Continuing Education Activity

Cefepime is a cephalosporin in the beta-lactam class of antibiotics used in the management and treatment of gram-negative and gram-positive bacterial infections. This activity outlines the indications, action, and contraindications for cefepime as a valuable agent in the management of bacterial infections for hospitalized patients. This activity will highlight the mechanism of action, adverse effects, and other essential factors such as dosing and monitoring that are appropriate for all members of the interprofessional team when treating patients with cefepime.

Objectives:

• Describe the mechanism of action of cefepime.
• Review the chemical structures of cefepime vs. penicillin and explain why IgE mediated cross-reactivity reaction is unlikely.
• Summarize the possible toxic effects that cefepime.
• Outline interprofessional team approaches for improving care coordination for the safe use of cefepime that will reduce morbidity and improve patient safety.

Indications

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] 

Mechanism of Action

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]

Administration

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]

Adverse Effects

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]

Contraindications

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]

Monitoring

It is essential to monitor every patient for signs of a hypersensitivity reaction, especially if they have reacted to other beta-lactams in the past. Since cefepime is often used empirically for broad-spectrum coverage, the culture sensitivities should have close monitoring to deescalate treatment to a narrow-spectrum antibiotic. 

Renal function should be monitored with blood urea nitrogen and serum creatinine, especially when administering to the aging adult or patients with pre-existing kidney dysfunction. It is essential to monitor for signs of neurological changes, particularly in the elderly, patients with renal dysfunction, and patients with febrile neutropenia. 

The effectiveness of cefepime can vary drastically with critically ill patients treated in the ICU. Drug monitoring is suggested if the patient's creatinine clearance is less than or equal to 50 mL/min or if the MIC for the given pathogen is greater or equal to 4 mg/L. If treating outside of these parameters, then dose adjustment is indicated.[19][20][21]

Toxicity

In the event of a suspected overdose, the clinician should discontinue the drug or adjust the dose. Determining if the symptoms are a result of an actual cefepime overdose or from preexisting comorbidities may be difficult. If suspicion is high or if symptoms do not subside after dose adjusting or discontinuing, blood and/or cerebral spinal fluid levels should be obtained to evaluate if the toxicity is stemming from elevated cefepime levels. Dialysis may be necessary in severe cases. 

Enhancing Healthcare Team Outcomes

Cefepime is a common antibiotic prescribed in the hospital setting. It is often prescribed empirically to septic patients before a pathogen is known as it covers a broad spectrum of gram-positive and gram-negative bacteria. All members of the health care team must monitor each patient for immediate hypersensitivity reactions after initial administration. 

Clinicians need to bear in mind that the pharmacokinetics of the drug can undergo alteration in patients with sepsis, renal dysfunction, or the older person leading to undesired peaks and troughs and potentially serious adverse effects. If a patient exhibits a change in mental status or develops neurological signs such as seizure activity, the offending agent might be cefepime, and discontinuation or dose adjustment may be necessary. These changes are more likely to occur in patients with sepsis or renal dysfunction, and the aging adult. However, cefepime can be overlooked as a possible source as it is a common medication given that is usually well tolerated.

The clinician will make the decision to treat with cefepime, but a consult with a pharmacist, particularly one with board certification in infectious disease, may be in order. Pharmacists can review the antibiogram and verify dosing and duration. Nursing can counsel the patient on how to take the medication, answer any questions, and monitor patient compliance and therapeutic effectiveness, reporting any concerns to the prescriber. Cefepime therapy requires the collaborative effort of an interprofessional healthcare team, to include physicians, specialty-trained nurses, pharmacists, and potentially infectious disease specialists, all working together to achieve optimal patient outcomes. [Level V]