Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Intra-abdominal Infections
Treatment of complicated intra-abdominal infections caused by E. coli, viridans streptococci, Ps. aeruginosa, K. pneumoniae, Enterobacter, or Bacteroides fragilis; used in conjunction with IV metronidazole.
Has been used alone for treatment of acute obstetric and gynecologic infections† (e.g., pelvic inflammatory disease [PID], pelvic surgical wound infection, postpartum endometritis), but safety and efficacy of cefepime monotherapy in these infections not established.
Respiratory Tract Infections
Treatment of moderate to severe pneumonia (with or without concurrent bacteremia) caused by susceptible Streptococcus pneumoniae.
Treatment of moderate to severe pneumonia caused by susceptible Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter.
Treatment of community-acquired pneumonia (CAP) caused by S. pneumoniae, Haemophilus influenzae†, Moraxella catarrhalis†, and Staphylococcus aureus†. ATS and IDSA recommend use of cefepime for treatment of CAP only when Ps. aeruginosa is known or suspected to be involved. For empiric treatment of CAP in patients with risk factors for Ps. aeruginosa, IDSA and ATS recommend a combination regimen that includes an antipneumococcal, antipseudomonal β-lactam (cefepime, impenem, meropenem, fixed combination of piperacillin and tazobactam) and ciprofloxacin or levofloxacin; one of these β-lactams, an aminoglycoside, and azithromycin; or one of these β-lactams, an aminoglycoside, and an antipneumococcal fluoroquinolone. If Ps. aeruginosa has been identified by appropriate microbiologic testing, these experts recommend treatment with a regimen that includes an antipseudomonal β-lactam (cefepime, ceftazidime, aztreonam, imipenem, meropenem, piperacillin, ticarcillin) and ciprofloxacin, levofloxacin, or an aminoglycoside.
Treatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (oxacillin-susceptible [methicillin-susceptible] strains only) or susceptible S. pyogenes (group A β-hemolytic streptococci).
Urinary Tract Infections (UTIs)
Treatment of mild to moderate uncomplicated and complicated UTIs (including those associated with pyelonephritis and/or with concurrent bacteremia) caused by susceptible Escherichia coli, K. pneumoniae, or Proteus mirabilis.
Treatment of severe uncomplicated and complicated UTIs (including those associated with pyelonephritis and/or concurrent bacteremia) caused by susceptible E. coli or K. pneumoniae.
Empiric Therapy in Febrile Neutropenic Patients
Empiric treatment of presumed bacterial infections in febrile neutropenic patients.
Has been effective as monotherapy for empiric therapy in febrile neutropenic patients, but manufacturer cautions that safety and efficacy data are limited to date and monotherapy may not be appropriate in patients at severe risk of infection (e.g., those with a history of recent bone marrow transplantation, hypotension on presentation, underlying hematologic malignancy, or severe or prolonged neutropenia).
Consult published protocols for the treatment of infections in febrile neutropenic patients for specific recommendations regarding selection of the initial empiric regimen, when to change the initial regimen, possible subsequent regimens, and duration of therapy in these patients. Consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients also is advised.
Dosage and Administration
Administration
Administer by IV infusion or deep IM injection.
IM route should be used only for treatment of mild to moderate, uncomplicated or complicated UTIs caused by E. coli when this route is considered more appropriate.
IV Infusion
If a Y-type administration set is used, discontinue other solution flowing through the tubing during cefepime infusion.
Reconstitute vials for IV infusion with 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 injection, Normosol®-R, or Normosol®-M in 5% dextrose injection.
Reconstitute vials containing 500 mg, 1 g, or 2 g of cefepime with 5, 10, or 10 mL of one of these IV solutions, respectively, to provide solutions containing approximately 100, 100, or 160 mg/mL, respectively, and then dilute the appropriate dose in a compatible IV solution.
Reconstitute ADD-Vantage® vials containing 1 or 2 g of cefepime with 50 or 100 mL of 0.9% sodium chloride or 5% dextrose injection according to the manufacturer’s directions.
Rate of Administration
Administer by IV infusion over approximately 30 minutes.
IM Injection
Reconstitution
For IM injection, reconstitute vial containing 500 mg or 1 g of cefepime with 1.3 or 2.4 mL, respectively, of sterile water for injection, 0.9% sodium chloride, 5% dextrose, 0.5 or 1% lidocaine hydrochloride, or bacteriostatic water for injection (with parabens or benzyl alcohol) to provide a solution containing approximately 280 mg/mL.
