Cefepime
Cefepime hydrochloride — formerly marketed as Maxipime
Indications
| Indication | Approved Population | Therapy Type | Status |
|---|---|---|---|
| Moderate to severe pneumonia | Adults & pediatrics ≥2 months | Monotherapy | FDA Approved |
| Empiric therapy for febrile neutropenia | Adults & pediatrics ≥2 months | Monotherapy | FDA Approved |
| Uncomplicated & complicated UTI (including pyelonephritis) | Adults & pediatrics ≥2 months | Monotherapy | FDA Approved |
| Uncomplicated skin & skin-structure infections | Adults & pediatrics ≥2 months | Monotherapy | FDA Approved |
| Complicated intra-abdominal infections | Adults | Combination with metronidazole | FDA Approved |
Cefepime provides broad-spectrum coverage of both gram-positive and gram-negative organisms, including Pseudomonas aeruginosa, Enterobacter species, K. pneumoniae, E. coli, P. mirabilis, S. pneumoniae, and MSSA. Its low affinity for chromosomal AmpC beta-lactamases gives it a key advantage over third-generation cephalosporins against Enterobacter and Citrobacter species. Cefepime is not active against MRSA, Enterococcus, or organisms producing extended-spectrum beta-lactamases (ESBLs). The IDSA Surviving Sepsis and febrile neutropenia guidelines position cefepime as a first-line empiric monotherapy option.
Bacterial meningitis: Cefepime crosses the inflamed blood-brain barrier and is used off-label for meningitis caused by susceptible gram-negative organisms, particularly when Pseudomonas coverage is needed. Evidence quality: Moderate — IDSA meningitis guidelines include cefepime as an option for susceptible gram-negative meningitis.
Hospital-acquired / ventilator-associated pneumonia (HAP/VAP): Cefepime is widely used as empiric therapy in HAP/VAP per ATS/IDSA 2016 guidelines. Evidence quality: High — included in guideline-recommended empiric regimens.
Dosing
Adults (CrCl >60 mL/min)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| Moderate-severe pneumonia (non-Pseudomonas) | 1–2 g IV q8–12h | Same | 2 g q8h | 10-day course Infuse over ~30 minutes |
| Pneumonia — suspected or confirmed P. aeruginosa | 2 g IV q8h | 2 g IV q8h | 6 g/day | 10-day course Higher dose required for Pseudomonas (FDA PI) |
| Febrile neutropenia — empiric therapy | 2 g IV q8h | 2 g IV q8h | 6 g/day | 7 days or until neutropenia resolves Monotherapy may not be appropriate in high-risk patients (recent BMT, hypotension, severe neutropenia) |
| Mild-moderate UTI (including pyelonephritis) | 0.5–1 g IV q12h | Same | 2 g/day | 7–10 day course |
| Severe UTI (including pyelonephritis) | 2 g IV q12h | 2 g IV q12h | 4 g/day | 10-day course |
| Moderate-severe uncomplicated skin & skin-structure infections | 2 g IV q12h | 2 g IV q12h | 4 g/day | 10-day course |
| Complicated intra-abdominal infections | 2 g IV q8–12h | Same | 6 g/day | 7–10 days Must combine with metronidazole for anaerobic coverage; use q8h for Pseudomonas |
Pediatric Patients (2 Months–16 Years, ≤40 kg)
| Clinical Scenario | Starting Dose | Maintenance Dose | Maximum Dose | Notes |
|---|---|---|---|---|
| UTI, skin infections, pneumonia (non-Pseudomonas) | 50 mg/kg IV q12h | Same | Adult dose | Duration as per adult recommendations |
| Pneumonia — P. aeruginosa | 50 mg/kg IV q8h | Same | 2 g/dose | 50 mg/kg IV is comparable to adult 2 g dose |
| Febrile neutropenia — empiric therapy | 50 mg/kg IV q8h | Same | 2 g/dose | 7 days or until neutropenia resolves Not recommended for suspected H. influenzae type b meningitis — use alternative agent |
Renal Impairment (Adults)
| CrCl (mL/min) | Standard q12h Regimens (0.5–2 g) | 2 g q8h Regimen (Neutropenia/Pseudomonas) | Notes |
