CEFEPIME

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.
Intravenous Administration
Intravenous (IV) Infusion
Powder Vials for Injection
Reconstitution
-Add 5 mL of compatible IV diluent to each 500 mg vial or 10 mL of diluent to each 1 g or 2 g vial. The resultant solution will be 100 mg/mL for the 500 mg and 1 g vials and 160 mg/mL for the 2 g vial. Further dilution is required.
-Compatible diluents include Sterile Water for Injection, 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 0.5% or 1% Lidocaine Hydrochloride Injection, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol.
-Storage: Reconstituted solutions are stable for up to 24 hours at room temperature or 7 days refrigerated (2 to 8 degrees C, 36 to 46 degrees F).

Dilution
-Dilute reconstituted solution with a compatible IV solution to provide a solution with a final concentration between 1 mg/mL and 40 mg/mL.
-Compatible solutions include 0.9% Sodium Chloride Injection, 5% Dextrose Injection, 10% Dextrose Injection, Lactated Ringer's Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringer's and 5% Dextrose Injection, or Normosol-R and Normosol-M in 5% Dextrose Injection.
-Storage: Diluted solutions are stable for up to 24 hours at controlled room temperature or 7 days refrigerated (2 to 8 degrees C, 36 to 46 degrees F).

ADD-Vantage Vials
-Constitute with 50 or 100 mL of 0.9% NaCl or 5% Dextrose injection.
-Storage: Solutions are stable for up to 24 hours at controlled room temperature or 7 days refrigerated (2 to 8 degrees C, 36 to 46 degrees F).

Frozen Pre-mixed Bags
-Constitute with 50 or 100 mL of 0.9% Sodium Chloride Injection or 5% Dextrose Injection.
-Storage: Solutions are stable for up to 24 hours at controlled room temperature or 7 days refrigerated (2 to 8 degrees C, 36 to 46 degrees F).

Frozen Pre-mixed Bags
-Thaw frozen container at room temperature or under refrigeration. Do not force thaw by immersion in water baths or by microwave irradiation.
-Storage: The thawed solution is stable for 7 days under refrigeration (5 degrees C, 41 degrees F) or for 24 hours at room temperature. Do not refreeze.

DUPLEX Drug Delivery System
-Use only if container and seals are intact. To inspect the drug powder for foreign matter or discoloration, peel the foil strip from the drug chamber.
-Protect from light after removal of foil strip. If the foil strip is removed and not used immediately, refold container and latch the side tab until ready to activate and use within 7 days.
-Once ready for activation, do not use directly after refrigeration; allow the product to reach room temperature before patient use.
-Unfold Duplex container and point the set port downward. Starting at the hanger tab end, fold the Duplex container just below the diluent meniscus trapping all air above the fold.
-To activate, squeeze the folded diluent chamber until the seal between the diluent and powder opens, releasing diluent into the drug powder chamber.
-Agitate the liquid-powder mixture until the drug powder completely dissolves.
-Storage: After reconstitution (activation), use within 12 hours if stored at room temperature or within 5 days if stored under refrigeration.

Intermittent IV Infusion
-Administer IV over a period of 30 minutes.
-DUPLEX Drug Delivery System: Prior to attaching to IV set, fold the Duplex container, starting at the hanger tab end, just below the solution meniscus trapping all air above the fold. Squeeze the Duplex container until the seal between the reconstituted drug solution and the set port opens, releasing the liquid to the set port. Do not use in series connections.

Intramuscular Administration
Powder Vials for Injection
Reconstitution
-Reconstitute with one of the following diluents: Sterile Water for Injection, 0.9% NaCl Injection, 5% Dextrose Injection, 0.5% or 1% Lidocaine Hydrochloride, or Sterile Bacteriostatic Water for Injection with Parabens or Benzyl Alcohol.
-Add 1.3 mL of diluent to each 500 mg vial or 2.4 mL of diluent to each 1 gram vial.
-The final concentration after reconstitution will be 280 mg/mL.
-Storage: Reconstituted solutions are stable for up to 24 hours at controlled room temperature or 7 days refrigerated (2 to 8 degrees C, 36 to 46 degrees F).

Intramuscular Injection
-Inject deeply into a large muscle (e.g., anterolateral thigh or deltoid [children and adolescents only]). To reduce injection site pain, mix cefepime with 1% lidocaine WITHOUT epinephrine.

Adverse events observed in pediatric cefepime trials were consistent with those observed in clinical trials in adults. Adverse event incidence rates reflect the occurrence in adult clinical studies.

