VA Class:AM118

AHFS Class:

• Fourth Generation Cephalosporins 8:12.06.16

Generic Name(s):

• Cefepime Hydrochloride

Chemical Name:

• [6 R -(6α,7β( Z )]]-1-[[7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl]methyl] -1-methylpyrrolidinium chloride monohydrochloride monohydrate

Molecular Formula:

• C₁₉H₂₅ClN₆O₅S₂ • HCl • H ₂O

Associated Monographs

• Cephalosporins General Statement

Cefepime is a semisynthetic, fourth generation cephalosporin antibiotic.1,6

Cefepime is used for the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis),1,3,5,6,7,8,9,14,15,16,92,95 uncomplicated skin and skin structure infections,1,3,5,6,7,8,14,17,92,95 and moderate to severe pneumonia caused by susceptible organisms.1,5,8,14,15,92,95 For the treatment of complicated intra-abdominal infections, cefepime is used in conjunction with IV metronidazole.1,37,69,70,92,95 In addition, cefepime is used alone or in conjunction with other anti-infectives for empiric anti-infective therapy in febrile neutropenic patients.1,26,34,35,36,59,62,69,89,90,92,95

Intra-abdominal Infections

IV cefepime is used in conjunction with IV metronidazole for the treatment of complicated intra-abdominal infections caused by Escherichia coli , viridans streptococci, Pseudomonas aeruginosa , Klebsiella pneumoniae , Enterobacter , or Bacteroides fragilis in adults.1,37,70,92,95 Safety and efficacy of cefepime used in conjunction with metronidazole has been evaluated in a randomized, double-blind, multicenter study in adults with surgically confirmed complicated intra-abdominal infections who were randomized to receive cefepime (2 g IV every 12 hours) and metronidazole (7.5 mg/kg or 500 mg IV every 6 hours) or monotherapy with imipenem and cilastatin sodium (500 mg IV every 6 hours).1,37 The overall clinical cure rate was 88% in those who received combination therapy with cefepime and metronidazole and 76% in those who received monotherapy with imipenem and cilastatin sodium.37

For initial empiric treatment of high-risk or severe community-acquired extrabiliary intra-abdominal infections in adults (e.g., those with advanced age, immunocompromised state, severe physiologic disturbance), the Infectious Diseases Society of America (IDSA) recommends either monotherapy with a carbapenem (doripenem, imipenem, meropenem) or the fixed combination of piperacillin and tazobactam, or a combination regimen that includes either a cephalosporin (cefepime, ceftazidime) or fluoroquinolone (ciprofloxacin, levofloxacin) in conjunction with metronidazole.70 IDSA also recommends cefepime in conjunction with metronidazole as one of several regimens that can be used for initial empiric treatment of health-care associated complicated intra-abdominal infections in adults and community-acquired complicated intra-abdominal infections in pediatric patients.70 For additional information regarding management of intra-abdominal infections, the current IDSA clinical practice guidelines available at [Web] should be consulted.70

While cefepime has been effective when used alone for the treatment of acute obstetric and gynecologic infections† (e.g., pelvic inflammatory disease, pelvic surgical wound infection, postpartum endometritis),41 safety and efficacy of the drug for use as monotherapy in the treatment of such infections have not been established.1

Respiratory Tract Infections

Cefepime is used in adult and pediatric patients 2 months of age or older for the treatment of moderate to severe pneumonia, including that associated with concurrent bacteremia, caused by susceptible Streptococcus pneumoniae .1,5,8,14,15,92,95 The drug also is used in adult and pediatric patients 2 months of age or older for the treatment of moderate to severe pneumonia caused by susceptible Ps. aeruginosa , K. pneumoniae , or Enterobacter .1,5,8,14,15,92,95

Community-acquired Pneumonia

Cefepime appears to be at least as effective and as well tolerated as ceftriaxone or ceftazidime for the treatment of community-acquired pneumonia (CAP).40,43 In an open-label, randomized study in hospitalized adults who were randomized to receive 5-10 days (14 days maximum) of therapy with either cefepime (2 g IV every 12 hours) or ceftriaxone (1 g IV every 12 hours) for empiric treatment of CAP, a satisfactory clinical response (cure or improvement) was achieved in 95% of those receiving cefepime and 97.8% of those receiving ceftriaxone.43 When cefepime (1 g IV or IM every 12 hours) was compared with ceftazidime (1 g IV every 8 hours) for empiric therapy in adults 21-90 years of age with community-acquired lower respiratory tract infections, the clinical cure rate was 87% in those who received cefepime and 86% in those who received ceftazidime.40 The most common pathogens in these studies were S. pneumoniae , Haemophilus influenzae , Moraxella catarrhalis , and/or Staphylococcal aureus .40,43

The American Thoracic Society (ATS) and IDSA recommend use of cefepime in the treatment of CAP only when Ps. aeruginosa is known or suspected to be involved.56 Factors that increase the risk of Ps. aeruginosa infection in CAP patients include severe CAP requiring treatment in an intensive care unit (ICU), structural lung disease (bronchiectasis), severe chronic obstructive pulmonary disease (COPD), smoking, alcoholism, chronic corticosteroid therapy, and frequent anti-infective therapy.56 In CAP patients with risk factors for Ps. aeruginosa , the ATS and IDSA recommend use of an empiric combination regimen that includes an antipneumococcal, antipseudomonal β-lactam (cefepime, imipenem, meropenem, fixed combination of piperacillin and tazobactam) given in conjunction with a fluoroquinolone (ciprofloxacin, levofloxacin); a combination regimen that includes one of these antipseudomonal β-lactams, an aminoglycoside, and azithromycin; or a combination regimen that includes one of these antipseudomonal β-lactams, an aminoglycoside, and an antipneumococcal fluoroquinolone.56 The ATS and IDSA state that if Ps. aeruginosa has been identified by appropriate microbiologic testing, the preferred treatment regimen is an antipseudomonal β-lactam (cefepime, ceftazidime, aztreonam, imipenem, meropenem, piperacillin, ticarcillin) given in conjunction with ciprofloxacin, levofloxacin, or an aminoglycoside and the preferred alternative regimen is an aminoglycoside given in conjunction with ciprofloxacin or levofloxacin.56

For additional information on use of cephalosporins in the treatment of CAP, see Community-acquired Infections under Uses: Respiratory Tract Infections, in the Cephalosporins General Statement 8:12.06.