|---|---|---|---|
| >60 | No adjustment | 2 g q8h | Normal dosing |
| 30–60 | Same dose, extend to q24h | 2 g q12h | Initial dose unchanged; extend interval |
| 11–29 | Reduce dose + q24h (see PI table) | 2 g q24h | e.g., 2 g q12h becomes 1 g q24h |
| <11 | Further reduce (see PI table) | 1 g q24h | e.g., 2 g q12h becomes 500 mg q24h |
| CAPD | Recommended dose q48h | 2 g q48h | Administer at standard dose but extend interval |
| Hemodialysis | 1 g day 1, then 500 mg q24h | 1 g q24h | 68% removed per 3-hour HD session; give post-HD on dialysis days |
Failure to adjust cefepime dosing in renal impairment is the most common cause of cefepime-associated neurotoxicity, including life-threatening or fatal encephalopathy, seizures, myoclonus, and nonconvulsive status epilepticus. This risk is especially high in elderly patients with age-related declines in CrCl. Always calculate CrCl before initiating cefepime and monitor renal function throughout therapy.
Pharmacology
Mechanism of Action
Cefepime is a fourth-generation cephalosporin that exerts bactericidal activity by binding to penicillin-binding proteins (PBPs) and inhibiting the transpeptidation step of peptidoglycan cell wall synthesis. A key pharmacological advantage of cefepime is its zwitterionic structure, which enables rapid penetration through the outer membrane porin channels of gram-negative bacteria. Cefepime also has a notably low affinity for chromosomally encoded AmpC beta-lactamases — an attribute that distinguishes it from third-generation cephalosporins and provides stable activity against organisms such as Enterobacter, Citrobacter freundii, and Serratia marcescens that can derepress AmpC production. Cefepime retains good activity against Pseudomonas aeruginosa while maintaining coverage of gram-positive organisms including MSSA and S. pneumoniae.
ADME Profile
| Parameter | Value | Clinical Implication |
|---|---|---|
| Absorption | IV: 100% bioavailable; IM: completely absorbed; Tmax (IM) ~1–2 h; linear PK from 250 mg to 2 g; no accumulation over 9 days | IV route preferred for serious infections; IM available for less severe infections or outpatient settings |
| Distribution | Vd 18.0 (±2.0) L; protein binding ~20%; penetrates skin blister fluid, bronchial mucosa, appendiceal tissue, peritoneal fluid, bile; crosses inflamed blood-brain barrier | Low protein binding ensures high free drug concentrations; CNS penetration potentially sufficient for meningitis in susceptible organisms; good tissue penetration at infection sites |
| Metabolism | Minimally metabolized; <1% to N-methylpyrrolidine (NMP), 6.8% to NMP-N-oxide, 2.5% to cefepime epimer; ~85% excreted unchanged in urine | Predominantly renal elimination; no CYP involvement; hepatic impairment does not affect PK; NMP metabolite may contribute to neurotoxicity |
| Elimination | t½ 2.0 (±0.3) h; total body clearance 120 (±8) mL/min; 85% renal excretion unchanged; 68% removed by 3-hour hemodialysis | Short half-life supports q8–12h dosing; extended-infusion strategies (3–4 hours) optimize time above MIC; aggressive dose reduction needed in renal impairment to prevent neurotoxicity |
Side Effects
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Positive Coombs’ test (without hemolysis) | 16.2% | Very common laboratory finding; clinical hemolysis is rare; can interfere with crossmatch testing; alert blood bank before transfusion |
| Adverse Effect | Incidence | Clinical Note |
|---|---|---|
| Rash (at 2 g q8h dose) | 4% | Dose-related: 1.1% at q12h dosing; rash was the primary reason for treatment discontinuation (51% of all drug-related discontinuations) |
