Mechanism Of Action
Cefepime is a cephalosporin antibacterial drug [See Microbiology].
Similar to other beta-lactam antimicrobial agents, the time that the unbound plasma concentration of cefepime exceeds the MIC of the infecting organism has been shown to best correlate with efficacy in animal models of infection. However, the pharmacokinetic/pharmacodynamics relationship for cefepime has not been evaluated in patients.
Pharmacokinetic parameters for cefepime in healthy adult male volunteers (n=9) following single 30-minute infusions (IV) of cefepime 500 mg, 1 g, and 2 g are summarized in Table 7. Elimination of cefepime is principally via renal excretion with an average (±SD) half-life of 2 (±0.3) hours and total body clearance of 120 (±8) mL/min in healthy volunteers. Cefepime pharmacokinetics are linear over the range 250 mg to 2 g. There is no evidence of accumulation in healthy adult male volunteers (n=7) receiving clinically relevant doses for a period of 9 days.
Table 7: Mean Pharmacokinetic Parameters for Cefepime (±SD), Intravenous Administration
|Parameter||500 mg IM||1 g IM||2 g IM|
|Cmax, mcg/mL||39.1 (3.5)||81.7 (5.1)||163.9 (25.3)|
|AUC, h•mcg/mL||70.8 (6.7)||148.5 (15.1)||284.8 (30.6)|
|Number of subjects (male)||9||9||9|
Pharmacokinetic parameters for cefepime following a single intramuscular injection are summarized in Table 8. The pharmacokinetics of cefepime are linear over the range of 500 mg to 2 g intramuscularly and do not vary with respect to treatment duration.
Table 8: Mean Pharmacokinetic Parameters for Cefepime (±SD), Intramuscular Administration
|Parameter||500 mg IM||1 g IM||2 g IM|
|Cmax, mcg/mL||13.9 (3.4)||29.6 (4.4)||57.5 (9.5)|
|Tmax, h||1.4 (0.9)||1.6 (0.4)||1.5 (0.4)|
|AUC, h•mcg/mL||60 (8)||137 (11)||262 (23)|
|Number of subjects (male)||6||6||12|
Following intramuscular (IM) administration, cefepime is completely absorbed.
The average steady-state volume of distribution of cefepime is 18 (±2) L. The serum protein binding of cefepime is approximately 20% and is independent of its concentration in serum.
Cefepime is excreted in human milk at a concentration of 0.5 mcg/mL. A nursing infant consuming approximately 1000 mL of human milk per day would receive approximately 0.5 mg of cefepime per day [see Use In Specific Populations].
Concentrations of cefepime achieved in specific tissues and body fluids are listed in Table 9.
Table 9: Mean Concentrations of Cefepime in Specific Body Fluids (mcg/mL) or Tissues (mcg/g) Mean Time of Sample Mean Tissue or Fluid Dose/Route # of Patients Post-Dose Concentration
|Tissue or Fluid||Dose/Route||# of Patients||
Mean Time of Sample Post-Dose
|Blister Fluid||2 g IV||6||1.5||81.4 mcg/mL|
|Bronchial Mucosa||2 g IV||20||4.8||24.1 mcg/g|
|Sputum||2 g IV||5||4||7.4 mcg/mL|
|Urine||500 mg IV||8||0 to 4||292 mcg/mL|
|1 g IV||12||0 to 4||926 mcg/mL|
|2 g IV||12||0 to 4||3120 mcg/mL|
|Bile||2 g IV||26||9.4||17.8 mcg/mL|
|Peritoneal Fluid||2 g IV||19||4.4||18.3 mcg/mL|
|Appendix||2 g IV||31||5.7||5.2 mcg/g|
|Gallbladder||2 g IV||38||8.9||11.9 mcg/g|
|Prostate||2 g IV||5||1||31.5 mcg/g|
Data suggest that cefepime does cross the inflamed blood-brain barrier. The clinical relevance of these data is uncertain at this time.
Metabolism And Excretion
Cefepime is metabolized to N-methylpyrrolidine (NMP) which is rapidly converted to the N-oxide (NMP-N-oxide). Urinary recovery of unchanged cefepime accounts for approximately 85% of the administered dose. Less than 1% of the administered dose is recovered from urine as NMP, 6.8% as NMP-N-oxide, and 2.5% as an epimer of cefepime. Because renal excretion is a significant pathway of elimination, patients with renal dysfunction and patients undergoing hemodialysis require dosage adjustment [see DOSAGE AND ADMINISTRATION] .
Patients With Renal impairment
Cefepime pharmacokinetics have been investigated in patients with various degrees of renal impairment (n=30). The average half-life in patients requiring hemodialysis was 13.5 (±2.7) hours and in patients requiring continuous peritoneal dialysis was 19 (±2) hours. Cefepime total body clearance decreased proportionally with creatinine clearance in patients with abnormal renal function, which serves as the basis for dosage adjustment recommendations in this group of patients [see DOSAGE AND ADMINISTRATION].
