Cefepime

J01D - Other beta-lactam antibacterials ATC J01DE01 Small molecule approved 1996 Parenteral Natural product

🧬 Cross-allergy: Cephalosporins

JFDA label: Cefepime/Demo

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.

Indications

Approved

Febrile neutropenia
Intra-abdominal infections
Pneumonia (moderate to severe)
Skin and skin structure infections
Urinary tract infections (including pyelonephritis)

Off-label

Bacterial meningitis
Endocarditis, prosthetic valve, treatment within 1 year of replacement (pediatric)
Osteomyelitis, native vertebral
Prosthetic joint infection

Antimicrobial Spectrum

Expected / intrinsic spectrum (EUCAST breakpoints & labels) — not local resistance. Source: EUCAST v16 · curated · openfda-label.

Bacteria

Organism	Activity	MIC
Acinetobacter calcoaceticus	Active	—
Aeromonas spp.	Susceptible	1.0 mg/L
Bacteroides fragilis	Active	—
Citrobacter diversus	Active	—
Citrobacter freundii	Active	—
Enterobacter agglomerans	Active	—
Enterobacter cloacae	Susceptible	1.0 mg/L
Enterobacterales	Susceptible	1.0 mg/L
Enterococcus faecalis	Active	—
Escherichia coli	Susceptible	1.0 mg/L
Haemophilus influenzae	Susceptible	0.25 mg/L
Klebsiella oxytoca	Active	—
Klebsiella pneumoniae	Susceptible	1.0 mg/L
Moraxella catarrhalis	Susceptible	4.0 mg/L
Morganella morganii	Active	—
Proteus mirabilis	Active	—
Proteus vulgaris	Active	—
Providencia rettgeri	Active	—
Providencia stuartii	Active	—
Pseudomonas aeruginosa	Susceptible	8.0 mg/L
Pseudomonas aeruginosa	Susceptible	0.001 mg/L
Serratia marcescens	Active	—
Staphylococcus aureus	Active	—
Staphylococcus epidermidis	Active	—
Staphylococcus saprophyticus	Active	—
Streptococcus agalactiae	Active	—
Streptococcus pneumoniae	Susceptible	1.0 mg/L
Streptococcus pneumoniae	Susceptible	1.0 mg/L
Streptococcus pyogenes	Active	—
Viridans group streptococci	Susceptible	0.5 mg/L
Enterobacter cloacae	Resistant	4.0 mg/L
Escherichia coli	Resistant	4.0 mg/L
Klebsiella pneumoniae	Resistant	4.0 mg/L
Pseudomonas aeruginosa	Resistant	8.0 mg/L

Class profile

gramStatus	Both
spectrumBreadth	Extended
atypicalCoverage	No
isBactericidal	1
moaCategory	Cell wall synthesis inhibitor (beta-lactam, 4th generation cephalosporin)
pdIndex	Time-dependent
postAntibioticEffect	None
mrsaCoverage	0
resistanceMechanisms	ESBL production (partial stability),Carbapenemase,AmpC overexpression

Contraindications

Source: Lexicomp

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

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Cardiac disorders (1)

Common Localized phlebitis

Nervous system disorders (1)

Common Headache

Hepatobiliary disorders (4)

Common abnormal partial thromboplastin time · abnormal prothrombin time · Increased serum ALT · increased serum AST

Blood and lymphatic system disorders (1)

Common Eosinophilia

Immune system disorders (1)

Common Hypersensitivity

Metabolism and nutrition disorders (1)

Common Hypophosphatemia

Gastrointestinal disorders (3)

Common Diarrhea · nausea · vomiting

Skin and subcutaneous tissue disorders (2)

Common pruritus · Skin rash

General disorders and administration site conditions (1)

Common Fever

Other (1)

