Cefepime: FDA Drug Safety Communication on…

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)	UTI^a	UTI^a, Pneumonia^b	Pneumonia^b, UTI^c, Intra-abdominal^d, SSSI^e	Febrile Neutropenia^f
> 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 500 mg IV Q 24h	1 g on day 1, then 500 mg IV Q 24h	1 g on day 1, then 500 mg IV Q 24h	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

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