P&T News: January 1997

Cefepime: A Cost-Effective Alternative to Ceftazidime in Adult Patients

Jane C. Blayney, Pharm.D. and Rebecca J. Johanning, Pharm.D.
Peer Review Status: Internally Peer Reviewed by Bradley E. Britigan, M.D., Professor and Director, Infectious Diseases Division, Department of Internal Medicine and Ronald N. Jones, M.D., Professor and Director, Medical Microbiology Division, Department of Pathology

Resistance to third-generation cephalosporins has been conferred both by inducible, chromosomally-mediated expression of B-lactamases and by plasmid-mediated production of extended spectrum B-lactamases.2 Moreover, third-generation cephalosporins either have good activity against gram-positive organisms and poor activity against Pseudomonas aeruginosa, as in the cases of cefotaxime and ceftriaxone, or visa versa, for agents such as ceftazidime.

New fourth-generation cephalosporins represent attempts to maintain activity against gram-positive and -negative organisms (including Pseudomonas aeruginosa) and avoid many of the problems of resistance that have affected earlier antimicrobial compounds in this class.2 Cefepime represents a prototype fourth- generation cephalosporin with enhanced stability against many B-lactamases, gram- positive activity equal to cefotaxime, and anti-pseudomonal activity equal to that of ceftazidime. The structure of cefepime is similar to the third-generation cephalosporins with the exception of a positively charged quaternized N-methyl pyrrolidine substitution at the C-3 position, creating a zwitterion. This zwitterionic property is an advantage allowing more rapid penetration of cefepime through the outer membrane of gram-negative bacteria and into some in vivo fluids and spaces. Additionally, cefepime has better stability to extended spectrum B- lactamases than the third-generation cephalosporins. This enhanced stability is due to a lower affinity for Bush group 1 B-1actamases and increased ability to penetrate the outer membrane of bacteria. Lastly, cefepime does not appear to have a high B- lactamase-inducing capacity. Induction of B-lactamases can occur during B-lactam therapy. The implication of this phenomenon is that resistant organisms can develop while a patient is receiving antibiotics which were appropriate based on original culture and sensitivity data. The potential for various antibiotics to induce B-lactamases varies. For example, piperacillin has a low potential; ceftazidime has an intermediate potential; and imipenem/cilastatin has a high potential.3 4

Cefepime's twice-a-day dosage schedule, enhanced activity against Enterobacteriaceae and gram-positive organisms, and lower cost per day of therapy provide it with several advantages over the third-generation cephalosporin, ceftazidime. Therefore, beginning in January, 1997, cefepime will be added to the UIHC formulary as a protocol drug for use in many of the clinical situations where ceftazidime is currently being applied.

Spectrum of Activity
As a result of cefepime's lower affinity and enhanced stability against B-lactamases, Bush group 1 B-1actamase-producing strains of Enterobacter spp, Citrobacter freundii, and Pseudomonas aeruginosa that confer resistance to ceftazidime and cefotaxime have less of an effect on cefepime.5~7 In the majority of in vitro studies, these organisms remained susceptible to cefepime, although they had developed resistance to ceftazidime and cefotaxime.8 The MIC90 for cefepime is less than 0.1 mcg/ml for Escherichia coli, Proteus mirabilis, Proteus vulgaris, Citrobacter diversus, and Klebsiella pneumoniae. Overall, the MIC90 for Enterobacteriaceae is < 1 mcg/ml; however, Serratia marcescens, C. freundii, and E. cloacae may have an MICso of 2 to 4 mcg/ml.2 Other gram-negative organisms, particularly Haemophilus influenzae, Neisseria meningitidis, Neisseria gonorrhoeae, and Moraxella catarrhalis, are highly susceptible to cefepime. In general, the breakpoint MIC values used to determine cefepime susceptibility are as follows: < 8 mcg/ml indicates susceptibility; 16 mcg/ml indicates intermediate susceptibility, and >32 mcg/ml defines resistance.3 These breakpoints may be applied to all organisms except Haemophilus spp., N. gonorrhoeae, and Streptococcus pneumoniae where lower break points are utilized. 3 Table 1 provides comparison of the antimicrobial activities of cefepime, ceftazidime, and cefotaxime.