Very Common Hematologic & oncologic: Positive direct Coombs test

Dosing

Source: Lexicomp

Febrile neutropenia: IV: 2 g every 8 hours Intra-abdominal infections, complicated, severe (in combination with metronidazole): IV: Note: 2010 IDSA guidelines recommend a duration of 4 to 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 [IDSA] 2010). Due to P. aeruginosa: 2 g every 8 hours for 7 to 10 days Not due to P. aeruginosa: 2 g every 8 to 12 hours for 7 to 10 days Pneumonia: IV: Manufacturer’s labeling: Due to P. aeruginosa: 2 g every 8 hours for 10 days Not due to P. aeruginosa: 1 to 2 g every 8 to 12 hours for 10 days Alternate dosing: Hospital-acquired or ventilator-associated: 2 g every 8 hours for 7 days; may consider shorter or longer duration depending on rate of clinical improvement. Administration as an extended infusion may be considered. When used as empiric therapy, use in combination with an agent active against MRSA (unless coverage of MSSA only is appropriate) with or without an additional antipseudomonal agent (dependent on patient and institution-specific risk factors) (Kalil 2016) Skin and skin structure infection, uncomplicated (moderate to severe): IV: 2 g every 12 hours for 10 days Urinary tract infections, complicated and uncomplicated: Mild-to-moderate: IM, IV: 0.5 to 1 g every 12 hours for 7 to 10 days Severe: IV: 2 g every 12 hours for 10 days Bacterial meningitis (off-label use): IV: 2 g every 8 hours duration of therapy varies depending on pathogen (IDSA [Tunkel 2004]) Osteomyelitis, native vertebral (off-label use) (IDSA [Berbari 2015]): IV: P. aeruginosa: 2 g every 8 to 12 hours for 6 weeks. Note: Double coverage may be considered (ie, cefepime plus an aminoglycoside or ciprofloxacin). Enterobacteriaceae: 2 g every 12 hours for 6 weeks Prosthetic joint infection, Enterobacter spp. or Pseudomonas aeruginosa (off-label use): IV: 2 g every 12 hours for 4 to 6 weeks. Note: When treating P. aeruginosa, consider addition of an aminoglycoside (Osmon 2013).

(For additional information see "Cefepime: Pediatric drug information") General dosing, susceptible infection (Red Book [AAP 2015]): Infants, Children, and Adolescents: IM, IV: Mild to moderate infection: 50 mg/kg/dose every 12 hours; maximum dose: 2,000 mg/dose Severe infection: 50 mg/kg/dose every 8 to 12 hours; maximum dose: 2,000 mg/dose Endocarditis, prosthetic valve, treatment within 1 year of replacement (off-label use): Children and Adolescents: IV: 50 mg/kg/dose every 8 to 12 hours in combination with vancomycin and rifampin for 6 weeks plus gentamicin for the first 2 weeks; maximum dose: 2,000 mg/dose (AHA [Baltimore 2015]) Febrile neutropenia: Infants, Children, and Adolescents: IV: 50 mg/kg/dose every 8 hours (maximum dose: 2,000 mg/dose) (Red Book [AAP 2015]) Pneumonia: Infants ≥2 months, Children, and Adolescents: IV: Due to P. aeruginosa: 50 mg/kg/dose every 8 hours for 10 days (maximum dose: 2,000 mg/dose) Not due to P. aeruginosa: 50 mg/kg/dose every 12 hours for 10 days (maximum dose: 2,000 mg/dose) Skin and skin structure infections (uncomplicated): Infants ≥ 2 months, Children, and Adolescents: IV: 50 mg/kg/dose every 12 hours for 10 days (maximum dose: 2,000 mg/dose) Urinary tract infections, complicated and uncomplicated: Infants ≥ 2 months, Children, and Adolescents: IV, IM: Note: IM may be considered for mild to moderate infection only. Mild to moderate infection: IV, IM: 50 mg/kg/dose every 12 hours for 7 to 10 days (maximum dose: 1,000 mg/dose) Severe infection: IV: 50 mg/kg/dose every 12 hours for 10 days (maximum dose: 2,000 mg/dose) Intra-abdominal infection, complicated (off-label): Infants, Children, and Adolescents: IV: 50 mg/kg/dose every 12 hours in combination with metronidazole (maximum dose: 2,000 mg/dose). Note: IDSA 2010 guidelines recommend duration of 4 to 7 days (provided source controlled) (Solomkin [IDSA] 2010).

Refer to adult dosing.

Adults: Recommended maintenance schedule based on creatinine clearance (may be estimated using the Cockcroft-Gault formula), compared to normal dosing schedule: See table. Cefepime Hydrochloride Creatinine Clearance (mL/minute) Recommended Maintenance Schedule >60 (normal recommended dosing schedule) 500 mg every 12 hours 1 g every 12 hours 2 g every 12 hours 2 g every 8 hours 30-60 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours 2 g every 12 hours 11-29 500 mg every 24 hours 500 mg every 24 hours 1 g every 24 hours 2 g every 24 hours 250 mg every 24 hours 250 mg every 24 hours 500 mg every 24 hours 1 g every 24 hours Intermittent hemodialysis (IHD) (administer after hemodialysis on dialysis days): IV: 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) or 2 g 3 times weekly after dialysis (Perez 2012). Note: Dosing dependent on the assumption of 3 times weekly, 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). Infants ≥ 2 months, Children, and Adolescents: There are no dosage adjustments provided in the manufacturer’s labeling; however, similar dosage adjustments to adults would be anticipated based on comparable pharmacokinetics between children and adults.

No dosage adjustment necessary.

