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Cefepime Hydrochloride

Pronunciation

Class: Fourth Generation Cephalosporins
Chemical Name: [6R - (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
CAS Number: 123171-59-5
Brands: Maxipime

Introduction

Antibacterial; β-lactam antibiotic; fourth generation cephalosporin.1 6

Uses for Cefepime Hydrochloride

Intra-abdominal Infections

Treatment of complicated intra-abdominal infections caused by Escherichia coli, viridans streptococci, Pseudomonas aeruginosa, Klebsiella pneumoniae, Enterobacter, or Bacteroides fragilis; used in conjunction with IV metronidazole.1 37 69 70 92 95

For initial empiric treatment of high-risk or severe community-acquired extrabiliary intra-abdominal infections in adults, 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

Has been used alone for treatment of acute obstetric and gynecologic infections (e.g., pelvic inflammatory disease [PID], pelvic surgical wound infection, postpartum endometritis),41 but safety and efficacy of cefepime monotherapy in these infections not established.1

Respiratory Tract Infections

Treatment of moderate to severe pneumonia (with or without concurrent bacteremia) caused by susceptible Streptococcus pneumoniae.1 5 8 14 15 92 95

Treatment of moderate to severe pneumonia caused by susceptible Ps. aeruginosa, K. pneumoniae, or Enterobacter.1 5 8 14 15 92 95

Treatment of community-acquired pneumonia (CAP)40 43 caused by S. pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and Staphylococcus aureus.43 ATS and IDSA recommend cefepime for treatment of CAP only when Ps. aeruginosa is known or suspected to be involved.56 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, imipenem, 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.56 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.56

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Treatment of nosocomial pneumonia.67 69 For empiric treatment in severely ill patients or in those with late-onset disease or risk factor for multidrug-resistant bacteria, used in conjunction with either an aminoglycoside (amikacin, gentamicin, tobramycin) or an antipseudomonal fluoroquinolone (ciprofloxacin, levofloxacin).69 In hospitals where methicillin-resistant (oxacillin-resistant) Staphylococcus is common or if there are risk factors for these strains, initial regimen also should include vancomycin or linezolid.67 69

Skin and Skin Structure Infections

Treatment of uncomplicated skin and skin structure infections caused by susceptible S. aureus (methicillin-susceptible [oxacillin-susceptible] strains only) or susceptible S. pyogenes (group A β-hemolytic streptococci).1 3 5 6 7 8 14 17 92 95

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 E. coli, K. pneumoniae, or Proteus mirabilis.1 3 5 6 8 9 16 92 95

Treatment of severe uncomplicated and complicated UTIs (including those associated with pyelonephritis and/or concurrent bacteremia) caused by susceptible E. coli or K. pneumoniae.1 6 7 14 45 92 95

Endocarditis

Empiric treatment of culture-negative endocarditis in prosthetic valve recipients.94 AHA recommends multiple-drug regimen of vancomycin, gentamicin, cefepime, and rifampin for empiric treatment of culture-negative endocarditis with onset within 1 year of valve placement.94 Selection of the most appropriate anti-infective regimen is difficult and should be guided by epidemiologic features and clinical course of the infection.94 Consultation with an infectious diseases specialist recommended.94

Meningitis and Other CNS Infections

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

Safety and efficacy not established.1 92 Manufacturers caution that 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 Some clinicians state additional study needed regarding efficacy for treatment of meningitis, particularly for infections caused by penicillin- and/or cefotaxime-resistant S. pneumoniae.46 79 In addition, cefepime may not be a good choice for empiric treatment of meningitis if Acinetobacter may be involved.83

IDSA states cefepime is one of several alternatives for 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 treatment of meningitis caused by Ps. aeruginosa, IDSA and other experts recommend a regimen that includes an antipseudomonal cephalosporin (cefepime or ceftazidime) or carbapenem (imipenem or meropenem) given with or without an aminoglycoside (amikacin, gentamicin, tobramycin).75 76 Use results of in vitro susceptibility tests to guide treatment.75

IDSA also recommends a regimen of cefepime and vancomycin as one of several options that can be used 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

Septicemia

Treatment of septicemia caused by susceptible gram-negative bacteria.69

Select anti-infective for treatment of sepsis syndrome based on probable source of infection, causative organism, immune status of patient, and local patterns of bacterial resistance.69

For initial treatment of life-threatening sepsis in adults, some clinicians suggest 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 also suggest including an aminoglycoside or fluoroquinolone during initial few days of treatment.69

