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Pronunciation

(SEF e pim)

Generic Available (U.S.)

Yes

Index Terms

• Cefepime Hydrochloride

Brand Names: U.S.

• Maxipime® [DSC]

Brand Names: Canada

• Maxipime®

Pharmacologic Category

• Antibiotic, Cephalosporin (Fourth Generation)

Pharmacologic Category Synonyms

• Cephalosporin, Fourth Generation
• Fourth Generation Cephalosporin

Use: Labeled Indications

Treatment of uncomplicated and complicated urinary tract infections, including pyelonephritis caused by Escherichia coli, Klebsiella pneumoniae, or Proteus mirabilis; monotherapy for febrile neutropenia; uncomplicated skin and skin structure infections caused by Streptococcus pyogenes or methicillin-susceptible staphylococci; moderate-to-severe pneumonia caused by Streptococcus pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae, or Enterobacter species; complicated intra-abdominal infections (in combination with metronidazole) caused by E. coli, P. aeruginosa, K. pneumoniae, Enterobacter species, or Bacteroides fragilis against methicillin-susceptible staphylococci, Enterobacter sp, and many other gram-negative bacilli.

Children 2 months to 16 years: Empiric therapy of febrile neutropenia patients, uncomplicated skin/soft tissue infections, pneumonia, and uncomplicated/complicated urinary tract infections, including pyelonephritis.

Use: Unlabeled

Brain abscess (postneurosurgical prevention); malignant otitis externa; septic lateral/cavernous sinus thrombosis

Pregnancy Risk Factor

B

Pregnancy Considerations

Teratogenic effects were not observed in animal studies; therefore, cefepime is classified as pregnancy category B. It is not known if cefepime crosses the human placenta.

Lactation

Enters breast milk/use caution

Breast-Feeding Considerations

Small amounts of cefepime are excreted in breast milk. The manufacturer recommends that caution be exercised when administering cefepime to nursing women. Nondose-related effects could include modification of bowel flora.

Contraindications

Hypersensitivity to cefepime, other cephalosporins, penicillins, other beta-lactam antibiotics, or any component of the formulation

Warnings/Precautions

Concerns related to adverse effects:

• Elevated INR: May be associated with increased INR, especially in nutritionally-deficient patients, prolonged treatment, hepatic or renal disease.

• Penicillin allergy: Use with caution in patients with a history of penicillin allergy, especially IgE-mediated reactions (eg, anaphylaxis, angioedema, urticaria).

• Superinfection: Prolonged use may result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis; CDAD has been observed >2 months postantibiotic treatment.

Disease-related concerns:

• Gastrointestinal disease: Use with caution in patients with a history of gastrointestinal disease, especially colitis.

• Renal impairment: Use with caution in patients with renal impairment (Cl_cr ≤60 mL/minute); dosage adjustments recommended. May increase risk of encephalopathy, myoclonus, and seizures.

• Seizure disorders: Use with caution in patients with a history of seizure disorder; high levels, particularly in the presence of renal impairment, may increase risk of seizures.

Adverse Reactions

>10%: Hematologic: Positive Coombs' test without hemolysis (16%)

1% to 10%:

Central nervous system: Fever (1%), headache (1%)

Dermatologic: Rash (1% to 4%), pruritus (1%)

Endocrine & metabolic: Hypophosphatemia (3%)

Gastrointestinal: Diarrhea (≤3%), nausea (≤2%), vomiting (≤1%)

Hematologic: Eosinophils (2%)

Hepatic: ALT increased (3%), AST increased (2%), PTT abnormal (2%), PT abnormal (1%)

Local: Inflammation, phlebitis, and pain (1%)

<1%, postmarketing, and/or case reports: Agranulocytosis, alkaline phosphatase increased, anaphylactic shock, anaphylaxis, bilirubin increased, BUN increased, colitis, coma, confusion, creatinine increased, encephalopathy, hallucinations, hematocrit decreased, hypercalcemia, hyperkalemia, hyperphosphatemia, hypocalcemia, leucopenia, myoclonus, neutropenia, oral moniliasis, pseudomembranous colitis, seizure, stupor, thrombocytopenia, urticaria, vaginitis

Reactions reported with other cephalosporins: Aplastic anemia, erythema multiforme, hemolytic anemia, hemorrhage, pancytopenia, renal dysfunction, Stevens-Johnson syndrome, superinfection, toxic epidermal necrolysis, toxic nephropathy

Metabolism/Transport Effects

None known.

