Cefepime

Cefepime is a broad-spectrum, bactericidal antibiotic, with activity against a wide range of Gram-positive and Gram-negative bacteria, including many strains resistant to aminoglycosides or third generation cephalosporins.

It is highly resistant to hydrolysis caused by most beta-lactamases. It has a reduced affinity for beta-lactamases changed via chromosomes and has a rapid penetration in the cells of the Gram-negative bacteria.

Resistance

The bacterial resistance to cefepime can depend on one or several mechanisms:

• Hydrolysis via beta-lactamases. Cefepime is stable to most beta-lactamases changed by plasmids and via chromosomes, but it can be hydrolysed effectively by certain beta-lactamases with broad-spectrum which are present mostly in Escherichia coli and Klebsiella pneumoniae and by enzymes changed by the chromosomes.
• Reduced affinity of the penicillin-binding proteins (PBPS) to cefepime. The resistance developed to Streptococcus pneumoniae and other streptococci caused by PBPs mutation; resistance of the staphylococci to methicillin caused by the production of additional PBPs with reduced affinity to cefepime.
• Non penetrable exterior membrane.
• Drugs efflux pumps.

There may be simultaneously more than one mechanism of resistance in each cell wall. Depending on the mechanism(s) present, there may be crossed resistance to several or to all other beta-lactam and/or antibacterial drugs of other types.

During treatment, resistance to the following species can develop: Citrobacter, Pseudomonas (especially P. aeruginosa), Morganella and Serratia.

Absorption

Cefepime is completely absorbed after IM administration.

Biotransformation

Cefepime is metabolised in N-methylpyrrolidinium, being converted quickly in N-oxide. About 85% of the administered dose is eliminated unchanged; high concentrations of unchanged cefepime are detected in urine. Less than 1% of the administered dose is eliminated in urine as N-methylpyrrolidinium, 6.8% as N-oxide and 2.5% as cefepime epimer.

Elimination

The elimination average half-life of cefepime is about 2 hours, and is independent of the dose for the range of 250 mg to 2 g. There is no evidence of accumulation in the healthy individuals receiving doses up to 2 g IV every 8 hours for 9 days. The total body clearance is 120 ml/min. The average renal clearance of cefepime is 110 ml/min, suggesting an elimination almost exclusively via the kidneys, mainly by glomerular filtration.

Pharmacokinetic/pharmacodynamic (PK/PD) relationship

The antibacterial activity depends on the time during which the free concentration serum/urine exceeds the minimum inhibitory concentration (MIC).

Special populations

Renal dysfunction

The elimination half-life is increased in patients with several degrees of renal failure, so the dosage adjustment is recommended.

Liver dysfunction

Cefepime pharmacokinetics was not changed in patients with hepatic insufficiency that received a dose of 1 g. It is not necessary to change the posology of cefepime in this population.

Elderly

Healthy voluntary individuals of 65 years old or more that received a single dose of 1 g IV of cefepime presented higher AUC values and lower renal clearance values when compared with younger adults.

It is recommended the dose adjustment in the elderly patient with renal function impairment.

From the more than 6400 adults treated with cefepime in clinical studies, 35% were aged 65 years old or more and 16% were aged 75 years old or more. In clinical studies when the elderly patient received the recommended dose for the adult patient, the clinical efficacy and safety were comparable to the clinical efficacy and safety in the non-elderly adult patient, unless the patient had renal failure. There was a mild increase in the elimination half-life time and lower renal clearance values when compared with those seen in younger individuals. Dose adjustments are recommended if the renal function is impaired.

Children

Cefepime pharmacokinetics with single and multiple doses was assessed in patients aged between 2.1 months and 11.2 years, with doses 50 mg/kg in IV infusion or IM injection; multiple doses were administered with intervals of 8 or 12 hours for at least 48 hours.

After the single IV administration, the total clearance was 3.3 ml/min/kg, with a distribution value of 0.3 l/kg. The elimination half-life was 1.7 hour, with an average recovery in urine of unchanged cefepime around 60.4% of the administered dose, being the renal clearance the main route of elimination (2.0 ml/min/kg).

The average plasma concentrations of cefepime in steady state after the administration of multiple IV doses were similar to those seen after the 1st dose, only with mild accumulation after repeated doses.

After the IM administration in steady state conditions, maximum cefepime plasma concentrations around 68 micrograms/ml were obtained in average in 0.75 hours. The bioavailability was in average 82% after intramuscular administration.

Other

Clinical improvement was seen with cefepime in the treatment of acute pulmonary exacerbations in patients with cystic fibrosis. Pharmacokinetics of cefepime did not change in patients with hepatic function impairment which received a single dose of 1 g and in patients with cystic fibrosis. No dose adjustment of cefepime is required in this population.

No long term studies were performed in the animal to assess the carcinogenic potential. In in vitro and in vivo genotoxicity tests, cefepime did no show to be genotoxic. In the rat no decreased fertility was seen.