Empiric Therapy in Febrile Neutropenic Patients

Empiric treatment of presumed bacterial infections in febrile neutropenic patients.1 26 34 35 36 58 59 62 69 92

Has been effective as monotherapy for empiric therapy in febrile neutropenic patients;34 35 36 58 59 62 used in conjunction with other anti-infectives in some patients.69 Manufacturers caution that safety and efficacy data 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, severe or prolonged neutropenia).1

Consult published protocols on treatment of infections in febrile neutropenic patients for specific recommendations regarding selection of initial empiric regimen, when to change initial regimen, possible subsequent regimens, and duration of therapy in these patients.26 Consultation with an infectious disease expert knowledgeable about infections in immunocompromised patients also advised.26 32 38

Cefepime Hydrochloride Dosage and Administration

Administration

Administer by IV infusion1 3 5 6 12 14 92 95 or deep IM injection.1 3 5 6 12 14

Use IM route only for treatment of mild to moderate, uncomplicated or complicated UTIs caused by E. coli when this route is considered more appropriate.1 5

IV Infusion

If Y-type administration set used, discontinue other solution flowing through the tubing during cefepime infusion.1 92 95

Manufacturers recommend that aminoglycosides, ampicillin (>40 mg/mL), metronidazole, vancomycin, or aminophylline be administered separately from cefepime.1 92 95 (See Drug Compatibility under Compatibility.)

Reconstitution and Dilution

Reconstitute vials containing 500 mg, 1 g, or 2 g of cefepime with 5, 10, or 10 mL, respectively, of compatible IV solution to provide solutions containing approximately 100, 100, or 160 mg/mL, respectively.1 Then further dilute the appropriate dose of reconstituted solution in a compatible IV solution.1 (See Solution Compatibility under Compatibility.)

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.1

Reconstitute (activate) commercially available Duplex drug delivery system that contains 1 or 2 g of cefepime and 50 mL of 5% dextrose injection in separate chambers according to the manufacturer's directions.95 If refrigerated after reconstitution (see Storage under Stability), allow solution to reach room temperature prior to administration.95

Thaw commercially available premixed injection (frozen) at room temperature (25°C) or under refrigeration (5°C); do not thaw by immersion in a water bath or by exposure to microwave radiation.92 A precipitate may have formed in the frozen injection, but should dissolve with little or no agitation after reaching room temperature.92 Discard thawed injection if an insoluble precipitate is present or if container seals or outlet ports are not intact or leaks are found.92 Do not use in series connections with other plastic containers; such use could result in air embolism from residual air being drawn from primary container before administration of fluid from secondary container is complete.92

Rate of Administration

Administer by IV infusion over approximately 30 minutes.1 92 95

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.1

Dosage

Available as cefepime hydrochloride; dosage expressed in terms of cefepime, calculated on the anhydrous basis.1 92 95

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.1 92 95

Neonates ≤28 days of age: AAP recommends 30 mg/kg every 12 hours; 50 mg/kg every 12 hours may be needed for Pseudomonas infections.64

Children beyond neonatal period: AAP recommends 100 mg/kg daily in 2 equally divided doses for treatment of mild to moderate infections and 100–150 mg/kg daily in 2 or 3 equally divided doses for treatment of severe infections.64

Do not use cefepime available in Duplex containers or the cefepime premixed injection (frozen) in pediatric patients who require less than the entire 1- or 2-g dose in the container.92 95

Intra-abdominal Infections
Complicated Infections
IV

50 mg/kg every 12 hours for 4–7 days (in conjunction with IV metronidazole) recommended by IDSA.70 Longer treatment duration not associated with improved outcome and not recommended unless adequate source control difficult to achieve.70

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.1 92 95

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.1 92 95

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.1 92 95

Endocarditis
Culture-negative Endocarditis
IV

150 mg/kg daily given in 3 equally divided doses in conjunction with vancomycin (40 mg/kg IV daily in 2 or 3 equally divided doses), gentamicin (3 mg/kg IV or IM daily in 3 equally divided doses), and rifampin (20 mg/kg orally or IV daily in 3 equally divided doses) recommended by AHA.94 Continue multiple-drug regimen for 6 weeks; discontinue gentamicin after first 2 weeks.94

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.1 92 95

Frequently reevaluate need for continued anti-infective therapy if fever resolves but neutropenia remains for >7 days.1 92 95

Adults

Intra-abdominal Infections
Complicated Infections
IV

2 g every 12 hours for 7–10 days; use in conjunction with IV metronidazole.1 92 95