Table 1. Comparative Activities of Cefepime, Cefotaxime, and Ceftazidime 5,9,10

	MIC90 (mcg/ml)*
Organism	Cefepime	Ceftazidime	Cefotaxime
Escherichia coli Klebsiella pneumoniae Proteus mirabilis Enterobacter cloacae Serratia marcescens Pseudomonas aeruginosa Staphylococcus aureus Streptococcus pyogenes Streptococcus pneumoniae	0.06 0.25 0.06 1.0 1.0 16 3.13 0.025 0.1	0.5 1.0 0.12 or less 32 2 16 12.5 0.2 0.39	0.12 or less 0.5 0.12 or less 16 8 more than 64 3.13 0.025 0.025

*MIC90 = minimal inhibitory concentration for 90% of strains

Despite ceftazidime's excellent activity against P. aeruginosa and other gram-negative bacteria, it has much poorer activity against gram-positive pathogens. Cefepime is comparable to cefotaxime in activity against susceptible gram-positive organisms and is a more potent anti-staphylococcal agent (4- to 8- fold) than ceftazidime. Cefepime is at least equivalent to penicillin G in activity against penicillin-susceptible S. pneumoniae; however, cefepime also retains good activity against relatively penicillin-resistant pneumococci.11 Table 2 outlines the susceptibilities of gram-positive organisms to cefepime.

Table 2. Susceptibilities of Gram-Positive Organisms to Cefepime5

Organism (Number of Isolates Tested)	MIC90 (mcg/ml)
Stephylococcus aureus, methicillin-susceptible (365) Staphylococcus epidermidis (175) Streptococcus pyogenes (99) Streptococcus agalactiae (111) Streptococcus pneumoniae (147) Streptococcus bovis (10) Enterococcus faecalis (848) Clostridium difficile (4)	1.56 - 8.0 2 - 12.5 less than 0.015 - 0.25 0.06 - 0.12 0.015 - 0.25 0.12 64 - 128 128

Cefepime, like ceftazidime, is used for: 1) treatment of proven or suspected P. aeruginosa infection resistant to piperacillin or in patients with a significant penicillin allergy; 2) treatment of a multi-resistant Enterobacter species infection where susceptibility has been documented for cefepime; 3) suspected P. aeruginosa infection with concomitant suspected H. influenzae and/or S. pneumoniae infection; and 4) patients with suspected P. aeruginosa infection who have chronic lung disease and have had recent cultures positive for P. aeruginosa resistant to mezlocillin or piperacillin. Unfortunately, there are limited data to support the use of cefepime in the treatment of proven P. aeruginosa meningitis. Until data are available and dosing regimens defined, cefepime should not be used for this indication, and ceftazidime would appear to remain the cephalosporin of choice for proven P. aeruginosa meningitis.

Additionally, cefepime should not be used for: 1) empiric therapy for patients who are not at risk for P. aeruginosa infection; 2) localized P. aeruginosa infection, such as lower urinary tract infections; 3) prophylaxis of surgical wound infections; 4) infections involving organisms that are susceptible to alternative beta-lactam antibiotics, or 5) pediatric patients, due to lack of clinical data in these patients.

Pharmacokinetic Properties
Cefepime is principally eliminated via renal excretion with an average half-life of two hours.12 Cefepime is widely distributed in biological fluids and tissue. Volume of distribution (13 to 22 L) and protein binding (16 to 19%) are similar to that observed with ceftazidime. Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 3.