Nosocomial Infections

Cefepime is used in the treatment of nosocomial pneumonia.67,69 The ATS, IDSA, and other clinicians recommend use of an antipseudomonal cephalosporin (cefepime, ceftazidime), antipseudomonal penicillin (piperacillin and tazobactam, ticarcillin and clavulanate), or an antipseudomonal carbapenem (imipenem or meropenem) for initial therapy of hospital-acquired pneumonia, ventilator-associated pneumonia, or health-care associated pneumonia because these drugs have a broad spectrum of activity against gram-positive, gram-negative, and anaerobic bacteria.67,69 In hospitals where methicillin-resistant S. aureus (MRSA; also known as oxacillin-resistant S. aureus or ORSA) is common or if there are risk factors for these strains, the initial regimen also should include vancomycin or linezolid.67,69

Skin and Skin Structure Infections

Cefepime is used in adult and pediatric patients 2 months of age or older for the treatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or susceptible Streptococcus pyogenes .1,3,5,6,7,8,14,17,92,95

Urinary Tract Infections

Cefepime is used in adult and pediatric patients 2 months of age or older for the treatment of severe uncomplicated and complicated urinary tract infections (including those associated with pyelonephritis and/or concurrent bacteremia) caused by susceptible E. coli or K. pneumoniae .1,6,7,14,45,92,95 Cefepime also is used in adult and pediatric patients 2 months of age or older for the treatment of mild to moderate uncomplicated and complicated urinary tract infections (including those associated with pyelonephritis and/or with concurrent bacteremia) when the causative organism is E. coli , K. pneumoniae , or Proteus mirabilis .1,3,5,6,8,9,16,92,95

Endocarditis

For empiric treatment of culture-negative endocarditis† in prosthetic valve recipients with early onset endocarditis (within 1 year after prosthetic valve placement), the American Heart Association (AHA) recommends a multiple-drug regimen that includes vancomycin, gentamicin, cefepime, and rifampin.94 Blood cultures are negative in up to 20% of patients with infective endocarditis because of inadequate microbiologic technique, infection with highly fastidious bacteria or nonbacterial pathogens, or administration of anti-infective agents prior to obtaining blood cultures.94 Selection of the most appropriate anti-infective regimen for the treatment of culture-negative endocarditis is difficult and should be guided by epidemiologic features and clinical course of the infection.94 Consultation with an infectious diseases specialist is recommended.94

Meningitis and Other CNS Infections

Cefepime has been used in adult and pediatric patients 2 months of age or older for the treatment of meningitis† caused by susceptible gram-negative bacteria (e.g., H. influenzae , Neisseria meningitidis , E. coli , E. aerogenes , Ps. aeruginosa ) or gram-positive bacteria (e.g., S. pneumoniae , S. aureus , S. epidermidis ).46,75,77,79,83,84 However, safety and efficacy of cefepime for the treatment of meningitis have not been established, and the manufacturers caution that an alternative anti-infective with demonstrated clinical efficacy in this setting should be used in patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented. 1,92,95

IDSA states that cefepime is one of several alternatives that can be used for the treatment of meningitis caused by H. influenzae or E. coli or treatment of meningitis caused by S. pneumonia susceptible to penicillins and third generation cephalosporins.75 For the treatment of meningitis caused by Ps. aeruginosa , IDSA and other experts recommend a regimen that consists of an antipseudomonal cephalosporin (cefepime or ceftazidime) or carbapenem (imipenem or meropenem) given with or without an aminoglycoside (amikacin, gentamicin, tobramycin).75,76 Treatment of these infections should be guided by results of in vitro susceptibility tests.75

IDSA also recommends a regimen of cefepime and vancomycin as one of several regimens that can be used in adult and pediatric patients for empiric treatment of penetrating head trauma or postneurosurgical infections caused by S. aureus , coagulase-negative staphylococci (especially S. epidermidis ), or aerobic gram-negative bacilli (including Ps. aeruginosa ).75

In a prospective, randomized study in infants and children 2 months to 15 years of age, IV cefepime was as effective as IV cefotaxime for the treatment of meningitis caused by susceptible gram-negative or gram-positive bacteria.46 However, some clinicians suggest that additional study is needed regarding cefepime's efficacy for the treatment of meningitis, particularly for infections caused by penicillin- and/or cefotaxime-resistant S. pneumoniae .46,79 In addition, it has been suggested that cefepime would not be a good choice for empiric treatment of meningitis if Acinetobacter may be involved.83

Septicemia

Cefepime is used for the treatment of septicemia† caused by susceptible gram-negative bacteria.69

The choice of anti-infective agent for the treatment of sepsis syndrome should be based on the probable source of infection, causative organism, immune status of the patient, and local patterns of bacterial resistance.69 For initial treatment of life-threatening sepsis in adults, some clinicians recommend that a third or fourth generation cephalosporin (cefepime, cefotaxime, ceftriaxone, ceftazidime), the fixed combination of piperacillin and tazobactam, or a carbapenem (imipenem or meropenem) be used in conjunction with vancomycin; some experts also suggest including an aminoglycoside or fluoroquinolone during the initial few days of treatment.69

Empiric Therapy in Febrile Neutropenic Patients

Cefepime is used in adult and pediatric patients 2 months of age or older as monotherapy for empiric anti-infective therapy of presumed bacterial infections in febrile neutropenic patients.1,26,34,35,36,58,59,62,69,89,90,92,95 The manufacturers caution that use of monotherapy for empiric therapy in patients at high risk for severe infection (e.g., those with a history of recent bone marrow transplantation, hypotension on presentation, underlying hematologic malignancy, or severe or prolonged neutropenia) may not be appropriate and data regarding efficacy of cefepime monotherapy in these patients is limited to date.1,92,95

Safety and efficacy of cefepime monotherapy for empiric therapy in febrile neutropenic patients were initially evaluated in a pilot study that involved 84 granulocytopenic cancer patients who received cefepime (2 g IV every 8 hours) for a minimum of 7 days or until infections resolved; the overall response rate in these patients was 71%.34 Cefepime also has been used in conjunction with amikacin for empiric therapy in febrile neutropenic patients in an open-label, randomized study in adults with chemotherapy-induced neutropenia who were considered at high risk of infection.25 Patients were randomized to receive empiric therapy with a combination regimen of cefepime (2 g IV every 12 hours) and amikacin (7.5 mg/kg every 12 hours) or ceftazidime (2 g IV every 8 hours) and amikacin (7.5 mg/kg every 12 hours); both regimens were comparable in terms of clinical response, rates of bacteriologic eradication, incidence of new infection, and survival.25

There is evidence from open-label, randomized studies in febrile neutropenic patients that empiric therapy with cefepime monotherapy is as effective as empiric monotherapy with ceftazidime,35,58,62 imipenem,59 or the fixed combination of piperacillin and tazobactam90 or empiric treatment with combination regimens that consist of piperacillin sodium and gentamicin sulfate36 or ceftriaxone and amikacin.89

Successful treatment of infections in granulocytopenic patients requires prompt initiation of empiric anti-infective therapy (even when fever is the only sign or symptom of infection) and appropriate modification of the initial regimen if the duration of fever and neutropenia is protracted, if a specific site of infection is identified, or if organisms resistant to the initial regimen are present.26,32,35,38,54 The initial empiric regimen should be chosen based on the underlying disease and other host factors that may affect the degree of risk and on local epidemiologic data regarding the type, frequency of occurrence, in vitro susceptibility of bacterial isolates recovered from other patients in the same health-care facility, and the individual patient's pattern of colonization and resistance.26,32,38,53,54 The fact that gram-positive bacteria have become a predominant pathogen in febrile neutropenic patients should be considered when selecting an empiric anti-infective regimen.26,32,38 However, although gram-positive bacteria reportedly account for about 60% and gram-negative bacteria account for about 35% of microbiologically documented infections, gram-negative infections are associated with greater mortality.26

No empiric regimen has been identified that would be appropriate for initial treatment of all febrile neutropenic patients.26,32,38,54 The IDSA recommends use of a parenteral empiric regimen in most febrile neutropenic patients; use of an oral regimen (e.g., oral ciprofloxacin and oral amoxicillin and clavulanate potassium) should be considered only for selected adults at low risk for complications who have adequate and stable renal and hepatic function, an expected duration of neutropenia less than 7 days, and no active medical comorbidities.26 All other patients are considered high risk and should receive an initial IV empiric regimen consisting of an antipseudomonal β-lactam (e.g., cefepime, imipenem, meropenem, fixed-combination of piperacillin and tazobactam).26 Other anti-infectives (e.g., aminoglycosides, fluoroquinolones, and/or vancomycin) may be added to the regimen for the management of complications (e.g., pneumonia) or when antimicrobial resistance is suspected or proven.26 Vancomycin or other anti-infectives active against aerobic gram-positive cocci are not usually included in the initial empiric regimen except in certain clinical scenarios, including suspected catheter-related infections, skin and soft tissue infections, pneumonia, or hemodynamic instability.26

Regardless of the initial regimen selected, patients should be reassessed daily and the anti-infective regimen altered (if indicated) based on the presence or absence of fever, identification of the causative organism, and the clinical condition of the patient; anti-infectives active against gram-positive organisms may be discontinued after 2 days if there is no evidence of such infections.26

Published protocols for the treatment of infections in febrile neutropenic patients should be consulted for specific recommendations regarding selection of the initial empiric anti-infective regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients.26 In addition, consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients is advised.26

For additional information on the role of parenteral cephalosporins in the treatment of these and other infections, see Uses in the Cephalosporins General Statement 8:12.06.