Some clinicians recommend 2 g every 8–12 hours for 4–7 days;70 longer treatment duration not associated with improved outcome and not recommended unless adequate source control difficult to achieve.70

Respiratory Tract Infections
Moderate to Severe Pneumonia
IV

1–2 g every 12 hours for 10 days.1 92 95

1–2 g every 8–12 hours recommended for initial therapy of hospital-acquired pneumonia, ventilator-associated pneumonia, or healthcare-associated pneumonia.67 92

Skin and Skin Structure Infections
Moderate to Severe Uncomplicated Infections
IV

2 g every 12 hours for 10 days.1 92 95

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.1 92 95

Severe Uncomplicated or Complicated UTIs
IV

2 g every 12 hours for 10 days.1 92 95

Endocarditis
Culture-negative Endocarditis
IV

6 g daily given in 3 equally divided doses in conjunction with vancomycin (30 mg/kg IV daily given in 2 equally divided doses), gentamicin (3 mg/kg IV or IM daily given in 3 equally divided doses), and rifampin (900 mg orally or IV daily in 3 equally divided doses) recommended by AHA.94 Continue multiple-drug regimen for 6 weeks; discontinue gentamicin after first 2 weeks.94

Empiric Therapy in Febrile Neutropenic Patients
IV

2 g every 8 hours for 7 days or until neutropenia resolves.1 34 35 36 92 95

Frequently reevaluate need for continued anti-infective therapy if fever resolves but neutropenia remains for >7 days.1 92 95

Prescribing Limits

Pediatric Patients

Do not exceed recommended adult dosage.1 92 95

Special Populations

Hepatic Impairment

Dosage adjustments not required.1 92

Renal Impairment

Dosage adjustments necessary in patients with Clcr ≤60 mL/minute.1 92 95

Adults with Clcr ≤60 mL/minute (not undergoing hemodialysis): Give an initial dose using usually recommended adult dosage followed by maintenance dosage based on Clcr.1 92 95 (See Table 1 and Table 2.)

Table 1. Maintenance Dosage for Treatment of Infections in Adults with Renal Impairment19295

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 Impairment19295

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.1 92 95 Administer the dose at the same time each day (given at completion of procedure on hemodialysis days).1 92 95

Adults undergoing CAPD: Give usually recommended dose once every 48 hours.1 6 10 12 92 95

Pediatric patients with renal impairment: Dosage adjustments required proportional to those recommended for adults.1 92

Cautions for Cefepime Hydrochloride

Contraindications

  • Immediate hypersensitivity to cefepime, other cephalosporins, penicillins, or other β-lactams.1 92 95

  • Solutions containing dextrose may be contraindicated in patients with known allergy or hypersensitivity to corn or corn products.92 95

Warnings/Precautions

Warnings

Superinfection/Clostridium difficile-associated Diarrhea and Colitis

Possible emergence and overgrowth of nonsusceptible organisms with prolonged therapy.1 92 95 Careful observation of the patient is essential.1 92 Institute appropriate therapy if superinfection occurs.1 92 95

Treatment with anti-infectives alters 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 development of CDAD;1 92 95 96 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.1 92 95

Consider CDAD if diarrhea develops and manage accordingly.1 92 95 96 Obtain a careful medical history since CDAD may occur as late as 2 months or longer after anti-infective therapy is discontinued.1 92 95

If CDAD is suspected or confirmed, discontinue anti-infectives not directed against C. difficile whenever possible.1 95 96 Initiate 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 indicated.1 92 95 96

Neurotoxicity

Serious adverse events, including life-threatening or fatal encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, coma), myoclonus, and seizures reported rarely.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 reported.85 91 93 95

Most cases of cefepime-associated neurotoxicity occurred in patients with renal impairment who received dosages of the drug inappropriately high for their renal status;1 85 86 87 88 91 92 93 95 some cases occurred in patients who received dosage adjusted for renal function1 92 95 or in patients with normal renal function.87 88 93

Symptoms of neurotoxicity generally were reversible and resolved after cefepime was discontinued and/or after hemodialysis.1 92 93 95

If neurotoxicity associated with cefepime therapy occurs, consider discontinuing the drug or making dosage adjustment appropriate for patient's renal function.1 92 95 (See Renal Impairment under Dosage and Administration.)

Increased Mortality

In November 2007, FDA announced initiation of a cefepime safety review 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

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 A 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 A patient-level meta-analysis 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

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.1 92 95

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).1 92 95

Cross-hypersensitivity

Partial cross-sensitivity among cephalosporins and other β-lactam antibiotics, including penicillins and cephamycins.1 92 95

Prior to initiation of therapy, make careful inquiry concerning previous hypersensitivity reactions to cephalosporins, penicillins, or other drugs.1 92 Cautious use recommended in individuals hypersensitive to penicillins:1 92 95 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.a

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.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

History of GI Disease

Use 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.)