Table 3. Average Concentration of Cefepime in Body Fluids (mcg/ml) or Tissues (mcg/g)12-14

Tissue/Fluid	Dose	Av* Concentration	Av* Time of Sample Post-dose
Blister fluid Bronchial mucosa Sputum Urine Cerebrospinal fluid	2 gm IV 2 gm IV 2 gm IV 1 gm IV 2 gm IV 50 mg/kg IV	81.4 mcg/ml 24.1 mcg/g 7.4 mcg/ml 926 mcg/ml 3120 mcg/ ml 5.7 mcg/ml; 3.3 mcg/ml	1.5 hr 4.8 hr 4 hr 0 to 4 hr 0 to 4 hr 30 min; 8 hr

*AV = Average

Adverse Drug Reactions
More than 2000 patients have been treated with cefepime in clinical trials, and adverse drug reactions associated with the drug have occurred in only 13.5% of patients.'5 This is comparable to the rate of ceftazidime, 15.6%. The most common adverse effects of cefepime are headache (2.4%), nausea (1.8%), rash (1.8%) and diarrhea (1.7%). Rash was the most common reason for discontinuation of cefepime; the incidence appears to be increased with higher doses.'5

Dosing
The usual dose for the treatment of a moderate infection is 1 gram every 12 hours. Severe infections require a dose of 2 grams every 12 hours. Because cefepime is 85% excreted by the kidneys, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment. See Table 4 for dosage recommendations in patients with renal impairment. No dosing adjustments are required for patients with hepatic dysfunction.

Table 4. Cefepime Dosing in Renal Dysfunction12

Drug	Normal Dose	CrCl 30 to 0 ml/min	CrCl 30 to 30 ml/min	Crcl less than 10 ml/min
Cefepime Ceftazidime	1 to 2 gm q 12 hr 1 to 2 gm q 8 hr	1 to 2 gm q 24 hr 1 gm q 12 hr	0.5 to 1 gm q 24 hr 0.5 to 1 gm q 24 hr	250 to 500 mg q 24 hr 500 mg q 48 hr

Data for cefepime use in pediatric patients are limited. Cefepime 50 mg/kg (maximum dose 2 grams) every 8 hours has been successfully used to treat patients with cystic fibrosis and meningitis.' 'l6 However, at this time, ceftazidime is still recommended as the preferred therapy to treat pediatric patients.

Summary
The Antibiotic Advisory and the Pharmacy and Therapeutics Subcommittees have approved changing from ceftazidime to cefepime in most clinical situations for adult patients. In their review of these agents, the Subcommittees noted that cefepime's advantages over ceftazidime include: 1) cefepime has a similar gram-negative antimicrobial spectrum as ceftazidime, but better gram-positive coverage; 2) in vitro data indicate that many organisms resistant to ceftazidime remain susceptible to cefepime; 3) cefepime has been successfully used to treat infections caused by organisms which typically develop resistance to third-generation cephalosporins (i.e., E. cloacae); 4) cefepime is dosed less frequently than ceftazidime; and 5) cefepime has a lower cost per day of therapy than ceftazidime (see Table 5). Due to less frequent dosing, additional decreases in costs should be realized by reducing nursing time and infusion materials, as well as simplifying administration (i.e., fewer IV lines) in patients receiving multiple IV medications.

Table 5. Dosage Equivalence and Cost Comparisons: Ceftazidime to Cefepime

Ordered		Equivalent
Drug	Dose	Drug	Dose
Ceftazidime Ceftazidime	1 gm Q 8 hr 2 gm Q 8 hr	Cefepime Cefepime	1 gm Q 12h 2 gm Q 12h

The conversion of ceftazidime to cefepime at UIHC will begin in January, 1997. For orders written for ceftazidime, the pharmacist will place a memo on the patient's medical record reminding the physician of the advantages of cefepime. A protocol drug order form must be completed for cefepime. Table 6 outlines the protocol criteria for use of cefepime. Protocol order forms for cefepime will be available on the patient care areas and pharmacy satellites. Until additional experience is gained with cefepime in the pediatric population, and in adult patients with P. aeruginosa meningitis, ceftazidime will continue to be available as a protocol drug for these indications.