Drug Interactions

Aminoglycosides: Cephalosporins (4th Generation) may enhance the nephrotoxic effect of Aminoglycosides. Risk C: Monitor therapy

BCG: Antibiotics may diminish the therapeutic effect of BCG. Risk X: Avoid combination

Probenecid: May increase the serum concentration of Cephalosporins. Risk C: Monitor therapy

Typhoid Vaccine: Antibiotics may diminish the therapeutic effect of Typhoid Vaccine. Only the live attenuated Ty21a strain is affected. Management: Vaccination with live attenuated typhoid vaccine (Ty21a) should be avoided in patients being treated with systemic antibacterial agents. Use of this vaccine should be postponed until at least 24 hours after cessation of antibacterial agents. Risk D: Consider therapy modification

Storage

Vials: Store at 20°C to 25°C (68°F to 77°F). Protect from light. After reconstitution, stable in normal saline, D₅W, and a variety of other solutions for 24 hours at room temperature and 7 days refrigerated.

Premixed solution: Store frozen at -20°C (-4°F). Thawed solution is stable for 24 hours at room temperature or 7 days under refrigeration; do not refreeze.

Compatibility

Stable in D₅LR, D₅NS, D₅W, D₁₀W, NS, bacteriostatic water, sterile water for injection; variable stability (consult detailed reference) in peritoneal dialysis solutions.

Y-site administration: Compatible: Amikacin, ampicillin/sulbactam, anidulafungin, aztreonam, bivalirudin, bleomycin, bumetanide, buprenorphine, butorphanol, calcium gluconate, carboplatin, carmustine, cyclophosphamide, cytarabine, dactinomycin, dexamethasone sodium phosphate, dexmedetomidine, docetaxel, doxorubicin liposome, fenoldopam, fluconazole, fludarabine, fluorouracil, furosemide, gentamicin, granisetron, hetastarch in lactate electrolyte injection (Hextend®), hydrocortisone sodium succinate, hydromorphone, imipenem/cilastatin, insulin (regular), ketamine, leucovorin calcium, lorazepam, melphalan, mesna, methotrexate, methylprednisolone sodium succinate, metronidazole, milrinone, mycophenolate, paclitaxel, piperacillin/tazobactam, ranitidine, remifentanil, sargramostim, sodium bicarbonate, sufentanil, sulfamethoxazole/trimethoprim, telavancin, thiotepa, ticarcillin/clavulanate, tigecycline, tobramycin, valproate sodium, zidovudine. Incompatible: Acetylcysteine, acyclovir, amphotericin B, amphotericin B cholesteryl sulfate complex, caspofungin, chlorpromazine, cimetidine, ciprofloxacin, cisplatin, dacarbazine, daunorubicin, diazepam, diphenhydramine, doxorubicin, droperidol, enalaprilat, erythromycin lactobionate, etoposide, etoposide phosphate, famotidine, filgrastim, floxuridine, gallium nitrate, ganciclovir, haloperidol, hydroxyzine, idarubicin, ifosfamide, magnesium sulfate, mannitol, mechlorethamine, meperidine, metoclopramide, midazolam, mitomycin, mitoxantrone, morphine, nalbuphine, nicardipine, ondansetron, phenytoin, prochlorperazine edisylate, promethazine, streptozocin, theophylline, vinblastine, vincristine. Variable (consult detailed reference): Dobutamine, dopamine, morphine, propofol, vancomycin.

Mechanism of Action

Inhibits bacterial cell wall synthesis by binding to one or more of the penicillin-binding proteins (PBPs) which in turn inhibits the final transpeptidation step of peptidoglycan synthesis in bacterial cell walls, thus inhibiting cell wall biosynthesis. Bacteria eventually lyse due to ongoing activity of cell wall autolytic enzymes (autolysis and murein hydrolases) while cell wall assembly is arrested.