Fever and headache were both reported during cefepime trials. The incidence of both was lower with lower doses, but increased to 1% in patients who received the maximum recommended dose.

Elevated hepatic enzymes, including ALT (2.8%) and AST (2.4%), have been reported in cefepime clinical trials. Hepatic dysfunction, including cholestasis, has been reported for cephalosporin-class antibiotics, but was not reported for cefepime during clinical trials. Changes occurring in < 1% but > 0.1% of patients included increased alkaline phosphatase and total bilirubin.

As with some other drugs in this class, encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), aphasia, myoclonus, seizures, and non-convulsive status epilepticus have been reported with cefepime use, including in pediatric patients. Although most reported cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules, some cases of neurotoxicity have occurred in patients receiving an appropriate dosage adjustment for their renal function. In the majority of cases, symptoms of neurotoxicity resolved after discontinuation of cefepime and/or after hemodialysis. If neurotoxicity associated with drug therapy occurs, consider discontinuing therapy or making necessary dosage adjustments in patients with renal insufficiency. Seizures are a rare (< 1%), but serious complication of cephalosporin and penicillin therapy in general. The epileptogenic properties of both penicillins and cephalosporins are thought to be related to their beta-lactam ring although penicillins are more commonly associated with seizures. High doses and renal impairment are associated risk factors for the development of seizures with penicillins and cephalosporins.

As with other cephalosporins, anaphylactoid reactions, including anaphylactic shock, have been reported with cefepime. Rash (unspecified) (1.1% to 4%), pruritus (> 0.1% to 1%), urticaria (> 0.1% to < 1%), and erythema (> 0.1% to < 1%) have also occurred in clinical trials. Angioedema has also been reported. In addition to the adverse reactions listed observed in patients treated with cefepime, the following adverse reactions have been reported for cephalosporin-class antibiotics: Stevens-Johnson syndrome, erythema multiforme, and toxic epidermal necrolysis (TEN).

Nausea, vomiting, and diarrhea were all reported during cefepime clinical trials. The incidence of these adverse reactions was > 0.1% to < 1% with lower doses, but increased with every 8 hour dosage regimens (2 g IV every 8 hours in adults). In these patients, nausea was reported at 2%, vomiting was reported at 1%, and diarrhea was reported at 3%.

Microbial overgrowth and superinfection can occur with antibiotic use. C. difficile-associated diarrhea (CDAD) or pseudomembranous colitis has been reported with cefepime. Colitis, including pseudomembranous colitis, was reported at an incidence of more than 0.1% to less than 1%. If pseudomembranous colitis is suspected or confirmed, ongoing antibacterial therapy not directed against C. difficile may need to be discontinued. Institute appropriate fluid and electrolyte management, protein supplementation, C. difficile-directed antibacterial therapy, and surgical evaluation as clinically appropriate. Other infectious complications occurring at an incidence of more than 0.1% to less than 1% include oral candidiasis and vaginitis.

Injection site reaction has been reported in 3% of patients during cefepime clinical trials. Such reactions have included phlebitis (1.3%) and pain/inflammation (0.6%).

Hematologic adverse events have been reported during cefepime use; pediatric incidences are not known. Events reported in adult clinical trials include positive Coombs' test without hemolysis (16.2%), eosinophilia (1.7%), abnormal PTT (1.6%), and abnormal PT (1.4%). Other hematologic abnormalities occurring at a rate of > 0.1% to < 1% were anemia, and decreased hematocrit, neutrophils, platelets, and WBC. Cefepime has also been associated with a fall in prothrombin activity (hypoprothrombinemia) with risk factors including renal/hepatic impairment, poor nutritional state, and a protracted antibiotic course. Prothrombin time should be monitored in at-risk patients and vitamin K administered as indicated. As with other cephalosporins, transient leukopenia, neutropenia, agranulocytosis, and thrombocytopenia have been reported. Extended therapy with cefepime may be associated with the development of neutropenia. In a comparative case review study in adult patients receiving long-term (6 weeks) cefepime therapy or other IV antimicrobial agents for osteomyelitis, 8 (62%) courses of cefepime (13 courses in 12 patients) resulted in neutropenia compared to none for the other antimicrobials (121 courses in 120 patients). Two cases of reversible, severe neutropenia (absolute neutrophil count of 39 and 20 cells/mm3, respectively) have also been reported in pediatric patients receiving prolonged cefepime therapy (approximately 3 weeks). Other adverse events associated with the cephalosporin class include aplastic anemia, hemolytic anemia, bleeding/hemorrhage, and pancytopenia.