Dosage
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Available as cefepime hydrochloride; dosage expressed in terms of cefepime, calculated on the anhydrous basis.
Pediatric Patients
General Pediatric Dosage
IV or IM
Children 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 12 hours.
AAP recommends 100–150 mg/kg daily in 3 divided doses for treatment of mild to moderate infections and 150 mg/kg daily in 3 divided doses for treatment of severe infections in children >1 month of age.
Respiratory Tract Infections
Pneumonia
IV
Children 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 12 hours for 10 days.
Skin and Skin Structure Infections
Uncomplicated Infections
IV
Children 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 12 hours for 10 days.
Urinary Tract Infections (UTIs)
Uncomplicated or Complicated UTIs
IV or IM
Children 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 12 hours for 7–10 days.
Empiric Therapy in Febrile Neutropenic Patients
IV
Children 2 months to 16 years of age weighing <40 kg: 50 mg/kg every 8 hours for 7 days or until neutropenia resolves.
Frequently reevaluate need for continued anti-infective therapy if fever resolves but neutropenia remains for >7 days.
Adults
Intra-abdominal Infections
Complicated Infections
IV
2 g every 12 hours for 7–10 days; use in conjunction with IV metronidazole.
Respiratory Tract Infections
Moderate to Severe Pneumonia
IV
1–2 g every 12 hours for 10 days.
1–2 g every 8–12 hours recommended for initial therapy of hospital-acquired pneumonia, ventilator-associated pneumonia, or healthcare-associated pneumonia.
Skin and Skin Structure Infections
Moderate to Severe Uncomplicated Infections
IV
2 g every 12 hours for 10 days.
Urinary Tract Infections (UTIs)
Mild to Moderate Uncomplicated or Complicated UTIs
IV or IM
0.5–1 g every 12 hours for 7–10 days.
Severe Uncomplicated or Complicated UTIs
IV
2 g every 12 hours for 10 days.
Empiric Therapy in Febrile Neutropenic Patients
IV
2 g every 8 hours for 7 days or until neutropenia resolves.
Frequently reevaluate need for continued anti-infective therapy if fever resolves but neutropenia remains for >7 days.
Prescribing Limits
Pediatric Patients
Dosage should not exceed recommended adult dosage.
Special Populations
Hepatic Impairment
Dosage adjustments not required.
Renal Impairment
Dosage adjustments necessary in patients with Clcr ≤60 mL/minute.
Adults with Clcr ≤60 mL/minute: give an initial loading dose using the usually recommended adult dosage followed by maintenance dosage based on Clcr. (See Table 1 and Table 2.)
Table 1. Maintenance Dosage for Treatment of Infections in Adults with Renal Impairment
Clcr (mL/minute)
Initial dose: 500 mg
Initial dose: 1 g
Initial dose: 2 g
30–60
500 mg every 24 h
1 g every 24 h
2 g every 24 h
11–29
500 mg every 24 h
500 mg every 24 h
1 g every 24 h
<11
250 mg every 24 h
250 mg every 24 h
500 mg every 24 h
Table 2. Maintenance Dosage for Empiric Therapy in Febrile Neutropenic Adults with Renal Impairment
Clcr (mL/minute)
Initial Dose: 2 g
30–60
2 g every 12 h
11–29
2 g every 24 h
<11
1 g every 24 h
Adults undergoing hemodialysis: 1 g on the first day of treatment followed by 500 mg every 24 hours for treatment of infections or 1 g on the first day followed by 1 g every 24 hours for empiric therapy in febrile neutropenic patients. Administer the dose at the same time each day (given at completion of procedure on hemodialysis days).
Adults undergoing CAPD: give usually recommended dose once every 48 hours.
Pediatric patients with renal impairment: make dosage adjustments similar to those recommended for adults.
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Superinfection/Clostridium difficile-associated Diarrhea and Colitis
Possible emergence and overgrowth of nonsusceptible organisms with prolonged therapy. Careful observation of the patient is essential. Institute appropriate therapy if superinfection occurs.
Treatment with anti-infectives alters normal colon flora and may permit overgrowth of Clostridium difficile. C. difficile-associated diarrhea and colitis (CDAD; also known as antibiotic-associated diarrhea and colitis or pseudomembranous colitis) has been reported with nearly all anti-infectives, including cefepime, and may range in severity from mild diarrhea to fatal colitis. Hypertoxin producing strains of C. difficile are associated with increased morbidity and mortality since they may be refractory to anti-infectives and colectomy may be required.
