Cefepime drug dose, brand name and side effects

Description of Cefepime 

Cefepime is a parenteral cephalosporin with pharmacokinetics and spectrum of activity similar to ceftazidime, a ‘third-generation’ cephalosporin. Because cefepime may be active against some organisms resistant to ceftazidime, some consider cefepime a ‘fourth-generation’ cephalosporin. Cefepime is comparable to ceftazidime in its coverage of Pseudomonas aeruginosa, and it may be more active than ceftazidime against Enterobacter sp. due to enhanced stability against beta-lactamases. Clinical uses of cefepime are similar to those of the third-generation cephalosporins. Cefepime was approved in January 1996. It was approved for the treatment of febrile neutropenia in June 1997 and for complicated intra-abdominal infections in January 1998. In early 2007, the safety of cefepime relative to other beta-lactam antibiotics was questioned. A meta-analysis evaluating the efficacy and safety of cefepime reported a higher all-cause mortality in patients treated with cefepime compared to other beta-lactams. The FDA has conducted additional analyses and determined that the data do not indicate a higher rate of death in cefepime-treated patients. While the FDA has concluded that cefepime remains an appropriate therapy for its approved indications, they will continue to review its safety.

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Mechanism of Action of Cefepime

Cefepime, a beta-lactam antibiotic, is mainly bactericidal. Like other cephalosporins and penicillins, cefepime inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin-binding proteins (PBPs) that are located inside the bacterial cell wall. PBPs are responsible for several steps in the synthesis of the cell wall and are found in quantities of several hundred to several thousand molecules per bacterial cell. PBPs vary among different bacterial species. Thus, the intrinsic activity of cefepime, as well as other cephalosporins and penicillins, against a particular organism depends on its ability to gain access to and bind with the necessary PBP. Like all beta-lactam antibiotics, cefepime’s ability to interfere with PBP-mediated cell wall synthesis ultimately leads to cell lysis. Lysis is mediated by bacterial cell wall autolytic enzymes (i.e., autolysins). The relationship between PBPs and autolysins is unclear, but it is possible that the beta-lactam antibiotic interferes with an autolysin inhibitor. Prevention of the autolysin response to beta-lactam antibiotic exposure through the loss of autolytic activity (mutation) or inactivation of autolysin (low-medium pH) by the microorganism can lead to tolerance to the beta-lactam antibiotic resulting in bacteriostatic activity.

Beta-lactams, including cefepime, exhibit concentration-independent or time-dependent killing. In vitro and in vivo animal studies have demonstrated that the major pharmacodynamic parameter that determines efficacy for beta-lactams is the amount of time free (non-protein bound) drug concentrations exceed the minimum inhibitory concentration (MIC) of the organism (free T above the MIC). This microbiological killing pattern is due to the mechanism of action, which is acylation of PBPs. There is a maximum proportion of PBPs that can be acylated; therefore, once maximum acylation has occurred, killing rates cannot increase. Free beta-lactam concentrations do not have to remain above the MIC for the entire dosing interval. The percentage of time required for both bacteriostatic and maximal bactericidal activity is different for the various classes of beta-lactams. Cephalosporins require free drug concentrations to be above the MIC for 35% to 40% of the dosing interval for bacteriostatic activity and 60% to 70% of the dosing interval for bactericidal activity.