Increased BUN (azotemia) and creatinine were reported in > 0.1% to < 1% of patients in cefepime clinical trials. Renal dysfunction and toxic nephropathy have been associated with the cephalosporin class of antibiotics.

Abnormal laboratory values reported during cefepime clinical trials include hypophosphatemia (2.8%), hypercalcemia (> 0.1% to < 1%), hyperphosphatemia (> 0.1% to < 1%), hyperkalemia (> 0.1% to < 1%), and hypocalcemia (> 0.1% to < 1%).

Cefepime is contraindicated in patients with cephalosporin hypersensitivity or cephamycin hypersensitivity. Cefepime should be used cautiously in patients with hypersensitivity to penicillin. The structural similarity between cefepime and penicillin means that cross-reactivity can occur. Penicillins can cause a variety of hypersensitivity reactions ranging from mild rash to fatal anaphylaxis. Patients who have experienced severe penicillin hypersensitivity should not receive cefepime. Cross-reactivity to cephalosporins is approximately 3% to 7% with a documented history to penicillin.

Cefepime is eliminated via renal mechanisms and should be used with caution in patients with renal impairment (creatinine clearance <= 60 mL/min) or renal failure; dosage adjustments are required for patients with renal impairment. Serious adverse events have occurred in patients with renal insufficiency given unadjusted doses of cefepime, including life-threatening or fatal encephalopathy, seizures, and non-convulsive status epilepticus. Although most reported cases occurred in patients with renal impairment who received doses of cefepime that exceeded the recommended dosage schedules, some cases of neurotoxicity have occurred in patients receiving an appropriate dosage adjustment for their renal function. In the majority of cases, symptoms of neurotoxicity resolved after discontinuation of cefepime and/or after hemodialysis. If neurotoxicity associated with drug therapy occurs, consider discontinuing therapy or making necessary dosage adjustments in patients with renal insufficiency. While data are unavailable for pediatric patients with impaired renal function, changes in dosing regimen similar to those for adults are recommended.

Consider pseudomembranous colitis in patients presenting with diarrhea after antibacterial use. Careful medical history is necessary as pseudomembranous colitis has been reported to occur over 2 months after the administration of antibacterial agents. Almost all antibacterial agents, including cefepime, have been associated with pseudomembranous colitis or C. difficile-associated diarrhea (CDAD) which may range in severity from mild to life-threatening. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile.

Many cephalosporins, including cefepime, have been rarely associated with a fall in prothrombin activity (hypoprothrombinemia). Those at risk include patients with renal or hepatic impairment, or poor nutritional state, as well as patients receiving a protracted course of antimicrobial therapy. Prothrombin time should be monitored in patients at risk, and exogenous vitamin K administered as indicated. Cephalosporins that contain the NMTT side chain (e.g., cefoperazone, cefamandole, cefotetan) have been particularly associated with an increased risk for bleeding. Cephalosporins should be used cautiously in patients with a preexisting coagulopathy (e.g., vitamin K deficiency, severe hepatic disease) because these patients may be at a higher risk for these complications.

Cefepime may cause laboratory test interference. Positive direct Coombs' tests have been reported during treatment with cefepime. In hematologic studies or in transfusion cross-matching procedures when antiglobulin tests are performed on the minor side or in Coombs' test of newborns whose mothers received cefepime before delivery, clinicians should keep in mind that a positive Coombs' test may be due to the drug. Discontinue cefepime and institute appropriate therapy in patients who develop hemolytic anemia. Also, a false-positive reaction for glucose in the urine has been observed in patients receiving cephalosporins, such as cefepime, and using Benedict's solution, Fehling's solution, or Clinitest tablets for urine glucose testing. However, this reaction has not been observed with glucose oxidase tests (e.g., Tes-tape, Clinistix, Diastix). Patients with diabetes mellitus who test their urine for glucose should use glucose tests based on enzymatic glucose oxidase reactions while on cefepime treatment.

Description: Cefepime is a parenteral broad-spectrum cephalosporin. Its pharmacokinetics and gram-negative spectrum of activity are similar to ceftazidime, a 'third-generation' cephalosporin, but because cefepime is also active against some organisms not covered by ceftazidime (e.g., certain gram-positive organisms), some consider cefepime to be 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. A meta-analysis evaluating the efficacy and safety of cefepime in adult patients reported a higher all-cause mortality in those treated with cefepime compared to other beta-lactams ; however, the FDA conducted additional analyses and determined that the data did not indicate a higher rate of death in cefepime-treated patients. A meta-analysis of pediatric clinical studies (n = 16) did not reveal higher all-cause mortality rates with cefepime compared with other beta-lactam antibiotics. Serious adverse events have occurred in patients with renal insufficiency given unadjusted doses of cefepime, including life-threatening or fatal encephalopathy and seizures. Cefepime is FDA-approved for use in pediatric patients as young as 2 months of age.