Consider CDAD if diarrhea develops and manage accordingly. 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.
If CDAD is suspected or confirmed, the anti-infective may need to be discontinued. Some mild cases may respond to discontinuance alone. Manage moderate to severe cases with fluid, electrolyte, and protein supplementation, anti-infective therapy active against C. difficile (e.g., oral metronidazole or vancomycin), and surgical evaluation when clinically indicated.
Neurotoxicity
Encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, coma), myoclonus, and seizures reported rarely.
Most cases occurred in patients with renal impairment who received dosages of the drug inappropriately high for their renal status; some cases of encephalopathy occurred in patients who received dosage adjusted for renal function.
Symptoms of neurotoxicity generally were reversible and resolved after cefepime was discontinued and/or after hemodialysis.
If seizures occur, discontinue the drug. Use anticonvulsant therapy if clinically indicated.
Increased Mortality
In November 2007, FDA released an early communication about an ongoing safety review of cefepime. The safety review 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. FDA is working with Bristol-Myers Squibb to further evaluate the findings presented in the meta-analysis as well as additional safety data. As of early September 2008, FDA had not completed the safety review and had not reached a definitive conclusion as to whether or not the increased mortality described in the published meta-analysis is due to cefepime.
Sensitivity Reactions
Hypersensitivity Reactions
Possible hypersensitivity reactions, including rash (maculopapular or erythematous), pruritus, fever, eosinophilia, urticaria, anaphylaxis, erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis.
If an allergic reaction occurs, discontinue cefepime and institute appropriate therapy as indicated (e.g., epinephrine, corticosteroids, and maintenance of an adequate airway and oxygen).
Cross-hypersensitivity
Partial cross-sensitivity among cephalosporins and other β-lactam antibiotics, including penicillins and cephamycins.
Prior to initiation of therapy, make careful inquiry concerning previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs. Cautious use recommended in individuals hypersensitive to penicillins: avoid use in those who have had an immediate-type (anaphylactic) hypersensitivity reaction and administer with caution in those who have had a delayed-type (e.g., rash, fever, eosinophilia) reaction.
General Precautions
Selection and Use of Anti-infectives
To reduce development of drug-resistant bacteria and maintain effectiveness of cefepime and other antibacterials, use only for treatment or prevention of infections proven or strongly suspected to be caused by susceptible bacteria.
When selecting or modifying anti-infective therapy, use results of culture and in vitro susceptibility testing. In the absence of such data, consider local epidemiology and susceptibility patterns when selecting anti-infectives for empiric therapy.
History of GI Disease
Use with caution in patients with a history of GI disease, particularly colitis. (See Superinfection/Clostridium difficile-associated Diarrhea and Colitis under Cautions.)
Specific Populations
Pregnancy
Category B.
Lactation
Distributed into milk; use with caution.
Pediatric Use
Safety and efficacy not established in children <2 months of age.
Not recommended for treatment of serious infections suspected or known to be caused by Haemophilus influenzae type b (Hib); use an alternative anti-infective if the possibility of meningeal seeding from a distant infection site or meningitis is suspected or documented.
Pharmacokinetic and adverse effect profiles similar to those reported in adults.
Geriatric Use
Safety and efficacy in those ≥65 years of age similar to that in younger adults.
Serious adverse effects (including life-threatening or fatal encephalopathy, myoclonus, and seizures) have occurred in geriatric patients who received cefepime dosage inappropriately high for their renal status.
Substantially eliminated by kidneys; risk of toxicity may be greater in those with impaired renal function. Select dosage with caution and assess renal function periodically because of age-related decreases in renal function. (See Renal Impairment under Dosage and Administration.)
Hepatic Impairment
Pharmacokinetics not affected.
Renal Impairment
Possible decreased clearance and increased serum half-life.
Neurotoxicity reported in some patients with renal impairment who received cefepime dosage inappropriately high for their renal status. (See Neurotoxicity under Cautions.)
Dosage adjustments necessary in patients with Clcr ≤60 mL/minute. (See Renal Impairment under Dosage and Administration.)
Common Adverse Effects
Diarrhea, nausea, vomiting, local reactions (e.g., phlebitis, pain, inflammation).
Closely monitor renal function if used concomitantly
Tests for glucose
Possible false-positive reactions in urine glucose tests using Clinitest®, Benedict’s solution, or Fehling’s solution
Use glucose tests based on enzymatic glucose oxidase reactions (e.g., Clinistix®, Tes-Tape®)
Pharmacokinetics
Absorption
Bioavailability
Not appreciably absorbed from GI tract; must be administered parenterally.