| Local IV site reactions | 3% | Includes phlebitis (1.3%) and pain/inflammation (0.6%); minimize by infusing over 30 minutes; rotate IV sites |
| Diarrhea (at 2 g q8h dose) | 3% | Higher at maximum doses; monitor for C. difficile if persistent |
| Decreased phosphorus | 2.8% | Laboratory finding; hypocalcemia more common in elderly; clinical consequences not reported |
| Increased ALT | 2.8% | Transient; monitor if hepatic symptoms develop |
| Increased AST | 2.4% | Transient; usually returns to normal after completion |
| Nausea (at 2 g q8h dose) | 2% | Dose-related; usually mild |
| Increased eosinophils | 1.7% | Typically asymptomatic; evaluate if associated with rash or systemic symptoms |
| Abnormal PTT / PT | 1.6% / 1.4% | Monitor PT in at-risk patients (renal/hepatic impairment, poor nutrition, protracted therapy); administer vitamin K as indicated |
| Rash (at q12h doses) | 1.1% | Distinguish from hypersensitivity; discontinuation rate increases with dose |
| Vomiting / Pruritus / Fever / Headache (at 2 g q8h) | 1% each | All reported at the highest recommended dose (N=795 patients receiving 2 g q8h) |
| Adverse Effect | Estimated Frequency | Typical Onset | Required Action |
|---|---|---|---|
| Neurotoxicity (encephalopathy, confusion, hallucinations, stupor, coma) | Uncommon overall; higher in renal impairment | Days 1–10 of therapy; can be rapid onset | Discontinue cefepime immediately; institute supportive measures; hemodialysis may accelerate clearance; symptoms usually reversible after discontinuation/dialysis |
| Seizures / myoclonus / nonconvulsive status epilepticus | Rare overall; life-threatening in renal impairment | Variable; higher risk with CrCl <60 and unadjusted dosing | Discontinue cefepime; anticonvulsant therapy; EEG monitoring for NCSE; hemodialysis removes 68% and may be required |
| Anaphylaxis / anaphylactic shock | Rare | Minutes to hours after dosing | Discontinue immediately; epinephrine, airway management, IV fluids; permanent discontinuation |
| C. difficile-associated diarrhea / pseudomembranous colitis | Uncommon | During or up to 2+ months after therapy | Discontinue cefepime if confirmed; stool C. difficile testing; treat with oral vancomycin or fidaxomicin |
| Agranulocytosis / pancytopenia | Very rare | Variable | Discontinue; CBC monitoring; hematology consultation; consider alternative antibiotic |
| Kounis syndrome (allergic angina / MI) | Very rare (class effect) | During or shortly after hypersensitivity reaction | Treat as acute coronary syndrome and anaphylaxis simultaneously; cardiology consultation |
| Reason for Discontinuation | Incidence | Context |
|---|---|---|
| Rash | ~0.8% (33/4137) | Accounted for 51% of all drug-related discontinuations; incidence increased with higher doses |
| All drug-related adverse reactions | 1.5% (64/4137) | Dose-related: 0.8% at 500 mg q12h, 1.1% at 1 g q12h, 2.0% at 2 g q12h |
Cefepime-associated neurotoxicity is a well-characterized adverse effect, particularly dangerous in patients with renal impairment receiving unadjusted doses. Clinical presentations include altered consciousness (confusion, hallucinations, stupor, coma), aphasia, myoclonus, seizures, and nonconvulsive status epilepticus (NCSE). Most cases occur within the first several days of therapy. Risk factors include CrCl <60 mL/min, age ≥65 years, critical illness, and pre-existing CNS disease. In the majority of cases, neurotoxicity is reversible after drug discontinuation and/or hemodialysis. Always calculate CrCl before prescribing and reassess renal function regularly during therapy.