Reconstitution and Administration

Cefepime preferably is administered by IV infusion1,3,5,6,12,14,16,92 but also can be given by deep IM injection when indicated depending on the severity of the infection being treated.1,3,5,6,12,14,16

The manufacturer states that IM administration of the drug is indicated only for the treatment of mild to moderate uncomplicated or complicated urinary tract infections caused by Escherichia coli and only when this route is considered more appropriate1,5

If an aminoglycoside, ampicillin (at a concentration exceeding 40 mg/mL), metronidazole, vancomycin, or aminophylline is administered concomitantly with cefepime, the drugs should be administered separately.1,92,95

Reconstituted and diluted solutions of cefepime should be inspected visually for particulate matter prior to administration whenever solution and container permit.1

Intermittent IV Infusion

For intermittent IV infusion, vials labeled as containing 500 mg, 1 g, or 2 g of cefepime should be reconstituted with 5, 10, or 10 mL, respectively, of a compatible IV solution to provide solutions containing approximately 100, 100, or 160 mg/mL of the drug, respectively.1 The appropriate dose of the drug should then be added to a compatible IV solution.1

Alternatively, ADD-Vantage^® vials containing 1 or 2 g of cefepime should be reconstituted with 50 or 100 mL, respectively, of 0.9% sodium chloride or 5% dextrose injection according to the manufacturer's directions and administered by IV infusion.1

Another alternative is the commercially available Duplex^® drug delivery system that contains 1 or 2 g of cefepime and 50 mL of 5% dextrose injection in separate chambers, which should be reconstituted (activated) according to the manufacturer's directions and administered by IV infusion.95 If stored in the refrigerator after reconstitution (see Chemistry and Stability: Stability), the solution should be allowed to reach room temperature prior to administration.95

Thawed solutions of the commercially available frozen premixed cefepime injection in dextrose should be administered only by IV infusion.92 The frozen injection should be thawed at room temperature (25°C) or under refrigeration (5°C); the injection should not be thawed by warming in a water bath or by exposure to microwave radiation.92 Precipitates that may have formed in the frozen injection usually will dissolve with little or no agitation when the injection reaches room temperature; potency is not affected.92 After thawing to room temperature, the injection should be agitated and the container checked for minute leaks by firmly squeezing the bag; the container may be fragile and should be handled with care.92 The injection should be discarded if container seals or outlet ports are not intact or leaks are found or if the solution is cloudy or contains an insoluble precipitate.92 Additives should not be introduced into the injection container.92 The injection should not be used in series connections with other plastic containers, since such use could result in air embolism from residual air being drawn from the primary container before administration of fluid from the secondary container is complete.92

If a Y-type administration set is used, the other solution flowing through the tubing should be discontinued while cefepime is being infused.1,92,95

Rate of Administration

The cefepime dose should be administered by IV infusion over approximately 30 minutes.1,92,95

IM Injection

IM injections of cefepime are prepared by adding 1.3 or 2.4 mL of an appropriate diluent (i.e., sterile water for injection, 0.9% sodium chloride, 5% dextrose, 0.5 or 1% lidocaine hydrochloride, bacteriostatic water for injection with parabens or benzyl alcohol) to a vial labeled as containing 500 mg or 1 g of cefepime, respectively, to provide a solution containing approximately 280 mg/mL.1

Dosage

Cefepime is commercially available as cefepime hydrochloride, which is monohydrated; dosage is expressed in terms of cefepime, calculated on the anhydrous basis.1,92,95

Adult Dosage

Intra-abdominal Infections

For the treatment of complicated intra-abdominal infections (in conjunction with IV metronidazole), the usual adult dosage of cefepime is 2 g given IV every 12 hours for 7-10 days.1,92,95

For the treatment of complicated intra-abdominal infections (in conjunction with IV metronidazole), some experts recommend that adults receive cefepime in a dosage of 2 g every 8-12 hours for 4-7 days.70 A longer duration of treatment has not been associated with improved outcome and is not recommended unless adequate source control is difficult to achieve.70

Respiratory Tract Infections

For the treatment of moderate to severe pneumonia caused by Streptococcus pneumoniae (including those with concurrent bacteremia), the usual adult dosage of cefepime is 1-2 g given IV every 12 hours for 10 days.1,92,95

For initial treatment of hospital-acquired pneumonia, ventilator-associated pneumonia, or health-care associated pneumonia, some clinicians recommend that adults receive a cefepime dosage of 1-2 g every 8-12 hours.67

Skin and Skin Structure Infections

For the treatment of moderate to severe uncomplicated skin and skin structure infections caused by Staphylococcus aureus or Streptococcus pyogenes , the usual adult dosage of cefepime is 2 g IV every 12 hours for 10 days.1,92,95

Urinary Tract Infections

For the treatment of mild to moderate uncomplicated or complicated urinary tract infections (including those associated with pyelonephritis and/or with concurrent bacteremia), the usual adult dosage of cefepime is 0.5-1 g administered IV or IM every 12 hours for 7-10 days.1,92,95

For the treatment of severe uncomplicated or complicated urinary tract infections (including those associated with pyelonephritis and/or concurrent bacteremia), adults should received 2 g of cefepime IV every 12 hours for 10 days.1,92,95

Endocarditis

If cefepime is used in a multiple-drug regimen for empiric treatment of culture-negative endocarditis† in prosthetic valve recipients (see Uses: Endocarditis), the American Heart Association (AHA) recommends that adults receive IV cefepime in a dosage of 6 g daily given in 3 equally divided doses in conjunction with vancomycin (30 mg/kg daily given IV in 2 equally divided doses), gentamicin (3 mg/kg daily given IV or IM in 3 equally divided doses), and rifampin (900 mg daily given orally or IV in 3 equally divided doses).94 The multiple-drug regimen should be continued for 6 weeks; gentamicin should be discontinued after the first 2 weeks of treatment.94

Meningitis and Other CNS Infections

For the treatment of meningitis† in adults, the Infectious Diseases Society of America (IDSA) recommends that IV cefepime be given in a dosage of 2 g every 8 hours.75

IDSA states that the duration of therapy should be individualized based on response and recommends a duration of 7 days for infections caused by Haemophilus influenzae or Neisseria meningitidis , 10-14 days for infections caused by S. pneumoniae , or 21 days for infections caused by aerobic gram-negative bacilli.75

