptogenic discharges.3 Furthermore, renally impaired patients may accumulate toxic organic agents, which will competitively inhibit active transport of antibiotics from cerebrospinal fluid to blood.
The purpose of this article is to review published reports of cefepime-associated non-convulsive status epilepticus, and to provide dosing recommendations in order to minimize the risk of cefepime-treated patients experiencing non-convulsive status epilepticus.
PUBLISHED REPORTS OF CEFEPIME-ASSOCIATED NON-CONVULSIVE STATUS EPILEPTICUS
To date, at least 26 cases of cefepime-associated non-convulsive status epilepticus have been published.5-19 Table 2 provides summaries of the 26 cases (see, below). Similar to the FDA Adverse Event Reporting System database, approximately 60% of the cases involved females and half of the cases involved patients between the ages of 65 years to 86 years.
Table 2. Summary of Published Cases of Cefepime-Associated Non-Convulsive Status Epilepticus
Patient [Reference] |
Age in Years, Gender |
Indication |
Dosing Regimen |
Renal Function |
Confounding Factors |
1 [5] |
54, M |
Febrile neutropenia |
1 g IV Q 24h |
CrCl – 12-27 mL/min |
None |
2 [5] |
60, F |
Febrile neutropenia |
1 g IV Q 24h |
CrCl – 13-15 mL/min |
None |
3 [6] |
79, F |
Urinary tract infection |
2 g IV Q 12h |
CrCl – 45 mL/min |
None |
4 [7] |
76, F |
Gangrenous pyoderma |
2 g IV Q 8h |
SCr – 3 mg/dL |
Chronic alcoholism |
5 [7] |
38, F |
Febrile neutropenia |
2 g IV Q 8h |
SCr – 3.2 mg/dL |
None |
6 [7] |
43, M |
Abdominal sepsis |
2 g IV Q 12h |
SCr – 1.7 mg/dL |
Chronic alcoholism |
7 [8] |
74, F |
Pneumonia |
4 g IV/day |
SCr – 10.1 mg/dL |
Prior ceftriaxone use |
8 [9] |
15, M |
Pneumonia |
12.5 mg/kg/day |
Peritoneal dialysis |
None |
9 [10] |
66, F |
Febrile neutropenia |
2 g IV Q 8h |
CrCl – 30 mL/min |
None |
10 [11] |
65, M |
Febrile neutropenia |
2 g IV Q 8h |
SCr – 2.8 mg/dL |
Prior cloxacillin use |
11 [12] |
82, M |
Pneumonia |
1 g IV Q 24h |
Hemodialysis |
None |
12 [13] |
65, M |
Gram-negative bacteremia |
2 g/day |
SCr – 12 mg/dL |
None |
13 [13] |
73, F |
Knee prosthesis infection |
2 g/day |
SCr – 17.7 mg/dL |
None |
14 [14] |
69, F |
Pneumonia |
2 g/day |
Peritoneal dialysis |
None |
15 [15] |
79, M |
Pneumonia |
1 g/day |
SCr – 4.5 mg/dL |
Erythropoietin use |
16 [15] |
67, F |
Pneumonia |
2 g IV Q 6h |
SCr – 3.5 mg/dL |
None |
17 [15] |
64, F |
Pneumonia |
1 g/day |
SCr – 5 mg/dL |
Cyclosporine use |
18 [15] |
54, M |
Immunocompromised |
2 g/day |
SCr- 3.2 mg/dL |
Ciprofloxacin use |
19 [15] |
86, M |
Osteomyelitis |
2 g IV Q 12h |
SCr – 5.1 mg/dL |
Ganciclovir use |
20 [15] |
79, F |
Pneumonia |
2 g IV Q 12h |
SCr – 5.2 mg/dL |
None |
21 [16] |
NR, NR |
Unable to translate |
Not reported |
Not reported |
Unable to translate |
22 [16] |
NR, NR |
Unable to translate |
Not reported |
Not reported |
Unable to translate |
23 [17] |
44, M |
Pneumonia |
2 g/day |
Hemodialysis |
Ciprofloxacin, Tacrolimus use |
24 [17] |
28, F |
Urinary tract infection |
1 g IV Q 12h |
SCr – 1.8 mg/dL |
Prior seizures, ceftazidime |
25 [18] |
15, F |
Gram-negative bacteremia |
1 g IV Q 12h |
Hemodialysis |
None |
26 [19] |
70, F |
Febrile neutropenia |
2 g IV Q 24h |
CrCl – 14-17 mL/min |
Prior seizure |
NR = Not reported
With the exception of 1 patient, all patients had impaired renal function (18 cases of chronic renal failure; 7 cases of acute renal failure). The dosage of cefepime exceeded manufacturer recommendations in 19 of the 26 cases. Of note, despite the absence of other risk factors for seizure, 4 of the 7 patients who received appropriate dose adjustment of cefepime still experienced non-convulsive status epilepticus, which raises the question of optimal dosing of cefepime in renally impaired patients.