Drug Interactions
Cefepime is minimally metabolized and does not interact via CYP enzymes. The primary interaction concerns involve nephrotoxic co-medications and lab test interference. It is compatible with many IV fluids but has known physical incompatibilities with certain drugs in solution.
Cefepime may cause false-positive urine glucose results with copper-reduction methods (Clinitest) but not with glucose oxidase-based tests. Positive direct Coombs’ tests occur in 16.2% of patients without clinical hemolysis — this may interfere with blood crossmatching. Many cephalosporins, including cefepime, have been associated with a fall in prothrombin activity, particularly in patients with renal/hepatic impairment or poor nutritional status.
Monitoring
- Renal FunctionBaseline + q48–72h
RoutineCalculate CrCl before initiating therapy and reassess regularly. Dose must be adjusted for CrCl ≤60 mL/min. Failure to do so is the most common cause of cefepime neurotoxicity. Elderly patients frequently have occult renal impairment not reflected by serum creatinine alone. - Neurological StatusDaily assessment
RoutineMonitor for confusion, altered consciousness, hallucinations, myoclonus, or seizure activity. Any change in neurological status should prompt cefepime discontinuation and EEG consideration to rule out nonconvulsive status epilepticus. - Clinical Response48–72 h after start
RoutineAssess for clinical improvement (fever defervescence, WBC normalization). If no response by 72 hours, reassess diagnosis, obtain cultures, and broaden or change coverage. - CBC with DifferentialBaseline + weekly
RoutineMonitor for neutropenia, thrombocytopenia, eosinophilia. Particularly important in febrile neutropenia patients to track neutrophil recovery. Positive Coombs’ test occurs in 16.2% and may affect crossmatch. - Hepatic PanelWeekly if prolonged
Trigger-basedALT elevated in 2.8% and AST in 2.4% of patients in trials. Usually transient, but monitor if therapy extends beyond 10–14 days or symptoms arise. - PT / INRBaseline + if at risk
Trigger-basedAbnormal PT in 1.4% and PTT in 1.6% of patients. Monitor in patients on warfarin, with hepatic/renal impairment, poor nutrition, or protracted therapy. Administer vitamin K as indicated. - IV SiteEach infusion
RoutinePhlebitis occurred in 1.3% of IV-treated patients. Inspect site for erythema, swelling, or tenderness; rotate sites as needed.
Contraindications & Cautions
Absolute Contraindications
- Prior immediate hypersensitivity reaction to cefepime, any cephalosporin, penicillin, or other beta-lactam
- Known allergy to corn or corn products (dextrose-containing solutions only)
Relative Contraindications (Specialist Input Recommended)
- Renal impairment (CrCl ≤60 mL/min) without dose adjustment — risk of life-threatening neurotoxicity including seizures and nonconvulsive status epilepticus; fatal outcomes reported
- History of seizure disorder — cefepime may lower seizure threshold, especially in renal impairment
Use with Caution
- Elderly patients — often have occult CrCl decline; serious and fatal neurotoxicity events reported in geriatric patients with unadjusted dosing
- Concurrent nephrotoxic agents (aminoglycosides, potent diuretics) — may precipitate renal impairment and cefepime accumulation
- History of GI disease, especially colitis — C. difficile risk
- Infants <2 months — safety and efficacy not established
- Suspected H. influenzae type b meningitis — insufficient data; use alternative agent with established meningitis efficacy
Serious adverse reactions have occurred in patients, particularly elderly patients with renal impairment, who were given unadjusted doses of cefepime. These include life-threatening or fatal occurrences of encephalopathy, myoclonus, seizures, and nonconvulsive status epilepticus. In the majority of cases, symptoms were reversible after discontinuation of cefepime and/or hemodialysis. Dose adjustment based on creatinine clearance is essential for all patients with CrCl ≤60 mL/min.