The susceptibility interpretive criteria for cefepime are delineated by pathogen. The Clinical and Laboratory Standards Institute (CLSI) and the FDA differ on MIC interpretation for Enterobacterales. The MICs for Enterobacterales are defined by the FDA as susceptible at 2 mcg/mL or less, intermediate at 4 to 8 mcg/mL, and resistant at 16 mcg/mL or more; for isolates with an intermediate susceptibility, the recommended dose is 2 g IV every 8 hours in patients with normal renal function. The MICs for Enterobacterales are defined by CLSI as susceptible at 2 mcg/mL or less, susceptible-dose dependent (SDD) at 4 to 8 mcg/mL, and resistant at 16 mcg/mL or more; the breakpoint for susceptible is based on a dose of 1 g IV every 12 hours, and the breakpoint for SDD is based on dosage regimens that result in higher cefepime exposure (up to the approved maximum dosage regimen). The CLSI and the FDA differ on MIC interpretation for P. aeruginosa. The MICs for P. aeruginosa are defined by the FDA as susceptible at 8 mcg/mL or less and resistant at 16 mcg/mL or more; the recommended dose is 2 g IV every 8 hours in patients with normal renal function. The MICs for P. aeruginosa are defined by CLSI as susceptible at 8 mcg/mL or less, intermediate at 16 mcg/mL, and resistant at 32 mcg/mL or more; the breakpoints are based on a dose of 1 g IV every 8 hours or 2 g IV every 12 hours. The MICs are defined for Acinetobacter sp. and non-Enterobacterales as susceptible at 8 mcg/mL or less, intermediate at 16 mcg/mL, and resistant at 32 mcg/mL or more. The MICs are defined for S. pneumoniae for meningitis isolates as susceptible at 0.5 mcg/mL or less, intermediate at 1 mcg/mL, and resistant at 2 mcg/mL or more. The MICs are defined for S. pneumoniae for non-meningitis isolates as susceptible at 1 mcg/mL or less, intermediate at 2 mcg/mL, and resistant at 4 mcg/mL or more. The MICs are defined for Streptococcus sp. Viridans group susceptible at 1 mcg/mL or less, intermediate at 2 mcg/mL, and resistant at 4 mcg/mL or more. The MICs are defined for beta-hemolytic streptococci and N. gonorrhoeae as susceptible at 0.5 mcg/mL or less. The MICs are defined for H. influenzae and H. parainfluenzae as susceptible at 2 mcg/mL or less. Methicillin-susceptible staphylococci may be considered susceptible to cefepime.

Compared with third-generation cephalosporins, cefepime possesses an increased ability to penetrate the bacterial cell’s outer membrane and a lower rate of hydrolysis by bacterial beta-lactamases. Cefepime exists as a zwitterion and it is thought that this property enhances its ability to penetrate porin channels in the cell walls of gram-negative bacteria. Cefepime has a low affinity for chromosomally-encoded beta-lactamases and is highly resistant to hydrolysis by most beta-lactamases.

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Pharmacokinetics of Cefepime

Cefepime is administered intravenously and intramuscularly. The average steady-state Vd in adults is 18 L. In general, pediatric patients have slightly faster clearance and larger Vd than adults. The Vd of cefepime in pediatric patients is approximately 0.37 L/kg. Approximately 20% of the circulating drug is protein-bound. It is distributed into most body tissues and fluids. In a pediatric pharmacokinetic trial, CSF concentrations peaked 30 minutes after the dose and were lowest immediately before the next dose; however, there was relatively little variation in CSF concentrations over the 8-hour dosing interval.

Cefepime is metabolized to N-methylpyrrolidine (NMP), which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose in adults. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of cefepime. The elimination half-life in children with normal renal function is approximately 1.7 hours compared to 2 hours in adults.

Affected cytochrome P450 isoenzymes and drug transporters: none

•Route-Specific Pharmacokinetics
Intravenous Route
Cefepime pharmacokinetics are linear over the dose range of 250 mg to 2 g IV. The mean peak serum concentrations (Cmax) are 39.1 mcg/mL with a 500 mg IV dose, 81.7 mcg/L with a 1 g IV dose, and 163.9 mcg/mL with a 2 g IV dose in healthy adult males. There is no evidence of accumulation in healthy adult male volunteers receiving clinically relevant doses for a period of 9 days.

Intramuscular Route
Cefepime pharmacokinetics are linear over the dose range of 500 mg to 2 g IM. The mean peak serum concentrations (Cmax) are 13.9 mcg/mL with a 500 mg IV dose, 29.6 mcg/L with a 1 g IV dose, and 57.5 mcg/mL with a 2 g IV dose in healthy adult males. Cmax occurs approximately 1.5 hours after IM administration in adults. In pediatric patients who received a 50 mg/kg/dose IV and IM, the absolute bioavailability of the IM dose was 82.3%.