Empiric Therapy in Febrile Neutropenic Patients

When cefepime is used as monotherapy for empiric anti-infective therapy in febrile neutropenic patients, adults should receive a dosage of 2 g IV every 8 hours for 7 days or until neutropenia resolves.1,34,35,36,92,95 The need for continued anti-infective therapy in patients whose fever resolves but who remain neutropenic for longer than 7 days should be frequently reevaluated.1,92,95

Pediatric Dosage

General Pediatric Dosage

For the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, or pneumonia, the manufacturers recommend that pediatric patients 2 months to 16 years of age weighing less than 40 kg receive cefepime in a dosage of 50 mg/kg given IV every 12 hours.1,92,95 Pediatric dosage should not exceed the recommended adult dosage.1,92,95

Although safety and efficacy of cefepime have not been established in neonates or infants younger than 2 months of age,1,92,95 the American Academy of Pediatrics (AAP) states that neonates 28 days of age or younger† may receive IV or IM cefepime in a dosage of 30 mg/kg every 12 hours and that a dosage of 50 mg/kg every 12 hours may be required for Pseudomonas infections.64

The AAP states that pediatric patients beyond the neonatal period may receive IV or IM cefepime in a dosage of 100 mg/kg daily in 2 equally divided doses for the treatment of mild to moderate infections or a dosage of 100-150 mg/kg daily in 2 or 3 equally divided doses for the treatment of severe infections.64

To avoid unintentional overdosage, the manufacturers state that the commercially available Duplex^® drug delivery systems containing cefepime and the commercially available frozen premixed cefepime injection should not be used in pediatric patients who require less than the entire 1- or 2-g dose in the container.92,95

Intra-abdominal Infections

For the treatment of complicated intra-abdominal infections (in conjunction with IV metronidazole) in pediatric patients, some experts recommend a cefepime dosage of 50 mg/kg every 12 hours for 4-7 days.70 A longer duration of treatment has not been associated with improved outcome and is not recommended unless adequate source control is difficult to achieve.70

Endocarditis

If cefepime is used in a multiple-drug regimen for empiric treatment of culture-negative endocarditis† in prosthetic valve recipients (see Uses: Endocarditis), the AHA recommends that pediatric patients receive IV cefepime in a dosage of 150 mg/kg daily given in 3 equally divided doses in conjunction with vancomycin (40 mg/kg daily given IV in 2 or 3 equally divided doses), gentamicin (3 mg/kg daily given IV or IM in 3 equally divided doses), and rifampin (20 mg/kg daily given orally or IV in 3 equally divided doses).94 The multiple-drug regimen should be continued for 6 weeks; gentamicin should be discontinued after the first 2 weeks of treatment.94

Meningitis and Other CNS Infections

For the treatment of meningitis†, infants and children 2 months to 15 years of age have received IV cefepime in a dosage of 50 mg/kg every 8 hours for 7-10 days.46

IDSA states that the duration of therapy should be individualized based on response and recommends a duration of 7 days for infections caused by H. influenzae or N. meningitidis , 10-14 days for infections caused by S. pneumoniae , or 21 days for infections caused by aerobic gram-negative bacilli.75

Empiric Therapy in Febrile Neutropenic Patients

When cefepime is used as monotherapy for empiric anti-infective therapy in febrile neutropenic pediatric patients 2 months to 16 years of age who weigh less than 40 kg, the manufacturers recommend a dosage of 50 mg/kg given IV every 8 hours.1,92,95 The need for continued anti-infective therapy in patients whose fever resolves but who remain neutropenic for longer than 7 days should be frequently reevaluated.1,92,95

Dosage in Renal and Hepatic Impairment

In patients with renal impairment (i.e., creatinine clearance of 60 mL/minute or less), doses and/or frequency of administration of cefepime should be modified in response to the degree of renal impairment, severity of the infection, and susceptibility of the causative organism.1,92,93,95

The manufacturers recommend that adults with creatinine clearance of 60 mL/minute or less (not receiving hemodialysis) receive the same initial dose of cefepime recommended for patients with normal renal function followed by a maintenance dosage of cefepime based on the patient's measured or estimated creatinine clearance.1,3,18,19,92,95 (See Table 1 and Table 2.)

The manufacturers recommend that adults undergoing hemodialysis receive an initial 1-g dose of cefepime on day 1, then 500 mg once daily thereafter for the treatment of infections or 1 g once daily for empiric therapy of presumed bacterial infections in febrile neutropenic patients.1,92,95 The manufacturers also recommend that the daily dose be given at the same time of day whenever possible; on hemodialysis days, the dose should be given after the procedure.1,92,95

Adults undergoing continuous ambulatory peritoneal dialysis (CAPD) should receive the usual cefepime dose every 48 hours.1,6,10,12,92,95

Data regarding use of cefepime in pediatric patients with impaired renal function are not available.1,92 Because the pharmacokinetics of cefepime are similar in pediatric and adult patients, the manufacturers recommend that dosage modifications proportional to those recommended for adults be used in pediatric patients with impaired renal function.1,92

Since pharmacokinetics of cefepime appear not to be altered in patients with hepatic impairment, the manufacturers state that dosage adjustments are not necessary in such patients.1,92

Adverse Effects

Adverse effects reported with cefepime are similar to those reported with other parenteral cephalosporins.33 (See Cautions in the Cephalosporins General Statement 8:12.06.) Cefepime generally is well tolerated.1,3,5,6,7,9,24,33 Most adverse effects are transient and mild to moderate in severity,1,9,24,33 but have been severe enough to require discontinuance of the drug in up to 3% of patients.1,6,33 Headache,33 rash,1,24,33 diarrhea,1,24,33 nausea,1,24,33 and vomiting1,23,33 have been reported in up to 2% and local reactions, including phlebitis, pain and/or inflammation, and rash, have been reported in up to 3% of patients receiving cefepime in a dosage of 0.5-2 g every 12 hours.1 In patients receiving cefepime in a dosage of 2 g every 8 hours, rash occurred in 4%, diarrhea in 3%, nausea in 2%, and vomiting, headache, pruritus, or fever in 1% of patients.1 Neutropenia has been reported rarely in patients receiving cefepime.63

Precautions and Contraindications

Cefepime shares the toxic potentials of other cephalosporins, and the usual cautions, precautions, and contraindications associated with cephalosporin therapy should be observed.1

Sensitivity Reactions

Prior to initiation of cefepime therapy, careful inquiry should be made concerning previous hypersensitivity reactions to cefepime, cephalosporins, penicillins, or other drugs.1,92,95 There is clinical and laboratory evidence of partial cross-allergenicity among cephalosporins and other β-lactam antibiotics, including penicillins and cephamycins.1,28,29,95

Cefepime is contraindicated in patients who are hypersensitive to the drug or other cephalosporins and should be used with caution in patients with a history of hypersensitivity to penicillins.1,92,95 Use of cephalosporins generally should be avoided in patients who have had an immediate-type (anaphylactic) hypersensitivity reaction to penicillins.1,29

The manufacturers of the commercially available Duplex^® drug delivery system containing cefepime and dextrose injection and the commercially available frozen premixed cefepime injection in dextrose state that solutions containing dextrose may be contraindicated in patients with known allergy or hypersensitivity to corn or corn products.92,95

Anaphylaxis, including anaphylactic shock, has been reported in a few patients receiving cefepime.1,33

If a hypersensitivity reaction occurs during cefepime therapy, the drug should be discontinued and the patient treated with appropriate therapy (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen) as indicated.1,92,95