Cross-hypersensitivity among beta-lactam antibacterials may occur in up to 10% of patients with a history of penicillin allergy. Hypersensitivity reactions can progress to Kounis syndrome, a serious allergic reaction that can result in myocardial infarction. If an allergic reaction occurs, discontinue the drug and institute appropriate supportive measures.
Patient Counselling
Purpose of Therapy
Cefepime is a powerful antibiotic given through an intravenous line (IV) to treat serious bacterial infections. It works by destroying the cell wall of bacteria, causing them to die. It is only effective against bacterial infections and will not treat viral illnesses. Completing the full course as prescribed is essential even if symptoms improve early.
How It Is Given
Cefepime is administered as an IV infusion over approximately 30 minutes. It is typically given every 8 or 12 hours depending on the type and severity of infection. Nursing staff will monitor the IV site during infusions. If you are receiving cefepime as an outpatient via a PICC line or home infusion, follow all instructions provided by your infusion service team.
Sources
- Cefepime Injection Prescribing Information (Galaxy Container). Baxter Healthcare Corporation. Revised December 2025. DailyMedCurrent FDA PI for premixed cefepime injection; source for dosing tables, renal adjustments, adverse events (N=4,137), neurotoxicity warning, and PK parameters.
- Maxipime (cefepime hydrochloride) Prescribing Information. Hospira/Pfizer. FDA.govBrand-name PI with complete clinical study data, pediatric PK parameters, and tissue penetration data.
- FDA Drug Safety Communication: Cefepime and risk of seizure in patients not receiving dosage adjustments for kidney impairment. U.S. FDA, 2012. FDA.govFDA safety communication that prompted enhanced neurotoxicity warnings in labeling; emphasized renal dose adjustment.
- 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):338-348. DOIMeta-analysis that raised initial concerns about cefepime mortality risk, prompting FDA review; subsequent analyses did not confirm excess mortality at recommended doses.
- Kim PW, Wu YT, Cooper C, et al. Meta-analysis of a possible signal of increased mortality associated with cefepime use. Clin Infect Dis. 2010;51(4):381-389. DOIFDA-sponsored meta-analysis that found no statistically significant increase in all-cause mortality with cefepime at recommended doses.
- 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 IDSA. Clin Infect Dis. 2011;52(4):e56-e93. DOIIDSA guideline recommending cefepime as first-line empiric monotherapy for febrile neutropenia.
- Kalil AC, Metersky ML, Klompas M, et al. Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the IDSA and ATS. Clin Infect Dis. 2016;63(5):e61-e111. DOIATS/IDSA guideline including cefepime in recommended empiric regimens for HAP/VAP.
- Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis: 2004. Clin Infect Dis. 2004;39(9):1267-1284. DOIIDSA meningitis guideline including cefepime as an option for susceptible gram-negative organisms.
- 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(3):552-557. DOIFoundational PK study establishing linear pharmacokinetics, renal elimination, and lack of accumulation.
- Payne LE, Gagnon DJ, Riker RR, et al. Cefepime-induced neurotoxicity: a systematic review. Crit Care. 2017;21(1):276. DOISystematic review characterizing risk factors, clinical features, and outcomes of cefepime neurotoxicity; identified renal impairment as the dominant risk factor.
- Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16(1):31-41. DOICrCl estimation formula referenced in the cefepime PI for renal dose adjustment calculations.
- Reed MD, Yamashita TS, Knupp CK, et al. Pharmacokinetics of intravenously and intramuscularly administered cefepime in infants and children. Antimicrob Agents Chemother. 1997;41(8):1783-1787. DOIPediatric PK study establishing that 50 mg/kg IV produces exposure comparable to 2 g in adults.
- Lamoth F, Buclin T, Pascual A, et al. High cefepime plasma concentrations and neurological toxicity in febrile neutropenic patients with mild impairment of renal function. Antimicrob Agents Chemother. 2010;54(10):4360-4367. DOIDemonstrated correlation between elevated cefepime trough concentrations and neurotoxicity in febrile neutropenia patients with even mild renal impairment.