•Special Populations
Hepatic Impairment
No differences in the pharmacokinetics of cefepime were reported in adults with hepatic impairment who received a single 1 g dose (n = 11).

Renal Impairment
In adults with renal impairment, the elimination half-life of cefepime is prolonged. The average half-life in adults requiring hemodialysis was 13.5 ± 2.7 hours and in patients requiring continuous peritoneal dialysis was 19 ± 2 hours. Cefepime total body clearance decreased proportionally with creatinine clearance in patients with renal impairment. Cefepime is removed by hemodialysis; approximately 68% of the total amount of cefepime present in the body at the start of dialysis will be removed during a 3-hour dialysis period.

Pediatrics
Infants, Children, and Adolescents
The combined results from 3 clinical studies in children (total n = 88; 2 months to 16 years) found mean values for clearance, Vd, and elimination half-life to be 3.1 mL/kg/minute, 0.37 L/kg, and 1.7 hours, respectively. In patients with bacterial meningitis, mean cerebrospinal fluid (CSF) concentrations ranged from 3.3 ± 2.8 mcg/mL to 5.7 ± 7.3 mcg/mL over the dosing interval, compared to mean plasma concentrations ranging from 4.9 ± 5.9 mcg/mL to 67.1 ± 57.2 mcg/mL.

Neonates
In a clinical study in 55 neonates (gestational age, 30.5 weeks ± 5.3; postnatal age, 14.7 days ± 14.5; weight, 1.91 kg ± 1.04), mean values for clearance, Vd, and elimination half-life were 1.15 mL/kg/minute, 0.43 L/kg, and 4.9 hours, respectively. The volume of distribution was larger in neonates with a postconceptional age younger than 30 weeks compared to those with a postconceptional age older than 30 weeks (0.51 vs. 0.39 L/kg, respectively). Clearance in neonates is approximately 40% lower than that of older pediatric patients, and there was not a significant relationship between gestational age at birth and cefepime clearance (r = 0.14, p more than 0.1). The authors concluded that a dose of 30 mg/kg/dose IV every 12 hours for neonates younger than 14 days regardless of postconceptual age should achieve concentrations at or above those achieved by doses of 50 mg/kg/dose IV every 8 hours in older populations.

Geriatric
Cefepime pharmacokinetics have been investigated in the elderly (65 years of age and older) whose mean creatinine clearance was 74 ± 15 mL/minute. There appeared to be a decrease in cefepime total body clearance as a function of creatinine clearance

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• Cefepime Hydrochloride

• Maxipime

• 4Th Generation Cephalosporin
• Antibiotic

• Febrile neutropenia, Empiric therapy: Adult
• Febrile neutropenia, Empiric therapy: Pediatric: yes (2 months up to 16 years)
• Infection of skin and/or subcutaneous tissue (Moderate to Severe), Uncomplicated: Adult
• Infection of skin and/or subcutaneous tissue (Moderate to Severe), Uncomplicated: Pediatric: yes (2 months up to 16 years)
• Infectious disease of abdomen, Complicated: Adult
• Pneumonia (Moderate to Severe): Adult
• Pneumonia (Moderate to Severe): Pediatric: yes (2 months up to 16 years)
• Urinary tract infectious disease: Adult
• Urinary tract infectious disease: Pediatric: yes (2 months up to 16 years)

• Dermatologic: Rash (1.1% to 4% )
• Endocrine metabolic: Hypophosphatemia (2.8% )
• Gastrointestinal: Diarrhea (0.1% to 3% )
• Hematologic: Direct Coombs test positive (16.2% )
• Hepatic: ALT/SGPT level raised (2.8% ), Aspartate aminotransferase serum level raised (2.4% )