Neurotoxicity

Serious adverse events, including life-threatening or fatal encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, and coma), myoclonus, and seizures, have been reported in patients receiving cefepime during postmarketing experience.1,85,86,87,88,91,92,95 Nonconvulsive status epilepticus, characterized by alteration of consciousness without convulsions that is associated with continuous epileptiform EEG activity, also has been reported.1,85,91,93

Most cases of cefepime-associated neurotoxicity have occurred in patients with renal impairment who received a cefepime dosage that exceeded the recommended dosage for such patients.1,85,86,87,88,91,92,93,95 However, some cases of neurotoxicity occurred in patients who received a dosage appropriately adjusted for renal impairment1,92,93,95 or in patients with normal renal function.87,88 In most reported cases, symptoms of neurotoxicity were reversible and resolved after discontinuance of cefepime and/or after hemodialysis.1,86,92,93,95

If neurotoxicity associated with cefepime therapy occurs, consideration should be given to discontinuing the drug or making appropriate dosage adjustments based on the patient's renal function.1,92,93,95 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Patients should be advised that neurologic adverse events can occur and to immediately contact a clinician if any neurologic signs and symptoms, including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, coma), myoclonus, seizures, or nonconvulsive status epilepticus, occur since immediate treatment, dosage adjustment, or discontinuance of cefepime therapy is required.1,92,93,95

Increased Mortality

In November 2007, FDA announced that a safety review of cefepime was initiated after a published meta-analysis described a higher risk of all-cause mortality in patients treated with cefepime compared with patients treated with comparator β-lactams.72,73,74 The published meta-analysis looked at all-cause mortality data from 57 randomized controlled trials that compared cefepime with other β-lactams for various indications and found a risk ratio of 1.26 in those who received cefepime.71 FDA began working with Bristol-Myers Squibb to further evaluate the findings presented in the published meta-analysis and additional safety data.72,73,74

On June 17, 2009, FDA announced that, although the safety review is ongoing, it has determined that cefepime remains an appropriate therapy for its approved indications based on results of FDA's additional meta-analyses.74 FDA performed meta-analyses based on both trial- and patient-level data derived from all available cefepime comparative clinical trials.74 FDA's trial-level meta-analysis included data from 88 clinical trials (total of 9467 cefepime-treated patients and 8288 comparator-treated patients) and found no statistically significant differences in mortality between cefepime and the comparator drugs.74 Results of the trial-level meta-analysis indicated that all-cause mortality rates 30 days after treatment were 6.21% for cefepime-treated patients and 6% for comparator-treated patients.74 FDA's patient-level meta-analysis included data from 35 clinical trials and results indicated that all-cause mortality rates 30 days after treatment were 5.63% for cefepime-treated patients and 5.68% for comparator-treated patients.74 In addition, in a trial-level meta-analysis of 24 febrile neutropenia trials, there was no statistically significant increase in mortality in cefepime-treated patients compared with comparator-treated patients.74 A review of deaths reported in 7 of these febrile neutropenia trials indicated that most patients appeared to have died from their underlying malignancies and/or comorbid conditions.74

Selection and Use of Anti-infectives

To reduce development of drug-resistant bacteria and maintain effectiveness of cefepime and other antibacterials, the drug should be used only for the treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.1,92,95 When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing.1,92,95 In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.1,92,95

Patients should be advised that antibacterials (including cefepime) should only be used to treat bacterial infections and not used to treat viral infections (e.g., the common cold).1,92,95 Patients also should be advised about the importance of completing the full course of therapy, even if feeling better after a few days, and that skipping doses or not completing therapy may decrease effectiveness and increase the likelihood that bacteria will develop resistance and will not be treatable with cefepime or other antibacterials in the future.1,92,95

Superinfection/Clostridium difficile-associated Diarrhea and Colitis

As with other anti-infectives, prolonged cefepime therapy may result in overgrowth of nonsusceptible organisms.1,92 Careful observation of the patient is essential.1,92,95 If superinfection occurs, appropriate therapy should be initiated.1,92,95

Treatment with anti-infectives alters the normal colon flora and may permit overgrowth of Clostridium difficile .1,92,95,96 C. difficile infection (CDI) and C. difficile -associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) have been reported with nearly all anti-infectives, including cefepime, and may range in severity from mild diarrhea to fatal colitis.1,92,95,96 C. difficile produces toxins A and B, which contribute to the development of CDAD;1,92,95,96 hypertoxin-producing strains of C. difficile are associated with increased morbidity and mortality since these infections may be refractory to anti-infective therapy and may require colectomy.1,92,95

CDAD should be considered in the differential diagnosis of patients who develop diarrhea during or after anti-infective therapy.1,92,95,96 Careful medical history is necessary since CDAD has been reported to occur as late as 2 months or longer after anti-infective therapy is discontinued.1,92,95

If CDAD is suspected or confirmed, anti-infective therapy not directed against C. difficile should be discontinued whenever possible.1,92,95,96 Patients should be managed with appropriate supportive therapy (e.g., fluid and electrolyte management, protein supplementation), anti-infective therapy directed against C. difficile (e.g., metronidazole, vancomycin), and surgical evaluation as clinically needed.1,92,95,96

Patients should be advised that diarrhea is a common problem caused by anti-infectives and usually resolves when the drug is discontinued; however, they should contact a clinician if severe watery or bloody diarrhea develops.1,92,95

Other Precautions and Contraindications

Cefepime should be used with caution in patients with a history of GI disease, particularly colitis.1,92,95 (See Superinfection/Clostridium difficile-associated Diarrhea and Colitis under Cautions: Precautions and Contraindications.)

Commercially available cefepime preparations contain l-arginine to adjust pH.1,92,95 (See Chemistry and Stability: Chemistry.) At concentrations 33 times higher than the amount provided by the maximum recommended human cefepime dosage, arginine has been shown to alter glucose metabolism and transiently increase serum potassium concentrations.1,92,95 The effect of lower arginine concentrations is not known.1,92,95

Like other dextrose-containing solutions, the commercially available Duplex^® drug delivery system containing cefepime and 5% dextrose injection should be used with caution in patients with overt or known subclinical diabetes mellitus or in patients with carbohydrate intolerance for any reason.95

High or prolonged serum cefepime concentrations can occur if usual dosage is used in patients with renal impairment or other conditions that may compromise renal function.1,92,95 Serious adverse events, including life-threatening or fatal encephalopathy, may occur if inappropriate cefepime dosage is used in patients with impaired renal function.1,85,86,87,91,92,95 (See Neurotoxicity under Cautions: Precautions and Contraindications.) The maintenance dosage of cefepime should be decreased whenever the drug is used in patients with renal impairment (i.e., creatinine clearance 60 mL/minute or less) and continued dosage should be determined by the degree of renal impairment, severity of the infection, and susceptibility of the causative organisms.1,92,95 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

For a more complete discussion of these and other precautions associated with the use of cefepime, see Cautions: Precautions and Contraindications in the Cephalosporins General Statement 8:12.06.