Arginine Content

Commercially available cefepime preparations contain l-arginine to adjust pH.1 92 95

At concentrations 33 times higher than the amount provided by the maximum recommended human cefepime dosage, arginine has altered glucose metabolism and transiently increased serum potassium concentrations.1 92 95 The effect of lower arginine concentrations not known.1 92 95

Patients with Diabetes

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

Specific Populations

Pregnancy

Category B.1 92 95

Lactation

Distributed into milk;1 6 92 95 use with caution.1 92 95

Pediatric Use

Safety and efficacy not established in neonates or infants <2 months of age.1 92 95

Safety and efficacy established for use in pediatric patients 2 months to 16 years of age for 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 supported by evidence from adequate and well-controlled adult studies and additional pharmacokinetic and safety data from pediatric studies.1 92 95

Not recommended for treatment of serious infections suspected or known to be caused by Haemophilus influenzae type b (Hib); manufacturers recommend use of an alternative anti-infective if the possibility of meningeal seeding from a distant infection site or meningitis is suspected or documented.1 92 95 (See Uses: Meningitis and Other CNS Infections.)

Do not use cefepime available in Duplex container or the commercially available cefepime premixed injection (frozen) in pediatric patients unless the entire 1- or 2-g dose in the container is required.92 95

Pharmacokinetic and adverse effect profiles similar to those reported in adults.1 92 95

Geriatric Use

Safety and efficacy in those ≥65 years of age similar to that in younger adults.1 92 95

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.1 92 95

Substantially eliminated by kidneys; risk of toxicity may be greater in those with impaired renal function.1 92 95 Select dosage with caution and assess renal function periodically because of age-related decreases in renal function.1 92 95 (See Renal Impairment under Dosage and Administration.)

Hepatic Impairment

Pharmacokinetics not affected.1 92

Renal Impairment

Possible decreased clearance and increased serum half-life.1 6 92 95

Serious adverse events, including life-threatening or fatal encephalopathy, may occur if inappropriately high dosage is used in patients with renal impairment.1 85 86 87 91 92 93 95 (See Neurotoxicity under Cautions.)

Dosage adjustments necessary in patients with Clcr ≤60 mL/minute.1 92 95 (See Renal Impairment under Dosage and Administration.)

Common Adverse Effects

Diarrhea,1 24 33 92 nausea,1 24 33 92 vomiting,1 23 33 92 rash,92 local reactions (e.g., phlebitis, pain, inflammation).1 92

Interactions for Cefepime Hydrochloride

Specific Drugs and Laboratory Tests

Drug or Test

Interaction

Comments

Aminoglycosides

Possible increased risk of nephrotoxicity and ototoxicity1 92 95

Closely monitor renal function if used concomitantly1 92 95

Tests for glucose

Possible false-positive reactions in urine glucose tests using Clinitest, Benedict’s solution, or Fehling’s solution1 92 95 a

Use glucose tests based on enzymatic glucose oxidase reactions (e.g., Clinistix, Tes-Tape)1 92 95 a

Cefepime Hydrochloride Pharmacokinetics

Absorption

Bioavailability

Not appreciably absorbed from GI tract; must be administered parenterally.1

Almost completely absorbed following IM administration;1 44 peak serum concentrations attained within 1.4–1.6 hours.1

Distribution

Extent

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

Distributed into CSF following IV administration in adults or pediatric patients.1 5 46 78 81 82 84 92

Distributed into milk.1 6

Plasma Protein Binding

20%.1

Elimination

Metabolism

Partially metabolized in vivo to N-methylpyrrolidine (NMP), which is rapidly converted to the N-oxide (NMP-N-oxide).1

Elimination Route

Eliminated principally unchanged in urine by glomerular filtration.1 47 49

In adults with normal renal function, 80–82% of a single dose excreted unchanged in urine;1 42 47 49 < 1% of the dose eliminated as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of the drug.1

Half-life

Adults with normal renal function: 2–2.3 hours.1 3 39 49

Children 2 months to 16 years of age: 1.5-1.9 hours.44

Neonates <2 months of age: 4.9 hours.80

Special Populations

Pharmacokinetics not affected by hepatic impairment.1

Patients with renal impairment: Clearance decreased and plasma half-life prolonged.1 42 Half-life averages 4.9, 10.5, 13.5 hours in those with Clcr 31–60, 11–30, or <10 mL/minute, respectively.42