Per the manufacturer, this drug has been shown to be active against most strains of the following microorganisms either in vitro and/or in clinical infections: Acinetobacter calcoaceticus, Acinetobacter lwoffii, Citrobacter diversus, Citrobacter freundii, Enterobacter sp., Escherichia coli, Haemophilus influenzae (beta-lactamase negative), Haemophilus influenzae (beta-lactamase positive), Hafnia alvei, Klebsiella oxytoca, Klebsiella pneumoniae, Moraxella catarrhalis, Morganella morganii, Pantoea agglomerans, Proteus mirabilis, Proteus vulgaris, Providencia rettgeri, Providencia stuartii, Pseudomonas aeruginosa, Serratia marcescens, Staphylococcus aureus (MSSA), Staphylococcus epidermidis, Staphylococcus saprophyticus, Streptococcus agalactiae (group B streptococci), Streptococcus pneumoniae, Streptococcus pyogenes (group A beta-hemolytic streptococci), Viridans streptococci
NOTE: The safety and effectiveness in treating clinical infections due to organisms with in vitro data only have not been established in adequate and well-controlled clinical trials.

This drug may also have activity against the following microorganisms: Aeromonas hydrophila, Gardnerella vaginalis, Neisseria gonorrhoeae, Neisseria meningitidis, Salmonella sp., Serratia liquefaciens, Shigella sp., Streptococcus bovis, Yersinia enterocolitica
NOTE: Some organisms may not have been adequately studied during clinical trials; therefore, exclusion from this list does not necessarily negate the drug's activity against the organism.

For empiric monotherapy of febrile neutropenia:
NOTE: Data are insufficient to support the efficacy of cefepime monotherapy in patients at high risk for severe infection (including patients with a history of recent bone marrow transplant, hypotension at presentation, underlying hematologic malignancy, or severe or prolonged neutropenia).
Intravenous dosage:
Infants 2 to 11 months, Children, and Adolescents: 50 mg/kg/dose IV every 8 hours (Max: 2 g/dose) for 7 days or until resolution of neutropenia. For patients whose fever resolves but who remain neutropenic for more than 7 days, the need for continued antimicrobial therapy should be reevaluated.

For the treatment of moderate to severe uncomplicated skin and skin structure infections:
Intravenous dosage:
Neonates younger than 36 weeks gestation*: 30 mg/kg/dose IV every 12 hours.
Neonates 36 weeks gestation and older*: 50 mg/kg/dose IV every 12 hours. May give 30 mg/kg/dose IV every 12 hours if target pathogen MIC is 4 mg/L or less.
Infants 1 month*: 50 mg/kg/dose IV every 12 hours.
Infants, Children, and Adolescents 2 months to 17 years: 50 mg/kg/dose (Max: 2 g/dose) IV every 12 hours for 10 days.

For the treatment of pneumonia, including community-acquired pneumonia (CAP), nosocomial pneumonia, and cases associated with concurrent bacteremia:
Intravenous dosage:
Neonates younger than 36 weeks gestation*: 30 mg/kg/dose IV every 12 hours.
Neonates 36 weeks gestation and older*: 50 mg/kg/dose IV every 12 hours. May give 30 mg/kg/dose IV every 12 hours if target pathogen MIC is 4 mg/L or less.
Infants 1 month*: 50 mg/kg/dose IV every 12 hours. For infections caused by P. aeruginosa, 50 mg/kg/dose IV every 8 hours.
Infants, Children, and Adolescents 2 months to 17 years: 50 mg/kg/dose (Max: 2 g/dose) IV every 12 hours for 10 days. For infections caused by P. aeruginosa, 50 mg/kg/dose (Max: 2 g/dose) IV every 8 hours.