Pharmacodynamics/Kinetics

Absorption: I.M.: Rapid and complete

Distribution: V_d: Adults: 16-20 L; penetrates into inflammatory fluid at concentrations ~80% of serum levels and into bronchial mucosa at levels ~60% of those reached in the plasma; crosses blood-brain barrier

Protein binding, plasma: ~20%

Metabolism: Minimally hepatic

Half-life elimination: 2 hours

Time to peak: I.M.: 1-2 hours; I.V.: 0.5 hours

Excretion: Urine (85% as unchanged drug)

Dosage

Usual dosage range:

Children: I.M., I.V.: 50 mg/kg/dose every 8-12 hours (not to exceed maximum adult dosing)

Adults: I.V.: 1-2 g every 8-12 hours; I.M.: 0.5-1 g every 12 hours

Indication-specific dosing:

Children ≥2 months to 16 years (<40 kg):

Febrile neutropenia: I.V.: 50 mg/kg/dose every 8 hours for 7 days or until neutropenia resolves

Skin and skin structure infections (uncomplicated) and pneumonia: I.V.: 50 mg/kg/dose every 12 hours for 10 days

Urinary tract infections, complicated and uncomplicated: I.M., I.V.: 50 mg/kg/dose every 12 hours for 7-10 days; Note: I.M. may be considered for mild-to-moderate infection only

Adults:

Brain abscess, postneurosurgical prevention (unlabeled use): I.V.: 2 g every 8 hours with vancomycin

Febrile neutropenia, monotherapy: I.V: 2 g every 8 hours for 7 days or until the neutropenia resolves

Intra-abdominal infections, complicated, severe (in combination with metronidazole): I.V.: 2 g every 12 hours for 7-10 days. Note: 2010 IDSA guidelines recommend 2 g every 8-12 hours for 4-7 days (provided source controlled). Not recommended for hospital-acquired intra-abdominal infections (IAI) associated with multidrug-resistant gram negative organisms or in mild-to-moderate community-acquired IAIs due to risk of toxicity and the development of resistant organisms (Solomkin, 2010).

Otitis externa, malignant (unlabeled use): I.V.: 2 g every 12 hours

Pneumonia: I.V.:

Nosocomial (HAP/VAP): 1-2 g every 8-12 hours; Note: Duration of therapy may vary considerably (7-21 days); usually longer courses are required if Pseudomonas. In absence of Pseudomonas, and if appropriate empiric treatment used and patient responsive, it may be clinically appropriate to reduce duration of therapy to 7-10 days (American Thoracic Society Guidelines, 2005).

Community-acquired (including pseudomonal): 1-2 g every 12 hours for 10 days

Septic lateral/cavernous sinus thrombosis (unlabeled use): I.V.: 2 g every 8-12 hours; with metronidazole for lateral

Skin and skin structure, uncomplicated: I.V.: 2 g every 12 hours for 10 days

Urinary tract infections, complicated and uncomplicated:

Mild-to-moderate: I.M., I.V.: 0.5-1 g every 12 hours for 7-10 days

Severe: I.V.: 2 g every 12 hours for 10 days

Dosing adjustment in renal impairment: Adults: Recommended maintenance schedule based on creatinine clearance (mL/minute), compared to normal dosing schedule: See table.

Intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days): I.V.: Initial: 1 g (single dose) on day 1. Maintenance: 0.5-1 g every 24 hours or 1-2 g every 48-72 hours (Heintz, 2009). Note: Dosing dependent on the assumption of 3 times/week, complete IHD sessions.

Peritoneal dialysis (PD): Removed to a lesser extent than hemodialysis; administer normal recommended dose every 48 hours

Continuous renal replacement therapy (CRRT) (Heintz, 2009; Trotman, 2005): Drug clearance is highly dependent on the method of renal replacement, filter type, and flow rate. Appropriate dosing requires close monitoring of pharmacologic response, signs of adverse reactions due to drug accumulation, as well as drug concentrations in relation to target trough (if appropriate). The following are general recommendations only (based on dialysate flow/ultrafiltration rates of 1-2 L/hour and minimal residual renal function) and should not supersede clinical judgment:

CVVH: Loading dose of 2 g followed by 1-2 g every 12 hours

CVVHD/CVVHDF: Loading dose of 2 g followed by either 1 g every 8 hours or 2 g every 12 hours. Note: Dosage of 1 g every 8 hours results in similar steady-state concentrations as 2 g every 12 hours and is more cost effective (Heintz, 2009).