Stability

Storage

Parenteral

Powder for IM Injection or IV Infusion

20–25° C; protect from light.1

Powder and reconstituted solutions may darken; does not indicate loss of potency.1

IV solutions containing 1–40 mg/mL prepared using compatible IV solution, are stable for 24 hours at 20–25°C or 7 days at 2–8°C.1

Reconstituted IM solutions containing 280 mg/mL are stable for 24 hours at 20–25°C or 7 days at 2–8°C.1

For Injection, for IV Infusion

Following reconstitution of ADD-Vantage vials, IV solutions containing 10–40 mg/mL are stable for 24 hours at 20–25°C or 7 days at 2–8°C.1

Store Duplex drug delivery system that contains 1 or 2 g of cefepime and 50 mL of 5% dextrose injection at 20–25°C (may be exposed to 15–30°C).95 Following reconstitution (activation), use within 12 hours if stored at room temperature or within 5 days if stored in a refrigerator; do not freeze.95

Injection (Frozen) for IV Infusion

-20°C or lower.92 Thawed solutions are stable for 24 hours at room temperature (25°C) or 7 days under refrigeration (5°C).92

Do not refreeze after thawing.92

Compatibility

For information on systemic interactions resulting from concomitant use, see Interactions.

Parenteral

Solution Compatibility

Compatible

Amino acids 4.25%, dextrose 25% with electrolytesHID

Dextrose 5% in Ringer’s injection, lactated1 HID

Dextrose 5% in sodium chloride 0.9%1 HID

Dextrose 5 or 10% in water1 HID

Normosol M in dextrose 5%1 HID

Normosol R1 HID

Normosol R in dextrose 5%

Sodium chloride 0.9%1 HID

Drug Compatibility
Admixture CompatibilityHID

Compatible

Amikacin sulfate

Clindamycin phosphate

Heparin sodium

Potassium chloride

Theophylline

Vancomycin HCl

Incompatible

Aminophylline

Gentamicin sulfate

Tobramycin sulfate

Variable

Ampicillin sodium

Metronidazole

Y-Site CompatibilityHID

Compatible

Amikacin sulfate

Ampicillin sodium–sulbactam sodium

Anidulafungin

Aztreonam

Bivalirudin

Bleomycin sulfate

Bumetanide

Buprenorphine HCl

Butorphanol tartrate

Calcium gluconate

Carboplatin

Carmustine

Clarithromycin

Co-trimoxazole

Cyclophosphamide

Cytarabine

Dactinomycin

Dexamethasone sodium phosphate

Dexmedetomidine HCl

Docetaxel

Doxorubicin HCl liposome injection

Fenoldopam mesylate

Fluconazole

Fludarabine phosphate

Fluorouracil

Furosemide

Gentamicin sulfate

Granisetron HCl

Hetastarch in lactated electrolyte injection (Hextend)

Hydrocortisone sodium phosphate

Hydrocortisone sodium succinate

Hydromorphone HCl

Imipenem–cilastatin sodium

Insulin

Isosorbide dinitrate

Leucovorin calcium

Lorazepam

Melphalan

Mesna

Methotrexate sodium

Methylprednisolone sodium succinate

Metronidazole

Milrinone lactate

Mycophenolate mofetil HCl

Paclitaxel

Piperacillin sodium–tazobactam sodium

Ranitidine HCl

Remifentanil HCI

Sargramostim

Sodium bicarbonate

Sufentanil citrate

Thiotepa

Ticarcillin disodium–clavulanate potassium

Tigecycline

Tobramycin sulfate

Valproate sodium

Zidovudine

Incompatible

Acetylcysteine

Acyclovir sodium

Amphotericin B

Amphotericin B cholesteryl sulfate complex

Caspofungin acetate

Chlordiazepoxide HCl

Chlorpromazine HCl

Cimetidine HCl

Ciprofloxacin

Cisplatin

Dacarbazine

Daunorubicin HCl

Diazepam

Diphenhydramine HCl

Doxorubicin HCl

Droperidol

Enalaprilat

Erythromycin lactobionate

Etoposide

Etoposide phosphate

Famotidine

Filgrastim

Floxuridine

Gallium nitrate

Ganciclovir sodium

Haloperidol lactate

Hydroxyzine HCl

Idarubicin HCl

Ifosfamide

Lansoprazole

Magnesium sulfate

Mannitol

Mechlorethamine HCl

Meperidine HCl

Metoclopramide HCl

Midazolam HCI

Mitomycin

Mitoxantrone HCl

Nalbuphine HCl

Nicardipine HCI

Ofloxacin

Ondansetron HCl

Phenytoin sodium

Plicamycin

Prochlorperazine edisylate

Promethazine HCl

Streptozocin

Theophylline

Vinblastine sulfate

Vincristine sulfate

Variable

Dobutamine hydrochloride

Dopamine HCI

Morphine sulfate

Propofol

Vancomycin HCI

Actions and Spectrum

  • Based on spectrum of activity, classified as a fourth generation cephalosporin.1 3 4 6 11 20 21 22 a