For the treatment of uncomplicated and complicated urinary tract infection (UTI), including pyelonephritis:
-for the treatment of mild to moderate UTI, including pyelonephritis:
Intravenous or Intramuscular dosage:
Neonates younger than 36 weeks gestation*: 30 mg/kg/dose IV every 12 hours. Neonates are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Neonates 36 weeks gestation and older*: 50 mg/kg/dose IV every 12 hours. May give 30 mg/kg/dose IV every 12 hours if target pathogen MIC is less than 4 mg/L. Neonates are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Infants younger than 2 months*: 50 mg/kg/dose IV or IM every 12 hours. Infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Infants, Children, and Adolescents 2 months to 17 years: 50 mg/kg/dose (Max: 1 g/dose) IV or IM every 12 hours. Treat for 24 to 48 hours or until patient is clinically stable and afebrile, followed by oral antibiotics for a total duration of 7 to 14 days.
-for the treatment of severe UTI, including pyelonephritis:
Intravenous dosage:
Neonates younger than 36 weeks gestation*: 30 mg/kg/dose IV every 12 hours. Neonates are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Neonates 36 weeks gestation and older*: 50 mg/kg/dose IV every 12 hours. May give 30 mg/kg/dose IV every 12 hours if target pathogen MIC is less than 4 mg/L. Neonates are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Infants younger than 2 months*: 50 mg/kg/dose IV every 12 hours. Infants younger than 2 to 3 months are at risk for systemic infection and rapid change in their clinical condition. Treat UTIs as presumed pyelonephritis in these patients.
Infants, Children, and Adolescents 2 months to 17 years: 50 mg/kg/dose (Max: 2 g/dose) IV every 12 hours. Treat for 24 to 48 hours or until patient is clinically stable and afebrile, followed by oral antibiotics for a total duration of 7 to 14 days.

For the treatment of intraabdominal infections, including peritonitis, appendicitis, intraabdominal abscess, and peritoneal dialysis-related peritonitis*:
-for the general treatment of complicated intraabdominal infections:
Intravenous dosage:
Neonates less than 36 weeks gestation*: 30 mg/kg/dose IV every 12 hours. FDA-labeling for other populations suggests a duration of 7 to 10 days.
Neonates 36 weeks gestation and older*: 50 mg/kg/dose IV every 12 hours. May give 30 mg/kg/dose IV every 12 hours if target pathogen MIC is 4 mg/L or less. FDA-labeling for other populations suggests a duration of 7 to 10 days.
Infants*, Children*, and Adolescents* 1 month to 16 years: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 to 12 hours. FDA-labeling for other populations suggests a duration of 7 to 10 days.
Adolescent 17 years: 2 g IV every 8 to 12 hours as part of combination therapy for 7 to 10 days.
-for the treatment of complicated community-acquired, healthcare-acquired, or hospital-acquired intraabdominal infections with adequate source control:
Intravenous dosage:
Neonates less than 36 weeks gestation*: 30 mg/kg/dose IV every 12 hours as part of combination therapy for 7 to 10 days.
Neonates 36 weeks gestation and older*: 50 mg/kg/dose IV every 12 hours for as part of combination therapy 7 to 10 days. May give 30 mg/kg/dose IV every 12 hours if target pathogen MIC is 4 mg/L or less.
Infants*, Children*, and Adolescents* 1 month to 16 years: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 to 12 hours as part of combination therapy for 3 to 7 days. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.
Adolescent 17 years: 1 to 2 g IV every 8 to 12 hours as part of combination therapy for 3 to 7 days. Complicated infections include peritonitis and appendicitis complicated by rupture, and intraabdominal abscess.
-for the treatment of uncomplicated intraabdominal infections*:
Intravenous dosage:
Infants, Children, and Adolescents 1 month to 16 years: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 to 12 hours as part of combination therapy. Antibiotics should be discontinued within 24 hours. Uncomplicated infections include acute appendicitis without perforation, abscess, or local peritonitis; traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.
Adolescent 17 years: 1 to 2 g IV every 8 to 12 hours as part of combination therapy. Antibiotics should be discontinued within 24 hours. Uncomplicated infections include acute appendicitis without perforation, abscess, or local peritonitis; traumatic bowel perforations repaired within 12 hours; acute cholecystitis without perforation; and ischemic, non-perforated bowel.
-for the treatment of peritoneal dialysis-related peritonitis*:
Intermittent Intraperitoneal dosage*:
Infants, Children, and Adolescents: 15 mg/kg intraperitoneally every 24 hours for 14 to 21 days.
Continuous Intraperitoneal dosage*:
Infants, Children, and Adolescents: 500 mg/L intraperitoneal loading dose, followed by 125 mg/L in each dialysate exchange. Treat for 14 to 21 days.