Based on the development of increasing bactgerial resistance to third-generation cephalosporins, the antibiotic advisory and the Pharmacy and Therapeutics Subcommittees have approved cefepime for use only in the following conditions:

Proven Pseudomonas aeruginosa infection* either:

• resistant to piperacillin; or
• in a patient with significant penicillin allergy.

Suspected Pseudomonas aeruginosa infection* if:

• the patient had surveillance cultures indicating the presence of Pseduomonas resistant to piperacillin; or
• the patient has a significant penicillin allergy; or
• the patient has chronic lung disease (such as cystic fibrosis) and had recent cultures positive for Pseudomonas aeruginosa resistant to piperacillin; _
• the patient has a concomitant suspected Haemophilus influenzae infection.

Multi-resistant Enterobacter species infections where cefepime has been documented to have activity.

Formal Infectious Diseases recommendation.

*In proven or suspected Pseudomonas aeruginosa infection, cefepime should be used D] conjunction with an aminoglycoside (e.g., gentamicin).

1. Am J Med. 1996;100(6A)IS-2.
2. J Antimicrob Chemother . 1993;32(Suppl B):87-94.
3. Am J Hosp Pharm. 1995; 52(6 Suppl 2):53-8.
4. CID. 1993; 17:369-79.
5. Am J Hosp Pharm. 1994; 51 :463- 77.
6. Antimicrob Agents Chemother. 1990;34:33742
7. Antimicrobial Agents Chemother . 1986;29:845-8.
8. Am J Med. 1996; 100(6A)20S-5.
9. Drug Exp Clin. Res. 1989; 15(10):1-10.
10. J Antimicrob Chemother. 1986;17:441-52.
11. Antimicrob Agents Chemother . 1985;28:58-63.
12. Maxipime Package Insert. Bristol Myers Squibb; Princeton NJ, January 1996.
13. Antimicrobial Agents Chemother . 1995;39:937-40.
14. Ann Pharmacotherapy. 1996;30:1414-24.
15. Am J Med. 1996;100(6A):68S-75S.
16. Am J Dis Child. 1992;146:797-802.

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The Adverse Drug Reaction Reporting Program at UIHC

Written by: Barbara A. Mutnick, R.Ph., M.H.P.
The Department of Pharmaceutical Care's Pharmacotherapy Evaluation and Consultation Service staff coordinate the hospital's Adverse Drug Reaction (ADR) Reporting Program. All reports are presented to the Pharmacy and Therapeutics Subcommittee for review. In cases where a report is identified as severe, unusual, occurring with a newly marketed drug, or taking place in newly emerging clusters or trends, the report is forwarded to the Food and Drug Administration (FDA) via the MedWatch Program and to the manufacturer. This process is initiated after receiving prior approval from the Subcommittee. In addition, before the MedWatch form is sent to the FDA, the patient's attending physician reviews the form and has the opportunity to recommend changes.

Total confidentiality is assured by not including the patient's name or registration number on the MedWatch form. Also, individual reporter's names are not included. If the FDA requires additional information, the name of the patient's physician is supplied only after permission for disclosure is received.

Although the FDA maintains its high standards for reviewing the efficacy and safety of new products, efforts have been made by the agency to decrease the time required for such reviews. As a result of such efforts, 53 new drug entities were approved for use during 1996 as compared with 26 new entities receiving approval in 1995. Clinical trials effectively assess efficacy and risk-benefit ratios, but they are generally not large enough or of long enough duration to provide all the information on a new drug's safety. Vigilant post-marketing surveillance must be performed by all health care professionals in order to continue the necessary monitoring of newly marketed agents. New data are used to update the prescribing information of recently approved agents. Table 1 1ists some of the labeling changes prompted by submission of adverse drug reaction reports to the MedWatch Program.