  • 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.3 4 11 20 21 22 More resistant to inactivation by chromosomally and plasmid-mediated β-lactamases than most other cephalosporins;a hydrolyzed by β-lactamases at a slower rate than third generation cephalosporins.a

  • Usually bactericidal.1 a

  • Like other β-lactam antibiotics, antibacterial activity results from inhibition of bacterial cell wall synthesis.1 64

  • Spectrum of activity includes many gram-positive bacteria3 4 and many gram-negative bacteria (including Pseudomonas aeruginosa and certain Enterobacteriaceae).3 4 23 Inactive against fungi and viruses.a

  • 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.1 a Also active in vitro against S. epidermidis (methicillin-susceptible [oxacillin-susceptible] strains only), S. saprophyticus, and S. agalactiae (group B streptococci).1 a Enterococci (e.g., Enterococcus faecalis), oxacillin-resistant (methicillin-resistant) staphylococci, and Listeria monocytogenes are resistant.1 a

  • Gram-negative aerobes: Active in vitro and in clinical infections against Enterobacter, E. coli, K. pneumoniae, P. mirabilis, and Ps. aeruginosa.1 a 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.1 a Inactive against Stenotrophomonas.1

  • 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.55

Advice to Patients

  • Advise patients 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

  • Importance of completing full course of therapy, even if feeling better after a few days.1 92 95

  • 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.1 92 95

  • Advise patients that diarrhea is a common problem caused by anti-infectives and usually ends when the drug is discontinued.1 92 95 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.1 92 95

  • Advise patients that neurologic adverse events can occur.1 92 95 Importance of immediately contacting a clinician if any neurologic signs and symptoms, including encephalopathy (disturbance of consciousness including confusion, hallucinations, stupor, coma), myoclonus, or seizures, occur since immediate treatment, dosage adjustment, or discontinuance of the drug is required.1 92 95

  • Importance of informing clinicians if an allergic reaction occurs.1 92 95

  • Importance of women informing clinician if they are or plan to become pregnant or plan to breast-feed.1 92 95

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs.1 92 95

  • Importance of informing patients of other precautionary information.1 92 95 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Cefepime Hydrochloride

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

For injection

500 mg (of anhydrous cefepime)*

Cefepime Hydrochloride for Injection

Maxipime

Hospira

1 g (of anhydrous cefepime)*

Cefepime Hydrochloride for Injection

Maxipime

Hospira

2 g (of anhydrous cefepime)*

Cefepime Hydrochloride for Injection

Maxipime

Hospira

For injection, for IV infusion

1 g (of anhydrous cefepime)*

Cefepime Hydrochloride for Injection (available in dual-chambered Duplex drug delivery system with 5% dextrose injection)

B Braun

Maxipime ADD-Vantage

Hospira

2 g (of anhydrous cefepime)*

Cefepime Hydrochloride for Injection (available in dual-chambered Duplex drug delivery system with 5% dextrose injection)

B Braun

Maxipime ADD-Vantage

Hospira

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Cefepime Hydrochloride in Dextrose

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Parenteral

Injection (frozen), for IV infusion

20 mg (of cefepime) per mL (1 g) in 2% Dextrose*

Cefepime Hydrochloride Iso-osmotic in Dextrose Injection (Galaxy [Baxter])

20 mg (of cefepime) per mL (2 g) in 2% Dextrose*

Cefepime Hydrochloride Iso-osmotic in Dextrose Injection (Galaxy [Baxter])

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions September 4, 2013. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

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. [IDIS 325765] [PubMed 8017411]

4. Rybak MJ, Palmer SM. Cefepime: part of the new generation. Am J Hosp Pharm. 1994; 51:459-60. [IDIS 325764] [PubMed 8017410]

5. Hardin TC, Jennings TS. Cefepime. Pharmacotherapy. 1994; 14:657-68. [IDIS 339294] [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. [IDIS 296000] [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. [IDIS 267800] [PubMed 2203309]

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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. [IDIS 298960] [PubMed 1510432]

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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]

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26. Freifeld AG, Bow EJ, Sepkowitz KA et al. Clinical Practice Guideline for the Use of Antimicrobial Agents in Neutropenic Patients with Cancer: 2010 Update by the Infectious Disease Society of America. Clin Infect Dis. 2011; 52:e56-93.