Pediatric Precautions

Safety and efficacy of cefepime have not been established in neonates or infants younger than 2 months of age.1,92,95

Safety and efficacy of cefepime have been established for use in pediatric patients 2 months to 16 years of age for the treatment of uncomplicated and complicated urinary tract infections (including pyelonephritis), uncomplicated skin and skin structure infections, and pneumonia and for empiric therapy for febrile neutropenic patients.1,92,95 Use of cefepime in this age group is supported by evidence from adequate and well-controlled studies evaluating the drug in adults and additional pharmacokinetic and safety data from pediatric studies.1,92,95

Adverse effects reported when cefepime was used in pediatric patients 2 months to 16 years of age have been similar to those reported in adults.1

The manufacturers caution that cefepime should not be used in pediatric patients of any age for the treatment of serious infections that are suspected or known to be caused by Haemophilus influenzae type b (Hib) and states that pediatric patients in whom meningeal seeding from a distant infection site or in whom meningitis is suspected or documented should receive an alternative anti-infective with demonstrated clinical efficacy in this setting.1,92,95

Although safety and efficacy for the treatment of meningitis† have not been established,1 cefepime has been used effectively in a limited number of children 2 months to 15 years of age for the treatment of meningitis caused by susceptible bacteria.46,75,77,79,83,84 (See Uses: Meningitis and Other CNS Infections.) In one study in pediatric patients with meningitis, adverse effects were reported in 18% of patients receiving cefepime and included diarrhea, macular rash, candidal thrush, and eosinophilia.46

The manufacturers state that the commercially available Duplex^® drug delivery system containing cefepime and the commercially available frozen premixed cefepime injection should be used in pediatric patients only if the entire 1- or 2-g dose in the container is required.92,95

Geriatric Precautions

Studies evaluating safety and efficacy of cefepime indicate that there are no age-related differences when the drug is used in geriatric patients or in younger adults.1,33,92,95

Cefepime is substantially eliminated by kidneys, and the risk of toxicity may be greater in those with impaired renal function.1,92,95 Serious adverse effects (e.g., life-threatening or fatal encephalopathy, myoclonus, or seizures) have occurred in geriatric patients with renal impairment who received cefepime dosages that were not adjusted based on the degree of renal impairment.1,92,95

Whenever cefepime is used in geriatric patients, select dosage with caution and monitor renal function because of age-related decreases in renal function.1,92,95 (See Dosage and Administration: Dosage in Renal and Hepatic Impairment.)

Mutagenicity and Carcinogenicity

In vivo and in vitro studies evaluating cefepime have not shown evidence of mutagenicity.1,92 Long-term animal studies have not been performed to evaluate the carcinogenic potential of the drug.1,57,92

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rats, rabbits, or mice using cefepime dosages approximately 1.6 times or 0.3 times, or equal to the recommended maximum human dosage (calculated on a mg/m² basis), respectively, have not revealed evidence of teratogenicity or embryotoxicity.1,92,95 There are no adequate and controlled studies using cefepime in pregnant women or during labor and delivery, and the drug should be used during pregnancy only when clearly needed.1,92,95

Fertility

Studies in rats using subcutaneous cefepime dosages 1.6 times the recommended maximum human dosage (calculated on a mg/m² basis) have not revealed evidence of impaired fertility.1,92

Lactation

Cefepime is distributed into milk in low concentrations following parenteral administration,1,6,92,95 and the drug should be used with caution in nursing women.1,92,95

Spectrum

Based on its spectrum of activity and decreased susceptibility to certain β-lactamases, cefepime is classified as a fourth generation cephalosporin.3,4,11,20,21,22 For information on the classification of cephalosporins and closely related β-lactam antibiotics based on spectra of activity, see Spectrum in the Cephalosporins General Statement 8:12.06.

Fourth generation cephalosporins (e.g., cefepime) usually have a spectrum of activity against gram-negative bacteria that includes organisms susceptible to most third generation cephalosporins;3,4 however, the drugs also are active against some gram-negative bacteria, including Pseudomonas aeruginosa and certain Enterobacteriaceae, that generally are resistant to most third generation cephalosporins.3,4,23 The activity of cefepime against Ps. aeruginosa is similar to that of ceftazidime.3,4,20,21 Cefepime is more active in vitro against some gram-positive bacteria (e.g., staphylococci) than some third generation cephalosporins (e.g., ceftazidime).3,4

In Vitro Susceptibility Testing

Strains of staphylococci resistant to penicillinase-resistant penicillins (methicillin-resistant [oxacillin-resistant] staphylococci) should be considered resistant to cefepime, although results of in vitro susceptibility tests may indicate that the organisms are susceptible to the drug.55

For information on interpreting results of in vitro susceptibility testing (disk susceptibility tests, dilution susceptibility tests) when cefepime susceptibility testing is performed according to the standards of the Clinical and Laboratory Standards Institute (CLSI; formerly National Committee for Clinical Laboratory Standards [NCCLS]), see Spectrum: In Vitro Susceptibility Testing, in the Cephalosporins General Statement 8:12.06.

Pharmacokinetics

Studies in adults indicate that cefepime exhibits linear dose-dependent pharmacokinetics over the dosage range of 250 mg to 2 g, and there is no evidence of accumulation following multiple doses in healthy adults with normal renal function receiving usual parenteral dosages of the drug.1,47,49 While there is no evidence of accumulation of cefepime in pediatric patients 2 months to 11 years of age when the drug is given in a dosage of 50 mg/kg every 12 hours, steady-state peak plasma concentration, area under the concentration-time curve (AUC), and plasma half-life are increased about 15% when the drug is given in a dosage of 50 mg/kg every 8 hours.1

There is no evidence of gender-related differences in the pharmacokinetics of cefepime,1,50 and differences in the pharmacokinetics of the drug in geriatric individuals appear to be related to changes in renal function rather than age.1,3,5,50

Studies in adults with impaired renal function indicate that the pharmacokinetics of cefepime are affected by the degree of renal impairment and that total body clearance of the drug decreases in proportion to decreases in creatinine clearance.1,42,52 The pharmacokinetics of cefepime do not appear to be affected by hepatic impairment.1

Absorption

Cefepime is almost completely absorbed following IM administration.1,44 In healthy adult males who received single 500-mg, 1-g, or 2-g IM doses of cefepime, peak plasma concentrations of the drug were attained within 1.4-1.6 hours and averaged 13.9, 29.6, or 57.5 mcg/mL, respectively; plasma concentrations averaged 1.9, 4.5, or 8.7 mcg/mL, respectively, 8 hours after the dose.1 In children 2 months to 16 years of age who received a single 50-mg/kg dose IM, plasma cefepime concentrations averaged 76, 75.2, 64, and 4.8 mcg/mL at 0.5, 0.75, 1, and 8 hours, respectively, after the dose.44 The absolute bioavailability of cefepime after a single 50-mg/kg IM dose in pediatric patients has been reported to be 82.3%.1

Following IV infusion over 30 minutes of a single 500-mg, 1-g, or 2-g dose of cefepime in healthy adult males, peak plasma concentrations of the drug average 31.6-39.1, 65.9-81.7, or 126-163.9 mcg/mL;1,47,49 plasma concentrations were still detectable 8 hours after the dose and averaged 1.4, 2.4, and 3.9 mcg/mL, respectively, in one study.1

In pediatric patients 2 months to 15 years of age with bacterial meningitis who received cefepime dosages of 50 mg/kg every 8 hours given by IV infusion over 15-20 minutes, plasma concentrations averaged 67.1, 44.1, 23.9, 11.7, and 4.9 mcg/mL at 0.5, 1, 2, 4, and 8 hours, respectively, after the third dose.46 The manufacturers state that IV administration of a single 50-mg/kg dose of cefepime in pediatric patients results in cefepime exposure similar to that reported in adults following IV administration of a single 2-g dose of the drug.1

