Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2017 Publisher: Renascience Pharma Ltd, 11 George Street West, Luton, Bedfordshire, LU1 2BJ, United Kingdom
Pharmacotherapeutic group: Antibacterials for systemic use. Other beta-lactam antibacterials. Fourth-generation cephalosporins, ATC code: J01DE01
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.
The bacterial resistance to cefepime can depend on one or several mechanisms:
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.
The critical concentration values to differentiate susceptible (S) pathogens from resistant (R) pathogens, in accordance with EUCAST (2009-05-25) are:
| Microorganism | Susceptible | Resistant |
|---|---|---|
| Critical concentration values related to species | non S≤4 mg/l | R>8 mg/l |
| Enterobacteriaceae | S≤1 mg/l | R>8 mg/l |
| Pseudomonasa | S≤8 mg/l | R>8 mg/l |
| Haemophilus influenzae | S≤0.25 mg/l | R>0.25 mg/l |
| and Moraxella catarrhalis | ||
| Streptococcus pneumoniae | S≤1 mg/l | R>2 mg/l |
| Streptococci A, B, C and Gb | ||
| Staphylococcusc |
a Critical concentration value is valid in high dose (2g x 3).
b Based on the critical concentration value for benzylpenicillin.
c Based on the critical concentration value for methicillin.
The prevalence of acquired resistance may vary geographically and with time for selected species and it is desirable to have local information on resistance, particularly when treating severe infections. As necessary, expert advice should be sought when the local prevalence of resistance is such that the utility of the agent in, at least some types of infections, is questionable.
Gram-positive aerobes:
Staphylococcus aureus and coagulase negative staphylococci including beta-lactamase producing strains
Streptococci. Pneumococci
Gram-negative aerobes:
Acinetobacteria
Aeromonas spp
Citrobacter
Enterobacteriae
Escherichia coli
Haemophilus influenzae including beta-lactamase producing stains
Klebsiella
Moraxella catarrhalis including beta-lactamase producing stains
Morganella morganii
Proteus
Providencia
Pseudomonas
Serratia
Gram-positive aerobes:
Enterococos
Listeria
Gram-negative aerobes:
Burkholderia cepacia
Legionella
Stenotrophomonas maltophilia
Anaerobes:
Anaerobic bacteria including Bacteroides and Clostridium difficile
Other microorganisms:
Chlamydia
Mycoplasma
Cefepime is completely absorbed after IM administration.
Average plasma concentrations of cefepime observed in the male adult, after a single IV infusion (30 minutes) or after the IM injection of doses of 500 mg, 1 g and 2 g are summarized in table 1; in table 2 are presented the average concentrations in the tissues and biological fluids. After the intramuscular administration, cefepime is completely absorbed.
Table 1. Average plasma concentrations of cefepime (micrograms/ml):
| Cefepime dose | 0.5 h | 1 h | 2 h | 4 h | 8 h | 12 h |
|---|---|---|---|---|---|---|
| 500 mg IV | 38.2 | 21.6 | 11.6 | 5.0 | 1.4 | 0.2 |
| 1 g IV | 78.7 | 44.5 | 24.3 | 10.5 | 2.4 | 0.6 |
| 2 g IV | 163.1 | 85.8 | 44.8 | 19.2 | 3.9 | 1.1 |
| 500 mg IM | 8.2 | 12.5 | 12.0 | 6.9 | 1.9 | 0.7 |
| 1 g IM | 14.8 | 25.9 | 26.3 | 16.0 | 4.5 | 1.4 |
| 2 g IM | 36.1 | 49.9 | 51.3 | 31.5 | 8.7 | 2.3 |
Cefepime concentrations in specific tissues and biological fluids are in Table 2.
The binding of cefepime to serum proteins is, on average, 16.4% and is independent of the serum concentration.
Table 2. Average concentrations of cefepime in several tissues (micrograms/g) and biological fluids (micrograms/g):
| Tissue or Fluid | Dose (IV) | Time after the collection (h) | Average Concentration |
|---|---|---|---|
| Urine | 500 mg | 0–4 | 292 |
| 1 g | 0–4 | 926 | |
| 2 g | 0–4 | 3120 | |
| Bile | 2 g | 9.4 | 17.8 |
| Peritoneal fluid | 2 g | 4.4 | 18.3 |
| Blister fluid | 2 g | 1.5 | 81.4 |
| Bronchial mucosa | 2 g | 4.8 | 24.1 |
| Expectoration | 2 g | 4.0 | 7.4 |
| Prostate | 2 g | 1.0 | 31.5 |
| Appendix | 2 g | 5.7 | 5.2 |
| Gall bladder | 2 g | 8.9 | 11.9 |
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.
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.
The antibacterial activity depends on the time during which the free concentration serum/urine exceeds the minimum inhibitory concentration (MIC).
The elimination half-life is increased in patients with several degrees of renal failure, so the dosage adjustment is recommended.
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 Renapime in this population.
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 (see sections 4.2 and 4.4).
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 (see section 4.2).
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.
The cefepime concentrations in cerebrospinal fluid (CSF) in relation to plasma are the following:
Table 3. Average concentrations in plasma and in CSF in children:
| Sample collection (h) | N | Plasma concentration (micrograms/ml) | CSF concentration (micrograms/ml) | CSF/plasma relation |
|---|---|---|---|---|
| 0.5 | 7 | 67.1 (51.2) | 5.7 (7.3) | 0.12 (0.14) |
| 1 | 4 | 44.1 (7.8) | 4.3 (1.5) | 0.10 (0.04) |
| 2 | 5 | 23.9 (12.9) | 3.6 (2.0) | 0.17 (0.09) |
| 4 | 5 | 11.7 (15.7) | 4.2 (1.1) | 0.87 (0.56) |
| 8 | 5 | 4.9 (5.9) | 3.3 (2.8) | 1.02 (0.64) |
* The age of the patients ranged from 3.1 month to 12 years. The patients with suspicion of CNS infection received 50 mg/kg every 8 hours, in 5 to 20 minutes infusion. The plasma and CSF were collected in the times determined in relation to the end of the infusion on the 2nd or 3rd day of treatment.
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 Renapime 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.
© All content on this website, including data entry, data processing, decision support tools, "RxReasoner" logo and graphics, is the intellectual property of RxReasoner and is protected by copyright laws. Unauthorized reproduction or distribution of any part of this content without explicit written permission from RxReasoner is strictly prohibited. Any third-party content used on this site is acknowledged and utilized under fair use principles.