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28. Kishiyam JL, Adelman DC. The cross-reactivity and immunology of β-lactam antibiotics. Drug Saf. 1994; 10:318-27. [PubMed 8018304]

29. Thompson JW, Jacobs RF. Adverse effects of newer cephalosporins: an update. Drug Saf. 1993; 9:132-42. [PubMed 8397890]

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31. Grassi GG, Grassi C. Cefepime: overview of activity in vitro and in vivo. J Antimicrob Chemother. 1993; 32(Suppl B):87-94. [PubMed 8150771]

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33. Neu HC. Safety of cefepime: a new extended-spectrum parenteral cephalosporin. Am J Med. 1996; 100(Suppl 6A):68S-75S. [IDIS 370420] [PubMed 8678100]

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35. Ramphal R, Gucalp R, Rotstein C et al. Clinical experience with single agent and combination regimens in the management of infection in the febrile neutropenic patient. Am J Med. 1996; 100(Suppl 6A):83-89S.

36. Yamamura D, Gucalp R, Carlisle P et al. Open randomized study of cefepime versus piperacillin-gentamicin for treatment of febrile neutropenic cancer patients. Antimicrob Agents Chemother. 1997; 41:1704-8. [IDIS 389693] [PubMed 9257745]

37. Barie PS, Vogel SB, Dellinger EP et al. A randomized, double-blind clinical trial comparing cefepime plus metronidazole with imipenem-cilastatin in the treatment of complicated intra-abdominal infections. Arch Surg. 1997; 132:1294-302. [IDIS 398335] [PubMed 9403533]

38. Viscoli C. The evolution of the empirical management of fever and neutropenia in cancer patients. J Antimicrob Chemother. 1998; 41(Suppl D):65-80. [IDIS 409104] [PubMed 9688453]

39. Nye KJ, Shi YG, Andrews JM et al. Pharmacokinetics and tissue penetration of cefepime. J Antimicrob Chemother. 1989; 24:23-8. [PubMed 2777727]

40. Léophonte P, Bertrand A, Nouvet G et al. A comparative study of cefepime and ceftazidime in the treatment of community-acquired lower respiratory tract infections. J Antimicrob Chemother. 1993; 31(Suppl B):165-73.

41. Newton ER, Yeomans ER, Pastorek JG et al. Randomized comparative study of cefepime and cefotaxime in the treatment of acute obstetric and gynaecological infections. J Antimicrob Chemother. 1993; 32(Suppl B):195-204. [PubMed 8150763]

42. Barbhaiya RH, Knupp CA, Forgue ST et al. Pharmacokinetics of cefepime in subjects with renal insufficiency. Clin Pharmacol Ther. 1990; 48:268-76. [IDIS 271948] [PubMed 2401125]

43. Zervos M, Nelson M, and the Cefepime Study Group. Cefepime versus ceftriaxone for empiric treatment of hospitalized patients with community-acquired pneumonia. Antimicrob Agents Chemother. 1998; 42:729-33. [IDIS 403741] [PubMed 9559773]

44. Reed MD, Yamashita TS, Knupp CK et al. Pharmacokinetics of intravenously and intramuscularly administered cefepime in infants and children. Antimicrob Agents Chemother. 1997; 41:1783-7. [IDIS 389702] [PubMed 9257761]

45. Kieft H, Hoepelman AIM, Rozenberg-Arska M et al. Cefepime compared with ceftazidime as initial therapy for serious bacterial infections and sepsis syndrome. Antimicrob Agents Chemother. 1993; 38:415-21.