Distribution

The volume of distribution of cefepime at steady state ranges from 13-22 L in healthy adults,1,3,39,49 and averages 0.3 L/kg in pediatric patients 2 months to 11 years of age.1

Following parenteral administration, cefepime is widely distributed into tissues and fluids, including blister fluid,1,39,48 bronchial mucosa,1 sputum,1 bile,1,27 peritoneal fluid,1,27 appendix,1 gallbladder,1,27 and prostate.1 In adults with acute cholecystitis who received 2 g of cefepime IV every 12 hours, concentrations of the drug in peritoneal fluid, bile, and gallbladder tissue in samples obtained 2-15 hours after a dose averaged 5.66 mcg/mL, 15.51 mcg/mL, and 5.35 mcg/g, respectively; concurrent plasma concentrations averaged 7.6 mcg/mL.27

Cefepime is distributed into CSF following IV administration in adult or pediatric patients.1,5,46,78,81,82,84,92 In a study in adults who received cefepime in a dosage of 2 g every 12 hours given by IV infusion over 30 minutes, CSF concentrations ranged from 0.34-11.8 mcg/mL and minimum CSF concentrations were 5-58% of minimum serum concentrations.82 In children 2 months to 15 years of age who received 50-mg/kg doses of cefepime every 8 hours given by IV infusion over 15-20 minutes, CSF concentrations of the drug were 5.7, 4.3, 3.6, 4.2, and 3.3 mcg/mL at 0.5, 1, 2, 4, and 8 hours, respectively, after the third dose.46 There is evidence from a limited study in neonates with meningitis that cefepime CSF concentrations in premature neonates are higher than those reported in full-term neonates.78

Cefepime is distributed into human milk.1,6,92 Following a single 1-g dose of cefepime given by IV infusion over 1 hour, peak concentrations of the drug in milk averaged 1.2 mcg/mL.6

Cefepime is approximately 20% bound to serum proteins; binding is independent of drug concentrations.1

Elimination

In healthy adults with normal renal function, the plasma half-life of cefepime averages 2-2.3 hours1,3,39,49 and total body clearance averages 120 mL/minute.1 In pediatric patients, the plasma half-life of cefepime averages 1.9 hours in those 2 months up to 6 months of age and 1.5-1.7 hours in those 6 months to 16 years of age.44 Total body clearance reportedly averages 3.3 mL/minute per kg in pediatric patients 2 months to 11 years of age.1 Limited data from neonates younger than 2 months of age indicate that the mean plasma half-life of cefepime is 4.9 hours in this age group.80

The plasma half-life of cefepime is prolonged in patients with renal impairment and averages 4.9, 10.5, and 13.5 hours in adults with creatinine clearances of 31-60, 11-30, or less than 10 mL/minute, respectively.42 Results of a single-dose study in a limited number of patients with impaired hepatic function indicate that the pharmacokinetics of cefepime are not affected by hepatic impairment.1

Cefepime is partially metabolized in vivo to N -methylpyrrolidine (NMP) which is rapidly converted to the N -oxide (NMP- N -oxide).1 The drug is eliminated principally unchanged in urine by glomerular filtration.1,47,49 In adults with normal renal function, 80-82% of a single dose of cefepime is excreted unchanged in urine;1,42,47,49 less than 1% of the dose is eliminated as NMP, 6.8% as NMP- N -oxide, and 2.5% as an epimer of cefepime.1 In adults with normal renal function who received single 500-mg, 1-g, or 2-g IV doses of cefepime, urine concentrations of the drug in samples obtained within 4 hours after the dose averaged 292, 926, or 3120 mcg/mL, respectively.1 In pediatric patients 2 months to 11 years of age who received a single 50-mg/kg IV dose of cefepime, 60% of the dose was excreted unchanged in urine and the average renal clearance was 2 mL/minute per kg.1

Cefepime is removed by hemodialysis1,3,42,52 and peritoneal dialysis.1,3,51 The amount of cefepime removed during hemodialysis depends on several factors (e.g., type of coil used, dialysis flow-rate); however, a 3- to 5-hour period of hemodialysis removes into the dialysate approximately 20-68% of a dose of the drug.1,3,42 In a study in patients with end-stage renal failure undergoing continuous ambulatory peritoneal dialysis (CAPD) who received a single 1- or 2-g IV dose of cefepime given over 30 minutes, approximately 25% of the dose was removed into the peritoneal dialysate over 72 hours; the plasma half-life of the drug in these patients ranged from 15.4-22.6 hours.51

Chemistry and Stability

Chemistry

Cefepime is a semisynthetic cephalosporin antibiotic.1,6,92,95 The drug is a parenteral zwitterionic aminothiazolyl cephalosporin.5,30,31 Cefepime is structurally similar to parenteral third generation cephalosporins that contain an aminothiazolyl side chain at position 7 of the cephalosporin nucleus (e.g., cefotaxime, ceftazidime, ceftriaxone).3,24,30,31 The aminothiazolyl side chain enhances antibacterial activity, particularly against Enterobacteriaceae, and generally results in enhanced stability against β-lactamases.3,24 However, cefepime contains an alkoxyimino group in the side chain rather than the methoxyimino group contained in many aminothiazolyl cephalosporins.3,24 The alkoxyimino group results in increased activity against staphylococci.3,24 In addition, cefepime contains a quaternary N -methylpyrrolidine (NMP) group at the 3-position, resulting in a zwitterion that enhances stability against certain β-lactamases and penetration through the outer membrane of gram-negative bacteria.3,4,5,24,30,31

Cefepime is commercially available for parenteral use as cefepime hydrochloride, which is monohydrated;1,92,95 potency of cefepime hydrochloride is expressed in terms of cefepime, calculated on the anhydrous basis.1,92,95 Cefepime hydrochloride occurs as a white to pale yellow powder and contains the equivalent of not less than 825 mcg and not more than 911 mcg of cefepime per mg, calculated on the anhydrous basis.1,95 The drug is highly soluble in water1,95 and has pK_as of 1.5-1.6 and 3.1-3.2.2

Cefepime hydrochloride powder for IM injection or IV infusion that is commercially available in vials contains a mixture of the drug and l-arginine; the powder for injection contains 707 mg of l-arginine per g of cefepime.1 When vials containing 500 mg, 1 g, or 2 g of cefepime are reconstituted as directed, the resultant cefepime hydrochloride solutions have a pH of 4-6 and range in color from pale yellow to amber.1

When the commercially available Duplex^® delivery system that contains 1 or 2 g of cefepime powder (with approximately 725 mg of l-arginine per g of cefepime) and 50 mL of 5% dextrose injection in separate chambers is reconstituted (activated) according to the manufacturer's directions, the resultant solution has a pH of 4-6 and an osmolality of approximately 431 or 577 mOsm/kg, respectively.95 The reconstituted solution may range in color from colorless to amber.95

Commercially available frozen premixed injections of cefepime hydrochloride in dextrose are sterile, nonpyrogenic, iso-osmotic solutions of the drug provided in a plastic container fabricated from specially formulated multilayered plastic PL 2040 (Galaxy^®).92 The 1- or 2-g frozen injections of cefepime contain 1.03 or 2.06 g of dextrose, respectively, to adjust osmolality.92 The 1- or 2-g frozen injections also contain 725 mg or 1.45 g of l-arginine, respectively, and may contain hydrochloric acid to adjust pH to 4-6.92 These premixed injections may range in color from colorless to amber.92

