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Cefepime is a relatively new cephalosporin (FDA approved 5/1997) with an extended spectrum of antibacterial activity that includes both aerobic Gram(-) and Gram(+) bacteria. It is active against many G(-) organisms resistant to ceftriaxone and cefotaxime, as well as many strains of Enterobacter and Citrobacter resistant to ceftazidime. In general, its spectrum of activity is similar to ceftazidime's, except that it has a far superior coverage of G(+) organisms. For this reason it has been described as the 1st member of the 4th generation of cephalosporins.
Cefepime has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections:
• Aerobic Gram-Negative Microorganisms:
  • Enterobacter
  • Escherichia coli
  • Klebsiella pneumoniae
  • Proteus mirabilis
  • Pseudomonas aeruginosa
• Aerobic Gram-Positive Microorganisms:
  • Staphylococcus aureus (methicillin-susceptible strains only)
  • Streptococcus pneumoniae
  • Streptococcus pyogenes (Lancefield's Group A streptococci)
Note that cefepime is inactive against many strains of Stenotrophomonas (formerly Xanthomonas maltophilia and Pseudomonas maltophilia), and it is also inactive against most strains of Clostridium difficile. Also, most strains of enterococci and methicillin-resistant staphylococci are resistant to cefepime.
It has been shown to be well tolerated and effective in the treatment of a variety of infections including moderate-to-severe pneumonia, skin/soft tissue infections, complicate urinary tract infections, septicemia and febrile neutropenia.

Cefepime is indicated for:

• Pneumonia (moderate to severe) caused by Streptococcus pneumoniae, including cases associated with concurrent bacteremia, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species.
• Empiric therapy for febrile neutropenia. However, cefepime monotherapy is not recommended in patients at high risk for severe infection (e.g., patients with sepsis, severe prolonged neutropenia, recent bone marrow transplantation, hematologic malignancies, etc..)
• Uncomplicated and complicated UTIs (including pyelonephritis) caused by Escherichia coli or Klebsiella pneumoniae, or Proteus mirabilis, especially when associated with concurrent bacteremia.
• Uncomplicated Skin and Skin Structure Infections caused by Staphylococcus aureus (methicillin-susceptible strains only) or Streptococcus pyogenes.
• Complicated Intra-abdominal Infections (used in combination with metronidazole) caused by Escherichia coli, viridans group streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter species, or Bacteroides fragilis.

Pharmacokinetics

• Cefepime distributes well in all tissues and appears to cross the inflammed blood-brain barrier. Plasma protein binding is only 20%.
• Cefepime is eliminated mainly via the kidneys, presumably by filtration and secretion. About 85% of the dose is excreted in the urine as cefepime.
• Cefepime's total body clearance is approximately 120 mL/min, independent of the dose.
• The elimination half-life of cefepime in patients with normal renal function is about 2 hrs.

Contraindications and Warnings

1. Cross-hypersensitivity can occur in patients with a history of allergy to penicillin, cephalosporins, or other beta-lactam antibiotics.
2. Cefepime is contraindicated in patients with documented hypersensitivity to cephalosporins.
3. Drug accumulation may occur in patients with renal impairment. This can lead to seizures.
4. Superinfections such as oral candidiasis and vaginitis can occur.

Available As

• Powder to be reconstitution into injectable solution: 0.5 , 1, and 2 g vials (regular or ADD-Vantage)
• The dry powder contains 725 mg of L-arginine per gram of cefepime HCl. The pH of the reconstituted solution ranges from 4 to 6.

Dose and Administration

The recommended dosage of cefepime in patients with normal renal function is 1 or 2 grams IV every 12 hours. Dosage
• Drug accumulation may occur in patients with renal impairment. This can lead to seizures.
• Cross-hypersensitivity can occur in patients with a history of allergy to penicillin, cephalosporins, or other beta-lactam antibiotics. Cefepime is contraindicated in patients with documented hypersensitivity to cephalosporins.
• Dose adjustments must be made in patients with renal impairment (CLcr <60 mL/min).
• The dose can be diluted in 50 to 100 mL of normal saline or 5% dextrose solutions and infused over 30 minutes.
• Cefepime can also be administered intramuscularly.
• Dilution: for intermittent infusion, the dose (£2 g) should be diluted in 50 or 100 mL of NS, D5W, or D5/NS, or D5/LR.
• Rate of infusion: dose should be infused over 30 minutes.
• Adult dosage (normal renal function):

  Indication	Dosage
  Pneumonia	1-2 g IV q12h x 10 days
  Febrile neutropenia	2 g IV q8h x 7 days
  Mild / Moderate UTI	0.5 - 1 g IV or IM q12h x 7-10 days
  Severe UTI	2 g IV q12h x 10 days
  Skin & Skin Structure	2 g IV q12h x 7 days
  Intra-abdominal (+metronidazole)	2 g IV q12h x 10 days

• Pediatric dosage: 50 mg/kg/dose q12h (neutropenia q8h). Pediatric dose should not exceed that recommended for adults.
• Renal Dose Adjustment:

  CLcr, mL/min	Recommended Dosage
  >60  (normal)	0.5 g q12h	1 g q12h	2 g q12h	2 g q8h
  30 - 60	0.5 g q24h	1 g q24h	2 g q24h	2 g q12h
  11 - 29	0.5 g q24h	0.5 g q24h	1 g q24h	2 g q24h
  <11	0.25 g q24h	0.25 g q24h	0.5 g q24h	1 g q24h

Main Side Effects

• Except for the local reactions (3%), all of the other adverse events listed below occur rarely (£1%)
• Phlebitis, pain or inflammation at the infusion site.
• Diarrhea, colitis, nausea, and vomiting,
• Drug fever, rash, pruritus, urticaria, and rarely Stevens-Johnson's syndrome.
• Decreased prothrombin activity
• Eosinophilia, neutropenia, thrombocytopenia, hemolytic anemia, and positive Coombs' test.
• Headache, lightheadedness, and seizures
• Cholestatic jaundice and slight elevation in LFTs.
• Nephrotoxicity (interstitial nephritis)

Drug Interactions

No clinically significant interactions have been reported. Potential interaction involves high dose probenecid decreasing cefepime renal clearance.

References

1. Asbel LE, Levison ME. Cephalosporins, carbapenems, and monobactams. Infect Dis Clin North Am. 2000; 14(2):435-47
2. Marshall WF, Blair JE. The cephalosporins. Mayo Clin Proc. 1999 ;74(2):187-95.
3. Giamarellou H. Fourth generation cephalosporins in the antimicrobial chemotherapy of surgical infections. J Chemother. 1999; 11(6):486-93.
4. Maxipime PI