46. Sáez-llorens X, Castano E, Garí R et al. Prospective randomized comparison of cefepime and cefotaxime for treatment of bacterial meningitis in infants and children. Antimicrob Agents Chemother. 1995; 39:937-40. [IDIS 345412] [PubMed 7785999]

47. Barbhaiya RH, Forgue ST, Gleason CR et al. Safety, tolerance, and pharmacokinetic evaluation of cefepime after administration of single intravenous doses. Antimicrob Agents Chemother. 1990; 34:1118-22. [IDIS 267815] [PubMed 2203303]

48. Kalman D, Barriere SL, Johnson BL. Pharmacokinetic disposition and bactericidal activities of cefepime, ceftazidime, and cefoperazone in serum and blister fluid. Antimicrob Agents Chemother. 1992; 36:453-7. [IDIS 292237] [PubMed 1605609]

49. Barbhaiya RH, Forgue ST, Gleason CR et al. Pharmacokinetics of cefepime after single and multiple intravenous administrations in healthy subjects. Antimicrob Agents Chemother. 1992; 36:552-7. [IDIS 292612] [PubMed 1622165]

50. Barbhaiya RH, Knupp CA, Pittman KA. Effects of age and gender on pharmacokinetics of cefepime. Antimicrob Agents Chemother. 1992; 36:1181-5. [IDIS 297435] [PubMed 1416818]

51. 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. [IDIS 298960] [PubMed 1510432]

52. Cronqvist J, Nilsson-Ehle I, Oqvist B et al. Pharmacokinetics of cefepime dihydrochloride arginine in subjects with renal impairment. Antimicrob Agents Chemother. 1992; 36:2676-80. [IDIS 306777] [PubMed 1482136]

53. Rolston KV. Expanding the options for risk-based therapy in febrile neutropenia. Diagn Microbiol Infect Dis. 1998; 31:411-6. [PubMed 9635917]

54. Link H, Maschmeyer G, Meyer P et al. Interventional antimicrobial therapy in febrile neutropenic patients. Ann Hematol. 1994; 69:231-43. [PubMed 7948312]

55. Clinical and Laboratory Standards Institute. Performance standards for antimicrobial susceptibility testing: Twenty-first informational supplement. CLSI document M100-S21. Wayne, PA; 2011.

56. Mandell LA, Wunderink RG, Anzueto A et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007; 44 Suppl 2:S27-72. [PubMed 17278083]

57. Bristol-Myers Squibb, Princeton, NJ: Personal communication.

58. Hathorn J, Chandrasakar P, Baird I et al. Double-blind comparison of cefepime vs ceftazidime to treat febrile neutropenia. Proceedings of ICAAC New Orleans 1996. Abstract No. LM22.

59. Biron P, Fuhrmann C, Cure H et al. Cefepime versus imipenem-cilastatin as empirical monotherapy in 400 febrile patients with short duration neutropenia. J Antimicrob Chemother. 1998; 42:511-8. [IDIS 414552] [PubMed 9818751]

60. O’Ryan M, Saez-llorens X, Santos JI et al. Cefepime vs. ceftriaxone for pediatric meningitis. Proceedings of ICAAC New Orleans 1996. Abstract No. LM23.

61. Reviewers’ comments (personal observations).

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86. Chow KM, Szeto CC, Hui AC et al. Retrospective review of neurotoxicity induced by cefepime and ceftazidime. Pharmacotherapy. 2003; 23:369-73. [PubMed 12627936]

87. Lam S, Gomolin IH. Authors’ reply. Pharmacotherapy. 2007; 27:e2. Letter.

88. Abanades S, Pardo-Lozano R, Farre M et al. New insights on cefepime associated neurotoxicity. Pharmacotherapy. 2007; 27:e1-2.

89. Pereira CA, Petrilli AS, Carlesse FA et al. Cefepime monotherapy is as effective as ceftriaxone plus amikacin in pediatric patients with cancer and high-risk febrile neutropenia in a randomized comparison. J Microbiol Immunol Infect. 2009; 42:141-7. [PubMed 19597646]

90. Uygun V, Karasu GT, Ogunc D et al. Piperacillin/tazobactam versus cefepime for the empirical treatment of pediatric cancer patients with neutropenia and fever: A randomized and open-label study. Pediatr Blood Cancer. 2009; 53:610-4. [PubMed 19484759]

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93. Food and Drug Administration. Drug safety communication: Cefepime and risk of seizure in patients not receiving dosage adjustments for kidney impairment. From FDA website. Accessed 2013 Jun 6.

94. Baddour LM, Wilson WR, Bayer AS et al. Infective endocarditis: diagnosis, antimicrobial therapy, and management of complications: a statement for healthcare professionals from the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease, Council on Cardiovascular Disease of the Young, and the Councils on Clinical Cardiology, Stroke, and Cardiovascular Surgery and Anesthesia, American Heart Association: endorsed by the Infectious Diseases Society of America. Circulation. 2005; 111:e394-433. [PubMed 15956145]

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96. Cohen SH, Gerding DN, Johnson S et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Rpidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010; 31:431-55. [PubMed 20307191]

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