Stability

Like some other cephalosporins, cefepime hydrochloride powder for injection and solutions of the drug tend to darken, depending on storage conditions; however, such discoloration does not indicate loss of potency.1

Vials containing cefepime hydrochloride powder for IM injection or IV infusion should be stored at 20-25°C and protected from light.1 Following reconstitution and dilution in 0.9% sodium chloride, 5 or 10% dextrose, (1/6) M sodium lactate, 5% dextrose and 0.9% sodium chloride, lactated Ringer's and 5% dextrose, Normosol^®-R, or Normosol^®-M in 5% dextrose injection, cefepime solutions for IV infusion containing 1-40 mg/mL are stable for 24 hours when stored at a room temperature of 20-25°C or for 7 days when refrigerated at 2-8°C.1

Following reconstitution with sterile water for injection, 0.9% sodium chloride, 5% dextrose, 0.5 or 1% lidocaine hydrochloride, sterile bacteriostatic water for injection with parabens or benzyl alcohol, cefepime solutions for IM injection containing 280 mg/mL are stable for 24 hours when stored at a room temperature of 20-25°C or for 7 days when refrigerated at 2-8°C.1

Following reconstitution of ADD-Vantage^® vials containing 1 or 2 g of cefepime according to the manufacturer's directions, IV solutions containing 10-40 mg/mL in 5% dextrose injection or 0.9% sodium chloride injection are stable for 24 hours at 20-25°C or 7 days at 2-8°C.1

The commercially available Duplex^® delivery system that contains 1 or 2 g of cefepime and 50 mL of 5% dextrose injection in separate chambers should be stored at 20-25°C, but may be exposed to temperatures ranging from 15-30°C.95 Following reconstitution (activation), these IV solutions must be used within 12 hours if stored at room temperature or within 5 days if stored in a refrigerator and should not be frozen.95

The commercially available frozen premixed cefepime hydrochloride injection in dextrose should be stored at -20°C or lower.92 The frozen injections should be thawed at room temperature (25°C) or under refrigeration (5°C) and, once thawed, should not be refrozen.92 Thawed solutions of the commercially available frozen injections are stable for 24 hours at room temperature (25°C) or 7 days under refrigeration (5°C).92 The commercially available frozen injections of the drug are provided in plastic containers fabricated from specially formulated multilayered plastic PL 2040 (Galaxy^®).92 Solutions in contact with PL 2040 can leach out some of its chemical components in very small amounts within the expiration period of the injection; however, safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.92

Additional Information

For further information on chemistry, mechanism of action, spectrum, resistance, uses, cautions, acute toxicity, drug interactions, or laboratory test interferences of cefepime, see the Cephalosporins General Statement 8:12.06.

1. Hospira. Maxipime^® (cefepime hydrochloride, USP) for injection for intravenous or intramuscular use prescribing information. Lake Forest, IL; 2013 Apr.

2. Bristol-Myers Squibb Company. Product information form for American hospital formulary service: Maxipime^® (cefepime hydrochloride). Princeton, NJ.

3. Okamoto MP, Nakahiro RK, Chin A et al. Cefepime: a new fourth-generation cephalosporin. Am J Hosp Pharm . 1994; 51:463-77. [PubMed 8017411]

4. Rybak MJ, Palmer SM. Cefepime: part of the new generation. Am J Hosp Pharm . 1994; 51:459-60. [PubMed 8017410]

5. Hardin TC, Jennings TS. Cefepime. Pharmacotherapy . 1994; 14:657-68. [PubMed 7885968]

6. Barradell LB, Bryson HM. Cefepime: a review of its antibacterial activity, pharmacokinetic properties and therapeutic use. Drugs . 1994; 47:471-505. [PubMed 7514976]

7. Gentry LO, Rodriguez-Gomez G. Randomized comparison of cefepime and ceftazidime for treatment of skin, surgical wound, and complicated urinary tract infections in hospitalized subjects. Antimicrob Agents Chemother . 1991; 35:2371-4. [PubMedCentral][PubMed 1804010]

8. Oster S, Edelstein H, Cassano K et al. Open trial of cefepime (BMY 28142) for infections in hospitalized patients. Antimicrob Agents Chemother . 1990; 34:954-7. [PubMedCentral][PubMed 2203309]

9. Preheim LC, Childs SJ, Rajfer J et al. Randomized, double-blind comparison of cefepime and ceftazidime therapy for urinary tract infection. Curr Ther Res . 1995; 56:729-37.

10. Barbhaiya RH, Knupp CA, Pfeffer M et al. Pharmacokinetics of cefepime in patients undergoing continuous ambulatory peritoneal dialysis. Antimicrob Agents Chemother . 1992; 36:1387-91. [PubMedCentral][PubMed 1510432]

11. Sanders CC. Cefepime: the next generation? Clin Infect Dis . 1993; 17:369-79. (IDIS 319852)

12. Woods M. Criteria for use of cefepime in adults. Am J Hosp Pharm . 1994; 51:531-2. [PubMed 8017425]

13. Segreti J, Levin S. Bacteriologic and clinical applications of a new extended-spectrum parenteral cephalosporin. Am J Med . 1996; 100(Suppl 6A):S45-51. [PubMed 8678097]

14. Holloway WJ, Palmer D. Clinical applications of a new parenteral antibiotic in the treatment of severe bacterial infections. Am J Med . 1996; 100(Suppl 6A):S52-9. [PubMed 8678098]

15. McCabe R, Chirurgi V, Farkas SA et al. A new therapeutic option for the treatment of pneumonia. Am J Med . 1996; 100(Suppl 6A):S60-7. [PubMed 8678099]

16. Sharifi R, Geckler R, Childs S. Treatment of urinary tract infections: selecting an appropriate broad-spectrum antibiotic for nosocomial infections. Am J Med . 1996; 100(Suppl 6A):S76-82. [PubMed 8678101]

17. Schwartz R, Das-Young LR, Ramirez-Ronda C et al. Current and future management of serious skin and skin-structure infections. Am J Med . 1996; 100(Suppl 6A):S90-5. [PubMed 8678103]

18. Okamoto MP, Nakahiro RK, Chin A et al. Cefepime clinical pharmacokinetics. Clin Pharmacokinet . 1993; 25:88-102. [PubMed 8403741]

19. Barbhaiya RH, Knupp CA, Forgue ST et al. Pharmacokinetics of cefepime in subjects with renal insufficiency. Clin Pharmacol Ther . 1990; 48:268-76. [PubMed 2401125]

20. Kessler RE, Fung-Tomc J. Susceptibility of bacterial isolates to β-lactam antibiotics from U.S. clinical trials over a 5-year period. Am J Med . 1996; 100(Suppl 6A):513-9.

21. Reviewers' comments (personal observations).

22. Bristol-Myers Squibb Company, Princeton, NJ: Personal communication.

23. Hancock REW, Bellido F. Factors involved in the enhanced efficacy against gram-negative bacteria of fourth generation cephalosporins. J Antimicrob Chemother . 1992; 29(Suppl A):1-6. [PubMed 1601751]

24. Wynd MA, Paladino JA. Cefepime: a fourth-generation parenteral cephalosporin. Ann Pharmacother . 1996; 30:1414-24. [PubMed 8968455]

25. Cordonnier C, Herbrecht R, Pico JL et al et al. Cefepime/amikacin versus ceftazidime/amikacin as empirical therapy for febrile episodes in neutropenic patients: a comparative study. Clin Infect Dis . 1997; 24:41-51. [PubMed 8994754]

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