For the treatment of meningitis* and ventriculitis*:
-for the treatment of meningitis* or ventriculitis* due to H. influenzae:
Intravenous dosage:
Neonates younger than 36 weeks gestation: 30 mg/kg/dose IV every 12 hours for 7 days. Although cefepime is included as a treatment option in guidelines for treatment of bacterial meningitis, the FDA-approved labeling recommends alternate therapy in children with meningitis or in those whom meningeal seeding from a distant site has occurred.
Neonates 36 weeks gestation and older: 50 mg/kg/dose IV every 12 hours for 7 days. Although cefepime is included as a treatment option in guidelines for treatment of bacterial meningitis, the FDA-approved labeling recommends alternate therapy in children with meningitis or in those whom meningeal seeding from a distant site has occurred.
Infants, Children, and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 hours for 7 days. Although cefepime is included as a treatment option in guidelines for treatment of bacterial meningitis, the FDA-approved labeling recommends alternate therapy in children with meningitis or in those whom meningeal seeding from a distant site has occurred.
-for the treatment of pneumococcal meningitis* or ventriculitis*:
Intravenous dosage:
Neonates younger than 36 weeks gestation: 30 mg/kg/dose IV every 12 hours for 10 to 14 days. Although cefepime is included as a treatment option in guidelines for treatment of bacterial meningitis, the FDA-approved labeling recommends alternate therapy in children with meningitis or in those whom meningeal seeding from a distant site has occurred.
Neonates 36 weeks gestation and older: 50 mg/kg/dose IV every 12 hours for 10 to 14 days. Although cefepime is included as a treatment option in guidelines for treatment of bacterial meningitis, the FDA-approved labeling recommends alternate therapy in children with meningitis or in those whom meningeal seeding from a distant site has occurred.
Infants, Children, and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 hours for 10 to 14 days. Although cefepime is included as a treatment option in guidelines for treatment of bacterial meningitis, the FDA-approved labeling recommends alternate therapy in children with meningitis or in those whom meningeal seeding from a distant site has occurred.
-for the treatment of meningitis* or ventriculitis* due to gram-negative organisms:
Intravenous dosage:
Neonates younger than 36 weeks gestation: 30 mg/kg/dose IV every 12 hours for 2 weeks beyond the first sterile CSF culture or at least 21 days, whichever is longer. Although cefepime is included as a treatment option in guidelines for treatment of bacterial meningitis, the FDA-approved labeling recommends alternate therapy in children with meningitis or in those whom meningeal seeding from a distant site has occurred.
Neonates 36 weeks gestation and older: 50 mg/kg/dose IV every 12 hours for 2 weeks beyond the first sterile CSF culture or at least 21 days, whichever is longer. Although cefepime is included as a treatment option in guidelines for treatment of bacterial meningitis, the FDA-approved labeling recommends alternate therapy in children with meningitis or in those whom meningeal seeding from a distant site has occurred.
Infants, Children, and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 hours for 10 to 21 days. Although cefepime is included as a treatment option in guidelines for treatment of bacterial meningitis, the FDA-approved labeling recommends alternate therapy in children with meningitis or in those whom meningeal seeding from a distant site has occurred.

For the treatment of infective endocarditis*:
Intravenous dosage:
Neonates less than 36 weeks gestation: 30 mg/kg/dose IV every 12 hours.
Neonates 36 weeks gestation and older: 50 mg/kg/dose IV every 12 hours. May give 30 mg/kg/dose IV every 12 hours if target pathogen MIC is 4 mg/L or less.
Infants: 50 mg/kg/dose IV every 8 to 12 hours.
Children and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 to 12 hours. Guidelines recommend cefepime plus vancomycin, gentamicin, and rifampin (if prosthetic material is present) for culture-negative nosocomial endocarditis associated with vascular cannulae or early (less than 1 year after surgery) prosthetic valve endocarditis; treat for 4 to 6 weeks, with a longer course for PVE. Cefepime is also a preferred therapy in combination with an aminoglycoside for at least 6 weeks for non-HACEK gram-negative microorganisms.

For the treatment of sepsis*:
Intravenous dosage:
Neonates younger than 36 weeks gestation: 30 mg/kg/dose IV every 12 hours.
Neonates 36 weeks gestation and older: 50 mg/kg/dose IV every 12 hours. May give 30 mg/kg/dose IV every 12 hours if target pathogen MIC is 4 mg/L or less. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well defined and dependent on patient- and infection-specific factors. Assess patient daily for de-escalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response. Neonates younger than 37 weeks gestational age were excluded from the scope of the Surviving Sepsis Campaign guidelines.
Infants, Children, and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 hours. Start within 1 hour for septic shock or within 3 hours for sepsis-associated organ dysfunction without shock. Duration of therapy is not well defined and dependent on patient- and infection-specific factors. Assess patient daily for de-escalation of antimicrobial therapy based on pathogen identification and/or adequate clinical response.