In nearly half of the cases, confounding factors that may have predisposed patients to experiencing non-convulsive status epilepticus included possible alcohol withdrawal, use of other seizure-provoking drugs, and history of seizures. The mean time to onset of non-convulsive status epilepticus approached 6 days (range, 1-15 days). Twenty-four patients recovered following cessation of cefepime therapy and administration of anticonvulsant agents, but 2 deaths occurred, with 1 fatality attributed to status epilepticus and multiorgan failure.
CEFTAZIDIME-ASSOCIATED NON-CONVULSIVE STATUS EPILEPTICUS
To date, there are far fewer published cases of ceftazidime-associated non-convulsive status epilepticus, compared with cefepime. Eight cases have been published from 1994 to 2012, showing onset times to non-convulsive status epilepticus of 3 to 8 days after starting ceftazidime therapy.4,8,14,15,20 All except 1 patient had renal impairment, and in the reports which provided dosing regimens, all patients received excessively high doses of ceftazidime. Three of the 8 patients had other risk factors for seizure, including receipt of ciprofloxacin and/or prior history of stroke.
CONCLUSION
Based on published reports and the warning from the FDA, the following guidelines should be considered by healthcare professionals:
- Refer to the FDA-approved package insert for reducing doses of cefepime in renally impaired patients.
- Providers should carefully consider the risks and benefits of using cefepime in patients with renal impairment and other risk factors predisposing them to seizure.
- Patients receiving cefepime should be monitored for changes in renal function and the appropriateness of dosage should be assessed periodically during treatment.
- Patients receiving cefepime should be monitored for signs and symptoms of non-convulsive status epilepticus, such as confusion, loss of attention, disorientation, abnormal behavior, agitation, hallucinations, mutism, myoclonic jerks, or coma. An electroencephalogram should be considered in older patients with unexplained mental status changes.
- Since cefepime-induced non-convulsive status epilepticus is able to be reversed, prompt treatment cessation can prevent further morbidity and mortality.
References
- FDA Drug Safety Communication: Cefepime and Risk of Seizure in Patients Not Receiving Dosage Adjustments for Kidney Impairment. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm309661.htm Accessed July 12, 2012.
- Cefepime Hydrochloride for Injection (Maxipimeµ) prescribing information. Princeton, NJ: Bristol-Myers Squibb Company; 2009 March.
- Ceftazidime for Injection (Fortaz) prescribing information. Research Triangle Park, NC: GlaxoSmithKline; 2010 August.
- Misra UK, et al. Association of antibiotics with status epilepticus. Neurol Sci 2012; DOI 10.1007/s10072-012-1001-5.
- Spriet I, et al. Meropenem-valproic acid interaction in patients with cefepime-associated status epilepticus. Am J Health-Syst Pharm 2007; 64: 54-8.
- Maganti R, et al. Nonconvulsive status epilepticus due to cefepime in a patient with normal renal function. Epilepsy Behav 2006; 8: 312-4.
- Fernandez-Torre JL, et al. Cephalosporin-induced nonconvulsive status epilepticus: clinical and electroencephalographic features. Epilepsia 2005; 46: 1550-2.
- Primavera A, et al. Nonconvulsive status epilepticus during cephalosporin therapy. Neuropsychobiology 2004; 49: 218-22.
- Alpay H, et al. Cefepime-induced non-convulsive status epilepticus in a peritoneal dialysis patient. Pediatr Nephrol 2004; 19: 445-7.
- Abanades S, et al. Reversible coma secondary to cefepime neurotoxicity. Ann Pharmacother 2004; 38: 606-8.
- Plensa E, et al. Nonconvulsive status epilepticus associated with cefepime in a patient undergoing autologous stem cell transplantation. Bone Marrow Transplant 2004; 33: 119-20.
- Ferrara N, et al. Neurotoxicity induced by cefepime in a very old hemodialysis patient. Clin Nephrol 2003; 59: 388-90.
- Chatellier D, et al. Cefepime-induced neurotoxicity: an underestimated complication of antibiotherapy in patients with acute renal failure. Intensive Care Med 2002; 28: 214-7.
- Chow KM, et al. Nonconvulsive status epilepticus in dialysis patients. Am J Kidney Dis 2001; 38: 400-5.
- Martinez-Rodriguez JE, et al. Nonconvulsive status epilepticus associated with cephalosporins in patients with renal failure. Am J Med 2001; 111: 115-9.
- Saurina A, et al. Non-convulsive status epilepticus secondary to adjusted cefepime doses in patients with chronic renal failure. Nefrologia 2000; 20: 554-8.
- Dixit S, et al. Status epilepticus associated with cefepime. Neurology 2000; 54: 2153-5.
- Thabet F, et al. Cefepime-induced nonconvulsive status epilepticus: case report and review. Neurocrit Care 2009; 10: 347-51.
- Gangireddy VR, Mitchell LC, Coleman T. Cefepime neurotoxicity despite renal adjusted dosing. Scand J Infect Dis 2011; 43: 827-9.
- Klion AD, et al. Ceftazidime-related nonconvulsive status epilepticus. Arch Intern Med 1994; 154: 586-9.
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