Note: Consider higher dosage of 4 g/day if treating Pseudomonas or life-threatening infections in order to maximize time above MIC (Trotman, 2005). Dosage of 2 g every 8 hours may be needed for gram-negative rods with MIC ≥4 mg/L (Heintz, 2009).

Administration: I.M.

Inject deep I.M. into large muscle mass.

Administration: I.V.

Inject direct I.V. over 5 minutes (Garrelts, 1999). Infuse intermittent infusion over 30 minutes.

Administration: I.V. Detail

pH: 4-6

Monitoring Parameters

Obtain specimen for culture and susceptibility prior to the first dose. Monitor for signs of anaphylaxis during first dose.

Test Interactions

Positive direct Coombs', false-positive urinary glucose test using cupric sulfate (Benedict's solution, Clinitest®, Fehling's solution), false-positive serum or urine creatinine with Jaffé reaction, false-positive urinary proteins and steroids

Patient Education

This medication is administered by infusion or injection. Report immediately any redness, swelling, burning, or pain at injection/infusion site; itching or hives; chest pain; or difficulty swallowing or breathing. Maintain adequate hydration, unless instructed to restrict fluid intake. May cause diarrhea, nausea, or vomiting. Report rash; breathing or swallowing difficulty; persistent diarrhea, nausea, vomiting, or abdominal pain; changes in urinary pattern or pain on urination; opportunistic infection (eg, vaginal itching or drainage, sores in mouth, blood in stool or urine, unusual fever or chills); or CNS changes (eg, irritability, agitation, nervousness, insomnia, hallucinations).

Geriatric Considerations

Adjust dose for changes in renal function.

Anesthesia and Critical Care Concerns/Other Considerations

Evidence-Based Information: The Food and Drug Administration (FDA) informed practitioners (November, 2007) of a review of new safety data and a request for additional data for cefepime after a recently published meta-analysis (Yahav, 2007) raised concerns of an increased risk of death in patients treated with cefepime. The authors of the meta-analysis reviewed the results from 57 randomized controlled trials comparing cefepime to other beta-lactams in a variety of infections. The primary outcome of the analysis was 30-day all-cause mortality; however, all-cause mortality data was only available in 41 of the trials. In addition, distribution of specific pathogens to infections in relation to all-cause mortality was not available, including patients with documented gram-negative and Pseudomonas infections. The authors reported an increase in all-cause mortality in the cefepime group relative to the comparator group (relative risk 1.26 [95% CI 1.08 to 1.40]; p=0.005). Only two subsets showed a significant difference in all cause mortality and include the group comparing cefepime to piperacillin-tazobactam (relative risk 2.14 [95% CI 1.17 to 3.89]; p=0.01) and the subset of patients with febrile neutropenia (relative risk 1.42 [95% CI 1.09 to 1.84]; p=0.009).

The FDA is currently evaluating the data, and in the interim, is reminding practitioners to consider the risks and benefits of cefepime prior to use. The FDA will provide additional communication and any recommendations, if necessary, following the conclusion of the evaluation.

Additional information may be found at http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm070797.htm.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

May cause nervousness; case reports of euphoria, delusion, illusions, and depersonalization with cephalosporins; has rarely been associated with encephalopathy (confusion, hallucinations, stupor, and coma); most cases occurred in patients with renal impairment who received doses that exceeded recommendations

Mental Health: Effects on Psychiatric Treatment

May rarely cause neutropenia; use caution with clozapine and carbamazepine

Nursing: Physical Assessment/Monitoring

Assess results of culture/sensitivity tests and patient's allergy history prior to therapy. Assess prothrombin time. Teach patient to report hypersensitivity, nephrotoxicity, and opportunistic infection.

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Infusion, premixed iso-osmotic dextrose solution, as hydrochloride: 1 g (50 mL); 2 g (100 mL)

Injection, powder for reconstitution, as hydrochloride: 500 mg, 1 g, 2 g

Maxipime®: 500 mg [DSC], 1 g [DSC], 2 g [DSC]

References

Allaouchiche B, Breilh D, Jaumain H, et al, “Pharmacokinetics of Cefepime During Continuous Veno-Venous Hemodiafiltration,” Antimicrob Agents Chemother, 1997, 41(11):2424-7.

American Thoracic Society and Infectious Diseases Society of America, “Guidelines for the Management of Adults With Hospital-Acquired, Ventilator-Associated, and Healthcare-Associated Pneumonia,” Am J Respir Crit Care Med, 2005, 171(4):388-416.