For the treatment of bone and joint infections*, including osteomyelitis*, infectious arthritis*, and infectious bursitis*:
-for the treatment of osteomyelitis*:
Intravenous dosage:
Neonates younger than 36 weeks gestation: 30 mg/kg/dose IV every 12 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates 36 weeks gestation and older: 50 mg/kg/dose IV every 12 hours. May give 30 mg/kg/dose IV every 12 hours if target pathogen MIC is 4 mg/L or less. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants 1 to 2 months: 50 mg/kg/dose IV every 8 to 12 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants, Children, and Adolescents 3 months to 17 years: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 to 12 hours. Treat for 2 to 4 days or until clinically improved, followed by oral step-down therapy for a total duration of 3 to 4 weeks for uncomplicated cases. A longer course (i.e., 4 to 6 weeks or longer) may be needed for severe or complicated infections.
-for the treatment of infectious arthritis*:
Intravenous dosage:
Neonates younger than 36 weeks gestation: 30 mg/kg/dose IV every 12 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Neonates 36 weeks gestation and older: 50 mg/kg/dose IV every 12 hours. May give 30 mg/kg/dose IV every 12 hours if target pathogen MIC is 4 mg/L or less. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants 1 to 2 months: 50 mg/kg/dose IV every 8 to 12 hours. Treat for 14 to 21 days or until clinically improved, followed by oral step-down therapy for a total duration of 4 to 6 weeks. A longer course (several months) may be needed for severe or complicated infections.
Infants, Children, and Adolescents 3 months to 17 years: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 to 12 hours. Treat for 2 to 4 days or until clinically improved, followed by oral step-down therapy for a total duration of 2 to 3 weeks for uncomplicated cases. A longer course (i.e., 4 to 6 weeks or longer) may be needed for septic hip arthritis or severe or complicated infections.
-for the treatment of infectious bursitis*:
Intravenous dosage:
Children and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 to 12 hours for 2 to 3 weeks. Generally, 2 weeks is appropriate for most patients; immunocompromised patients may require a longer duration.

Maximum Dosage Limits:
-Neonates
Neonates less than 36 weeks gestation: Safety and efficacy have not been established; however, doses up to 60 mg/kg/day IV have been used off-label.
Neonates 36 weeks gestation and older: Safety and efficacy have not been established; however, doses up to 100 mg/kg/day IV have been used off-label.
-Infants
1 month: Safety and efficacy have not been established; however, doses up to 150 mg/kg/day IV or 100 mg/kg/day IM have been used off-label.
2 to 11 months: 150 mg/kg/day IV or 100 mg/kg/day IM.
-Children
150 mg/kg/day IV (Max: 6 g/day) or 100 mg/kg/day IM (Max: 2 g/day).
-Adolescents
150 mg/kg/day IV (Max: 6 g/day) or 100 mg/kg/day IM (Max: 2 g/day).

Patients with Hepatic Impairment Dosing
No dosage adjustment is required.

Patients with Renal Impairment Dosing
Pediatric patients (non-neonatal)
Specific data in pediatric patients with impaired renal function are not available. Because cefepime pharmacokinetics are similar in adults and non-neonatal pediatric patients, changes in the dosage regimen proportional to those in adults are recommended for pediatric patients. The below recommendations for maintenance dose adjustments in pediatric patients are consistent with recommendations for adult patients with renal impairment.

Pediatric patients receiving a usual dose of 50 mg/kg/dose IV every 12 hours with a Max of 1 g/dose (FDA-labeling)

CrCl more than 60 mL/minute: No dosage adjustment needed.
CrCl 30 to 60 mL/minute: 50 mg/kg/dose (Max: 1 g/dose) IV every 24 hours.
CrCl 11 to 29 mL/minute: 50 mg/kg/dose (Max: 1 g/dose) IV once, then 25 mg/kg/dose (Max: 500 mg/dose) IV every 24 hours.
CrCl less than 11 mL/minute: 50 mg/kg/dose (Max: 1 g/dose) IV once, then 12.5 mg/kg/dose (Max: 250 mg/dose) IV every 24 hours.

Pediatric patients receiving a usual dose of 50 mg/kg/dose IV every 12 hours with a Max of 2 g/dose (FDA-labeling)

CrCl more than 60 mL/minute: No dosage adjustment needed.
CrCl 30 to 60 mL/minute: 50 mg/kg/dose (Max: 2 g/dose) IV every 24 hours.
CrCl 11 to 29 mL/minute: 50 mg/kg/dose (Max: 2 g/dose) IV once, then 25 mg/kg/dose (Max: 1 g/dose) IV every 24 hours.
CrCl less than 11 mL/minute: 50 mg/kg/dose (Max: 2 g/dose) IV once, then 12.5 mg/kg/dose (Max: 500 mg/dose) IV every 24 hours.