Table 1. Labeling Changes Due to Post-marketing Surveillance

Fluoroquinolones September 1996	The FDA has taken steps to revise the package insert for the fluoroquinolones: ciprofloxacin, enoxacin, lomefloxacin, norfloxacin, sparfloxacin, levofloxacin, and ofloxacin. The warning will state that ruptures of the shoulder, hand, and Achilles tendon have been reported with fluoroquinolone antibiotics. The antibiotics should be discontinued if a patient experiences pain, inflammation, or rupture of a tendon. Rupture can occur any time during or after therapy.
Alendronate March 1996	The manufacturer updated dosage instructions in the package insert regarding patients with underlying gastrointestinal disease. Patient instructions about the proper time and method of taking alendronate to avoid esophageal irritation were updated, as well as a description of symptoms requiring that patients consult their physicians.
Tramadol March 1996	Tramadol should not be used in patients with a history of addiction to or dependency on opioids, as there have been cases reports of drug abuse, dependency, withdrawal, or intentional overdose. Seizures have been reported. The risk of seizures is increased in patients taking concomitant medications that may reduce the seizure threshold (e.g., tricyclic antidepressants, selective serotonin reuptake inhibitors) and with certain medicalconditions. Anaphylactic reactions have been reported. Tramadol is contraindicated in patients sensitive to tramadol, any component of the product, or opioids.
Nefazodone December 1995	The manufacturer of nefazodone warned of a drug interaction with cisapride. Nefazodone is an inhibitor of cytochrome P4503A4. Coadministration of nefazodone and cisapride is contraindicated because of the association with QT prolongation and rare cases of serious cardiovascular adverse events, including death, due principally to ventricular arrhythmia of the torsades de pointes type.
Cisapride October 1995	Serious cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes, and QT prolongation have been reported in patients taking cisapride with other drugs that inhibit cytochrome P4503A4: ketoconazole, itraconazole, miconazole, troleandomycin, erythromycin, fluconazole, clarithromycin, and nefazodone. Some of these events have been fatal. Cisapride is contraindicated in patients taking any of these drugs.

Fiscal Year 1995-96 Summary
During fiscal year 1995-96, 519 adverse drug reaction reports were reviewed by the Pharmacy and Therapeutics Subcommittee. Figure 1 demonstrates the sources of these reports. Ninety-seven (19%) of these reports were forwarded to the FDA through the MedWatch program. During the year, the 12 most frequently reported causative agents in alphabetical order were: cimetidine, gentamicin, heparin, immune globulin IV, morphine, nafcillin, phenytoin, piperacillin, ranitidine,1 sulfamethoxazole/trimethoprim, sumatriptan, and vancomycin.

Major Initiatives
One of the primary goals of the UIHC ADR Reporting Program is to prevent the future occurrence of adverse reactions secondary to drug use. During the past year, 15 ADRs were attributed to sumatriptan. Most of these reports were identified through a drug use evaluation. As a result of this review, an Ambulatory Care Sumatriptan Drug Use Evaluation is ongoing in order to identify and document potential risk factors and contraindications to the use of sumatriptan, and thereby ensure greater patient safety.

During the past year, the hospital underwent an Hz-receptor antagonist conversion and identified cimetidine as its primary agent. Due to heightened scrutiny of ADRs secondary to cimetidine, there were 24 reports attributed to it. Although this type of in-depth review was not carried out for other Hz-receptors antagonist agents, a retrospective review was completed that included 50 patients receiving ranitidine and cimetidine. The review revealed very similar adverse reaction profiles for ranitidine and cimetidine. Overall, for the year, the incidence of reported adverse effects was low and quite similar - cimetidine was 0.27% (24/8808 patients) and ranitidine was 0.22% (9/4175 patients).

Summary
All health care professionals are reminded to report ADRs. Of great importance in the process is the documentation of the ADR in the patient's medical record. This documentation will aid in the establishment of a clear cause and effect relationship that readily becomes available as part of the patient's medical history.

Over the past five years, the number of reports supplied to the Pharmacy and Therapeutics Subcommittee for review has increased each year. The continued reporting of ADRs will provide sufficient data to recognize developing trends and aid in the initiation of proactive programs to prevent subsequent ADRs.

Ranitidine was only stocked for four months of the fiscal year; it was removed from formulary in November 1995.

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