Arguedas AG, Stutman HR, Zaleska M, et al, “Cefepime. Pharmacokinetics and Clinical Response in Patients With Cystic Fibrosis,” Am J Dis Child, 1992, 146(7):797-802.

Barbhaiya RH, Knupp CA, and Pittman KA, “Effects of Age and Gender on Pharmacokinetics of Cefepime,” J Antimicrob Chemother, 1992, 36(6):1181-5.

Barradell LB and Bryson HM, “Cefepime. A Review of Its Antibacterial Activity, Pharmacokinetic Properties, and Therapeutic Use,” Drugs, 1994, 47(3):471-505.

Blumer JL, Reed MD, Lemon E, et al, “Pharmacokinetics (PK) of Cefepime in Pediatric Patients Administered Single and Multiple 50 mg/kg Doses Every 8 Hours by the Intravenous (I.V.) or Intramuscular (I.M.) Route,” 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, 1994, Orlando, Fl. Abs. A69.

Garrelts JC, Wagner DJ, "The Pharmacokinetics, Safety, and Tolerance of Cefepime Administered as an Intravenous Bolus or as a Rapid Infusion," Ann Pharmacother, 1999, 33(12):1258-61.

Heintz BH, Matzke GR, Dager WE, “Antimicrobial Dosing Concepts and Recommendations for Critically Ill Adult Patients Receiving Continuous Renal Replacement Therapy or Intermittent Hemodialysis,” Pharmacotherapy, 2009, 29(5):562-77.

Malone RS, Fish DN, Abraham E, et al, "Pharmacokinetics of Cefepime During Continuous Renal Replacement Therapy in Critically Ill Patients," Antimicrob Agents Chemother, 2001, 45(11):3148-55.

Saez-Llorens X, Castano E, Garcia R, et al, “Prospective Randomized Comparison of Cefepime and Cefotaxime for Treatment of Bacterial Meningitis in Infants and Children,” Antimicrob Agents Chemother, 1995, 39(4):937-40.

Solomkin JS, Mazuski JE, Bradley JS, et al, “Diagnosis and Management of Complicated Intra-Abdominal Infections in Adults and Children: Guidelines by the Surgical Infection Society and the Infectious Diseases Society of America,” Clin Infect Dis, 2010, 50(2):133-64.

Trotman RL, Williamson JC, Shoemaker DM, et al, "Antibiotic Dosing in Critically Ill Adult Patients Receiving Continuous Renal Replacement Therapy," Clin Infect Dis, 2005, 41(8):1159-66.

Tunkel AR, Hartman BJ, Kaplan SL, et al, “Practice Guidelines for the Management of Bacterial Meningitis,” Clin Infect Dis, 2004, 39(9):1267-84.

Yahav D, Paul M, Fraser A, et al, “Efficacy and Safety of Cefepime: A Systematic Review and Meta-Analysis,” Lancet Infect Dis, 2007, 7(5):338-48.

International Brand Names

• Aspime (TH)
• Axepim (FR)
• Axera (PH)
• Caprifim (ID)
• Cefemax (TW)
• Cefepima (CO)
• Cefepitax (BR)
• Ceficad (IN)
• Cepiram (PH)
• Dimipra (PH)
• Efectus (DO)
• Emax (ID)
• Exepime (ID)
• Forzyn Beta (PY)
• Funjapin (TW)
• Interprim (ID)
• Kabol (DO)
• Macef (ID)
• Macepim (TW)
• Maxcef (AR, UY)
• Maxef (MX)
• Maxfrom (AR)
• Maxicef (ID)
• Maxilan (ID)
• Maxipime (AT, AU, BE, BG, CH, CL, CN, CZ, DE, DK, EC, EE, ES, FI, GR, HK, HN, HU, IT, JP, KP, LU, MX, MY, NL, NZ, PE, PK, PL, PT, RU, SE, SG, TH, TR, TW, VE, ZA)
• Megapime (MY)
• Orpime (TH)
• Pimcep (PH)
• Pime (TH)
• Procepim (ID)
• Rapime (ID)
• Sanpime (PH)
• Sefpime (TH)
• Silex (PH)
• Supecef (TW)
• Zepim (PH)
• Zepime (PH)

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Last full review/revision March 2012