Pediatric patients receiving a usual dose of 50 mg/kg/dose IV every 8 hours (FDA-labeling)

CrCl more than 60 mL/minute: No dosage adjustment needed.
CrCl 30 to 60 mL/minute: 50 mg/kg/dose (Max: 2 g/dose) IV every 12 hours.
CrCl 11 to 29 mL/minute: 50 mg/kg/dose (Max: 2 g/dose) IV every 24 hours.
CrCl less than 11 mL/minute: 50 mg/kg/dose (Max: 2 g/dose) IV once, then 25 mg/kg/dose (Max: 1 g/dose) IV every 24 hours.

Pediatric patients (alternative)*
GFR more than 50 mL/minute/1.73 m2: No dosage adjustment needed.
GFR 10 to 50 mL/minute/1.73 m2: 50 mg/kg/dose (Max: 2 g/dose) IV every 24 hours.
GFR less than 10 mL/minute/1.73 m2: 50 mg/kg/dose (Max: 2 g/dose) IV every 48 hours.

Intermittent hemodialysis
NOTE: 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. Administer doses at the same time each day and after the completion of hemodialysis on hemodialysis days.

Pediatric patients receiving a usual dose of 50 mg/kg/dose IV every 12 hours (FDA-labeling)

25 mg/kg/dose (Max: 1 g/dose) IV on day 1, then 12.5 mg/kg/dose (Max: 500 mg/dose) IV every 24 hours thereafter.

Pediatric patients receiving a usual dose of 50 mg/kg/dose IV every 8 hours (FDA-labeling)

25 mg/kg/dose (Max: 1 g/dose) IV every 24 hours.

Alternative*
50 mg/kg/dose (Max: 2 g/dose) IV every 24 hours.

Peritoneal dialysis
FDA-approved labeling
For continuous ambulatory peritoneal dialysis (CAPD), FDA-labeling suggests administering recommended doses of cefepime as indicated for the infection and extend the dosing interval to every 48 hours.

Alternative*
50 mg/kg/dose (Max: 2 g/dose) IV every 24 hours.

Continuous renal replacement therapy (CRRT)*
NOTE: Various CRRT modalities include continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), continuous venovenous hemodiafiltration (CVVHDF), continuous venovenous high-flux hemodialysis (CVVHFD), continuous arteriovenous hemofiltration (CAVH), continuous arteriovenous hemodialysis (CAVHD), and continuous arteriovenous hemodiafiltration (CAVHDF). Dosing should take into consideration patient-specific factors (e.g., intrinsic renal function), type of infection, the duration of renal replacement therapy, the effluent flow rate, and the replacement solution administered. Pediatric recommendations are based on limited study data, mainly derived from adult patients, and extrapolation of CRRT clearance based on cefepime pharmacokinetic parameters.
25 to 50 mg/kg/dose (Max: 2 g/dose) IV every 12 hours.

Hybrid hemodialysis*
NOTE: Hybrid hemodialysis modalities include prolonged intermittent renal replacement therapy (PIRRT), sustained low-efficiency dialysis (SLED), slow extended daily dialysis/diafiltration (SLEDD-f), and extended daily dialysis (EDD). Dosing should take into consideration patient-specific factors (e.g., intrinsic renal function), the type of infection, the duration of renal replacement therapy, the ultrafiltration rate, the dialysis flow rate, and how often dialysis sessions occur.
Cefepime dosing data are not available in pediatric patients receiving hybrid hemodialysis. Based on adult data, dosage adjustments may be necessary.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: 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 Aeromonas sp. and Vibrio sp.as susceptible at 2 mcg/mL or less, intermediate at 4 to 8 mcg/mL, and resistant at 16 mcg/mL or more based on a dosage regimen of 1 g IV every 12 hours. 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, Abiotrophia sp., Granulicatella sp., and Corynebacterium sp. 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. The MICs are defined for E. rhusiopathiae as susceptible at 1 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.

Pharmacokinetics: Cefepime is administered intravenously and intramuscularly. 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.

Intramuscular Route
Cefepime is well absorbed after IM administration. Cmax occurs approximately 1.5 hours after 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
Pediatrics
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.

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.

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
Data are limited in pediatric patients; however, 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.