Warnings & Precautions

Source: Lexicomp

Elevated INR

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

Hypersensitivity

May occur; use caution in patients with a history of penicillin sensitivity; cross-hypersensitivity may occur. If a hypersensitivity reaction occurs, discontinue therapy and institute supportive measures.

Neurotoxicity

Severe neurological reactions (some fatal) have been reported, including encephalopathy, aphasia, myoclonus, seizures, and nonconvulsive status epilepticus. Risk may be increased in the presence of renal impairment; ensure dose adjusted for renal function and discontinue therapy if patient develops neurotoxicity; effects are often reversible upon discontinuation of cefepime.

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:

Renal impairment

Use with caution in patients with renal impairment (CrCl ≤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. Concurrent drug therapy issues:

Drug-drug interactions

Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information. Special populations:

Elderly

Serious adverse reactions have occurred in elderly patients with renal insufficiency given unadjusted doses of cefepime, including life-threatening or fatal occurrences of encephalopathy, myoclonus, and seizures.

Pregnancy & Lactation

Pregnancy

FDA category B

Adverse events were not observed in animal reproduction studies. Cefepime crosses the placenta.

Lactation

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.

Monitoring

Efficacy	Culture and susceptibility testing; clinical resolution (temperature, WBC, CRP, procalcitonin)
Toxicity	Renal function (dose adjustment in renal impairment); hepatic function for hepatically cleared agents; signs of C. difficile infection (diarrhoea)
Clinical pearl	Culture results guide de-escalation to narrower-spectrum therapy. Review antibiotic appropriateness at 48–72 h (antimicrobial stewardship).
Counseling	Complete the full course. Report persistent diarrhoea, rash, or lack of improvement after 48–72 h.

Chemistry & Properties

Formula	C19H24N6O5S2
Molecular weight	480.57 g/mol
IUPAC name	(6R,7R)-7-[[(2Z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
CAS	88040-23-7
PubChem CID	5479537
InChIKey	`HVFLCNVBZFFHBT-ZKDACBOMSA-N`
logP	-1.28 (XLogP -0.1)
Polar surface area	150.04 Å²
H-bond acceptors / donors	10 / 2
Drug-likeness (QED)	0.21
Lipinski violations	0

SMILES

CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[N+]3(C)CCCC3)CS[C@H]12)c1csc(N)n1

Biology & Pharmacokinetics

Pharmacokinetics predicted

Bioavailability	70.0%
Half-life	2.166 h
Volume of distribution	0.367 L/kg
Protein binding	21.0%
BBB penetrant	No

Transporters

BCRP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OCTN2 (Inhibitor)P-gp (Inhibitor)PEPT1 (Inhibitor)PEPT2 (Inhibitor)P-gp (Substrate)

Drug–drug interactions (12, DDInter)

Interacting drug	Severity	Management
Amikacin	moderate
Amikacin (liposome)	moderate
Chloramphenicol	moderate
Dicoumarol	moderate
Ethinylestradiol	moderate
Gentamicin	moderate
Kanamycin	moderate
Mycophenolic acid	moderate
Neomycin	moderate
Picosulfuric acid	moderate
Streptomycin	moderate
Warfarin	moderate

Registered Products (13)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Cefamax	Vial 2 g	1 vial	The Arab Pharmaceutical Manufactruing Co.	—
Cefamax 1g Vials	Vial 1 g	1 vial	The Arab Pharmaceutical Manufactruing Co.	—
Cefepime/Demo	Ampoule 2 g	1 ampoule pack varies	Al Hilal Drug Store	—
Cefepime/Demo	Ampoule 1 g	1 ampoule pack varies	Al Hilal Drug Store	—
Cefepime/Demo	Ampoule 1 g	10 ampoule pack varies	Al Hilal Drug Store	—
Cefepime/Demo	Ampoule 1 g	50 ampoule pack varies	Al Hilal Drug Store	—
Cefepime/Demo	Ampoule 2 g	10 ampoule pack varies	Al Hilal Drug Store	—
Cefepime/Demo	Ampoule 2 g	50 ampoule pack varies	Al Hilal Drug Store	—
Cepim	Vial 1 g	1 vial pack varies	Pharma International Company/ Jordan	—
Cepim	Vial 1 g	10 vial pack varies	Pharma International Company/ Jordan	—
Cepim 1gm IV	Ampoule 2 g Equivalent to 1 g Cefepime	10 ml	Pharma International Company/ Jordan	—
Cepim 2g IV Powder For Inj	Powder for Injection 2 g	1 vial	Pharma International Company/ Jordan	—
Cepim1gm IM	Ampoule 2gm Equivalent to 1 g Cefepime	5 ml	Pharma International Company/ Jordan	—