Almost completely absorbed following IM administration; peak serum concentrations attained within 1.4–1.6 hours.
Distribution
Extent
Widely distributed into tissues and fluids, including blister fluid, bronchial mucosa, sputum, bile, peritoneal fluid, appendix, gallbladder, and prostate.
Distributed into CSF following parenteral administration, but clinical importance unclear.
Distributed into milk.
Plasma Protein Binding
20%.
Elimination
Metabolism
Partially metabolized in vivo to N-methylpyrrolidine (NMP), which is rapidly converted to the N-oxide (NMP-N-oxide).
Elimination Route
Eliminated principally unchanged in urine by glomerular filtration.
In adults with normal renal function, 80–82% of a single dose excreted unchanged in urine; < 1% of the dose eliminated as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of the drug.
Half-life
Adults with normal renal function: 2–2.3 hours.
Children 2 months to 16 years of age: 1.5-1.9 hours.
Special Populations
Pharmacokinetics not affected by hepatic impairment.
Patients with renal impairment: clearance decreased and plasma half-life prolonged. Half-life averages 4.9, 10.5, 13.5 hours in those with Clcr 31–60, 11–30, or <10 mL/minute, respectively.
Stability
Storage
Parenteral
Powder for Injection or Infusion
2–25° C; protect from light.
Powder and reconstituted solutions may darken; does not indicate loss of potency.
Reconstituted IV solutions containing 1–40 mg/mL are stable for 24 hours at 20–25°C or 7 days at 2–8°C.
IV solutions in ADD-Vantage® vials are stable for 24 hours at 20–25°C or 7 days at 2–8°C at concentrations of 10–40 mg/mL in 0.9% sodium chloride or 5% dextrose injection.
Reconstituted IM solutions containing 280 mg/mL are stable for 24 hours at 20–25°C or 7 days at 2–8°C.
Compatibility
For information on systemic interactions resulting from concomitant use, see Interactions.
Based on spectrum of activity, classified as a fourth generation cephalosporin.
Expanded spectrum of activity compared with first and second generation cephalosporins and more active than third generation cephalosporins against Enterobacteriaceae that produce inducible β-lactamases. More resistant to inactivation by chromosomally and plasmid-mediated β-lactamases than most other cephalosporins; hydrolyzed by β-lactamases at a slower rate than third generation cephalosporins.
Usually bactericidal.
Like other β-lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis.
Spectrum of activity includes many gram-positive bacteria and many gram-negative bacteria (including Pseudomonas aeruginosa and certain Enterobacteriaceae). Inactive against fungi and viruses.
Gram-positive aerobes: active in vitro and in clinical infections against S. aureus, S. pneumoniae, S. pyogenes (group A β-hemolytic streptococci), and viridans streptococci. Also active in vitro against S. epidermidis (oxacillin-susceptible [methicillin-susceptible] strains only), S. saprophyticus, and S. agalactiae (group B streptococci). Enterococci (e.g., Enterococcus faecalis), oxacillin-resistant (methicillin-resistant) staphylococci, and Listeria monocytogenes are resistant.
Gram-negative aerobes: active in vitro and in clinical infections against Enterobacter, E. coli, K. pneumoniae, P. mirabilis, and Ps. aeruginosa. Also active in vitro against Acinetobacter calcoaceticus, Citrobacter diversus, C. freundii, E. agglomerans, H. influenzae (including β-lactamase-producing strains), Havnia alvei, K. oxytoca, Moraxella catarrhalis (including β-lactamase-producing strains), Morganella morganii, P. vulgaris, Providencia rettgeri, P. stuartii, and Serratia marcescens. Inactive against Stenotrophomonas.
Strains of staphylococci resistant to penicillinase-resistant penicillins (oxacillin-resistant [methicillin-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.
Advice to Patients
Pending revision, the material in this section should be considered in light of more recently available information in the MEDWATCH notification at the beginning of this monograph.
Importance of completing full course of therapy, even if feeling better after a few days.
Advise patients that skipping doses or not completing the full course of 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.
Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued. Importance of contacting a clinician if watery and bloody stools (with or without stomach cramps and fever) occur during or as late as 2 months or longer after the last dose.
Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.
Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.
Importance of informing patients of other precautionary information. (See Cautions.)
Preparations
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
† Use is not currently included in the labeling approved by the US Food and Drug Administration.
Remember, keep this and all other medicines out of the reach of children,
never share your medicines with others, and use this medication only for the indication prescribed.
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