• Dermatologic: Stevens-Johnson syndrome, Toxic epidermal necrolysis
• Gastrointestinal: Clostridioides difficile infection, Colitis
• Immunologic: Anaphylaxis
• Neurologic: Aphasia, Encephalopathy, Myoclonus, Neurotoxicity, Nonconvulsive status epilepticus, Seizure

• Intravenous: Reconstitute the single-dose 0.5-g, 1-g, or 2-g vials with one of the following diluents: Sterile water for injection, NS, D5W, 0.5% or 1% lidocaine hydrochloride injection, or bacteriostatic water for injection with parabens or benzyl alcohol .
• Intravenous: For the 500-mg single-dose vial, add 5 mL diluent to obtain an approximate concentration of 100 mg/mL; withdraw 5 mL of reconstituted solution to administer the dose .
• Intravenous: For the 1-g single-dose vial, add 10 mL diluent to obtain an approximate concentration of 100 mg/mL; withdraw 10.5 mL of reconstituted solution to administer the dose .
• Intravenous: For the 2-g single-dose vial, add 10 mL diluent to obtain an approximate concentration of 160 mg/mL; withdraw 12.5 mL of reconstituted solution to administer the dose .
• Intravenous: Reconstitute the ADD-Vantage vials with 50 or 100 mL of D5W or NS in ADD-Vantage flexible diluent containers .
• Intravenous: For the 1-g ADD-Vantage vial, add either 50 mL of diluent to obtain a final concentration of 20 mg/mL and a withdrawal volume of 50 mL or add 100 mL to obtain a final concentration of 10 mg/mL and a withdrawal volume of 100 mL .
• Intravenous: For the 2-g ADD-Vantage vial, add either 50 mL of diluent to obtain a final concentration of 40 mg/mL and a withdrawal volume of 50 mL or add 100 mL to obtain a final concentration of 20 mg/mL and a withdrawal volume of 100 mL .
• Intravenous: Dilute the reconstituted solution with one of the following compatible infusion solutions prior to IV infusion: NS, D5W or D10W, M/6 sodium lactate injection, D5NS, D5LR, Normosol(TM)-R and Normosol(TM)-M in D5W .
• Intravenous: Diluted solutions may be stored for up to 24 hours at room temperature, 20 to 25 degrees C (68 to 77 degrees F), or 7 days refrigerated at 2 to 8 degrees C (36 to 46 degrees F) .
• Intravenous: Infuse IV over approximately 30 minutes .
• Intravenous: Although intermittent IV infusion with a Y-type administration set can be accomplished with compatible solutions, it is preferable to discontinue the other solution during administration of cefepime .
• Intravenous: Powder or reconstituted solution color may darken depending on storage conditions; however, this does not affect potency .
• Intravenous: (IV bolus administration) Dilute 1-g doses with 10 mL sterile water for injection (SWFI) or NS; dilute 2-g doses with 10 or 20 mL SWFI or NS; administer IV over 2 to 5 minutes .
• Intramuscular: Reconstitute a 0.5-g, 1-g, or 2-g single-dose vial with one of the following diluents: Sterile water for injection, NS, D5W, 0.5% or 1% lidocaine hydrochloride, or sterile bacteriostatic water for injection with parabens or benzyl alcohol .
• Intramuscular: For the 500-mg single-dose vial, add 1.3 mL diluent to obtain an approximate concentration of 280 mg/mL; withdraw 1.8 mL of reconstituted solution to administer the dose .
• Intramuscular: For the 1-g single-dose vial, add 2.4 mL diluent to obtain an approximate concentration of 280 mg/mL; withdraw 3.6 mL of reconstituted solution to administer the dose .
• Intramuscular: The reconstituted solution may be stored for up to 24 hours at room temperature, 20 to 25 degrees C (68 to 77 degrees F), or 7 days refrigerated at 2 to 8 degrees C (36 to 46 degrees F) .
• Intramuscular: Powder or reconstituted solution color may darken depending on storage conditions; however, this does not affect potency .