Cefepime

Cefepime hydrochloride is a fourth-generation cephalosporin that belongs to a class of antibiotics known as beta-lactams. It is indicated to treat gram-positive and gram-negative bacterial infections that are susceptible to its activity. These include: 

• Pneumonia
• Complicated and uncomplicated urinary tract infections
• Skin and soft tissue infections
• Complicated intra-abdominal infections (with metronidazole)
• Empiric treatment for neutropenic fever

Selections of bacteria that are susceptible to cefepime are as follows: Streptococcus pneumoniae, Klebsiella pneumoniae, Enterobacter group, Haemophilus influenza, Pseudomonas aeruginosa, Escherichia coli, Proteus mirabilis, Streptococcus pyogenes, methicillin-susceptible Staphylococcus aureus, Streptococci viridans species, Bacteroides fragilis. 

An ever-growing number of bacteria are becoming resistant to the activity of beta-lactams, known as extended-spectrum beta-lactamase (ESBL) producing organisms. Many ESBL organisms are resistant to cefepime. However, there is a sub-group of ESBLs known as Amp-C producers that are susceptible. Although these organisms may be susceptible to cefepime, the minimum inhibitory concentration (MIC) and the dosing regimen must be carefully evaluated before treatment to ensure effective coverage.[1][2][3][4][5] 

Cefepime has a similar mechanism of action to other beta-lactams. Cefepime inhibits bacterial cell wall synthesis by covalently binding enzymes responsible for the final step in transpeptidation during peptidoglycan wall synthesis. This binding causes defects in the cell wall leading to autolysis and subsequent death of the organism. 

Cefepime has increased gram-negative coverage and is more stable against beta-lactamases when compared to third-generation cephalosporins due to a few mechanisms. One such mechanism is the penicillin-binding enzymes have a lower affinity for cefepime. Another is the chemical structure differs from older generations with a substitution of a side chain, lending it more activity against staphylococcal species. Cefepime is also a zwitterion giving it an advantage for faster cell wall penetration of gram-negative bacteria, which is why it has broader gram-negative coverage than the third-generation.

Cefepime, like most cephalosporins, is widely distributed throughout body tissue and fluids, including pleural fluid, synovial fluid, bones, cerebral spinal fluid, and breast milk. Cefepime rapidly metabolizes with less than 10% of the metabolized product undergoing excretion. The remaining compound gets excreted through glomerular filtration as an unchanged drug. The half-life is about 2 to 2.3 hours and is longer in patients with renal failure.[1][6]

Cefepime is not well absorbed by the gastrointestinal tract and must be administered intravenously (IV) or intramuscularly (IM). The most common method is by IV — typical administration is 1 to 2 g every 8 to 12 hours depending on the infection treated. Infusions are usually over 30 minutes. There have been studies that looked at extended infusions of 4 hours showing lower overall mortality and reduced intensive care unit (ICU) lengths of stay when compared with the standard 30-minute rate; however, other studies have failed to confirm these findings. Extended infusion rates for febrile neutropenia have been studied and appear feasible for treatment. 

Pediatric administration is usually 50 mg/kg (up to a 40 kg child) every 8 to 12 hours. 

No adjustment in dosing is necessary for hepatic impairment. The dose requires adjustment for patients with renal dysfunction, defined as a creatinine clearance less than or equal to 60 mL/min.[7][8][9]

Cefepime is usually well tolerated by both adults and pediatric patients. The most common adverse effects in adults are diarrhea and rash. The most common adverse effects in the pediatric population are fevers, diarrhea, and rash.

There are multitudes of other less common adverse effects listed according to the system affected:

• Neurological: headache, fever, and neurotoxicity
• Gastrointestinal: nausea, vomiting, abdominal pain, hepatic injury, colitis including pseudomembranous colitis, oral candidiasis
• Genitourinary: vaginitis, renal injury
• Dermatological: local site injection irritation, pruritus, urticaria, Stevens-Johnson syndrome, and erythema mutiforme 
• Hematological: positive Coombs test without hemolysis, pancytopenia, and anaplastic anemia

Adverse effects typically reverse upon removal of the medication. 

Neurotoxicity is a serious, life-threatening adverse effect that deserves special mention. Symptoms can present as altered mental status, encephalopathy, seizures, myoclonus, hallucinations, coma, and stroke-like symptoms. The onset of symptoms is typically four days after starting cefepime. Risk factors include renal failure (creatinine less than or equal to 60 mL/min), the aging adult, critically ill patients in ICU, strokes, Alzheimer disease, brain malignancy, seizure history, and a compromised blood-brain barrier (BBB). The theorized mechanism is that cefepime can cross the BBB and antagonize gamma-aminobutyric acid receptors. 

Treatment consists of stopping the drug, seizure management with benzodiazepines, or renal replacement therapy in severe refractory cases. It is important to monitor and adjust dosing with renal dysfunction; however, reports exist of neurotoxicity in patients with normal kidney function.[10][11][12][13][14]

Cefepime is contraindicated in patients with prior hypersensitivity reactions to the drug in the past.

Cephalosporins have a long history as being contraindicated in patients with severe hypersensitivity reactions to penicillin. Early testing of cephalosporins (up until the 1980s) came from the Penicillium mold of penicillin. The thinking is that these early cephalosporins were contaminated with penicillin and accounted for cross-reactivity allergic response. Avoiding cephalosporins with patients who have penicillin allergies likely developed from these early studies. 

Cephalosporins are similar to penicillins with the beta-lactam ring but differ by the various side chains. It is the similarities of these side chains to the penicillin structure that account for the IgE mediated cross-reactivity and not the beta-lactam ring as previously thought. The newer the generation of cephalosporins, the greater the difference in the side chain structures. A severe IgE mediated hypersensitivity reaction to cefepime in a penicillin-allergic patient is rare. It is worth mentioning that the delayed T-cell hypersensitive reactions can still occur; this is because T-cells can recognize the entire beta-lactam ring as well as the side chains. 

Caution is advisable with use in patients with compromised renal function (creatinine clearance less than or equal to 60 mL/min) as roughly 85% of the drug is excreted through the urine unchanged. 

Cefepime is listed as category B for pregnancy and gets excreted in breast milk. Caution is necessary with cefepime in women who are pregnant or breastfeeding and should only be used if absolutely needed.[1][15][16][17][18]