Patients With Hepatic impairment
The pharmacokinetics of cefepime were unaltered in patients with hepatic impairment who received a single 1 g dose (n=11).
Cefepime pharmacokinetics have been investigated in elderly (65 years of age and older) men (n=12) and women (n=12) whose mean (SD) creatinine clearance was 74 (±15) mL/min. There appeared to be a decrease in cefepime total body clearance as a function of creatinine clearance. Therefore, dosage administration of cefepime in the elderly should be adjusted as appropriate if the patient’s creatinine clearance is 60 mL/min or less [see DOSAGE AND ADMINISTRATION].
Cefepime pharmacokinetics have been evaluated in pediatric patients from 2 months to 11 years of age following single and multiple doses on every 8 hours (n=29) and every 12 hours (n=13) schedules. Following a single intravenous dose, total body clearance and the steady-state volume of distribution averaged 3.3 (±1) mL/min/kg and 0.3 (±0.1) L/kg, respectively. The urinary recovery of unchanged cefepime was 60.4 (±30.4)% of the administered dose, and the average renal clearance was 2 (±1.1) mL/min/kg. There were no significant effects of age or gender (25 male vs. 17 female) on total body clearance or volume of distribution, corrected for body weight. No accumulation was seen when cefepime was given at 50 mg per kg every 12 hours (n=13), while Cmax, AUC, and t½ were increased about 15% at steady state after 50 mg per kg every 8 hours. The exposure to cefepime following a 50 mg per kg intravenous dose in a pediatric patient is comparable to that in an adult treated with a 2 g intravenous dose. The absolute bioavailability of cefepime after an intramuscular dose of 50 mg per kg was 82.3 (±15)% in eight patients.
Mechanism Of Action
Cefepime is a bactericidal drug that acts by inhibition of bacterial cell wall synthesis. Cefepime has a broad spectrum of in vitro activity that encompasses a wide range of Gram-positive and Gram-negative bacteria. Within bacterial cells, the molecular targets of cefepime are the penicillin binding proteins (PBP).
Cefepime has been shown to be active against most isolates of the following microorganisms, both in vitro and in clinical infections as described in the Indications and Usage section (1).
Staphylococcus aureus (methicillin-susceptible isolates only)
Viridans group streptococci
The following in vitro data are available, but their clinical significance is unknown. At least 90 percent of the following bacteria exhibit an in vitro minimum inhibitory concentration (MIC) less than or equal to the susceptible breakpoint for cefepime against isolates of similar genus or organism group. However, the efficacy of cefepime in treating clinical infections due to these bacteria has not been established in adequate and well-controlled clinical trials.
Staphylococcus epidermidis (methicillin-susceptible isolates only)
NOTE: Most isolates of enterococci, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to cefepime.
Acinetobacter calcoaceticus subsp. lwoffii
NOTE: Cefepime is inactive against many isolates of Stenotrophomonas maltophilia.
Susceptibility Test Methods
When available, the clinical microbiology laboratory should provide cumulative reports of in vitro susceptibility test results for antimicrobial drugs used in local hospitals and practice areas to the physician as periodic reports that describe the susceptibility profile of nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.
Quantitative methods are used to determine antimicrobial minimum inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized test method 1,2 (broth and/or agar). The MIC should be interpreted according to criteria provided in Table 10.
Quantitative methods that require measurement of zone diameters can also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized test method 2,3. This procedure uses paper discs impregnated with 30 mcg cefepime to test the susceptibility of microorganisms to cefepime. The disk diffusion interpretive criteria are provided in Table 10.
Table 10: Susceptibility Test Interpretive Criteria for Cefepime¥
|Pathogen||Minimum Inhibitory Concentrations (mcg/ml)||Disk Diffusion Zone Diameters (mm)|
|Enterobacteriaceae||≤2||4 to 8||≥16||≥25||19 to 24||≤18|
|Streptococcus pneumoniaeb non-meningitis isolates||≤1||2||≥4||-||-||-|
|Viridans group streptococci||≤1||2||≥4||≥24||22 to 23||≤21|
¥For patients with renal impairment see Table 2 in Dosage and Administration.
For isolates of Enterobacteriaceae with intermediate susceptibility, use a dose of 2 g every 8 hours in patients with normal renal function.
§For P. aeruginosa, use 2 g IV every 8 hours in patients with normal renal function
bFor non-meningitis isolates, a penicillin MIC of < 0.06 mcg/ml (or oxacillin zone > 20 mm) can predict susceptibility to cefepime.
Susceptibility of staphylococci to cefepime may be deduced from testing only penicillin and either cefoxitin or oxacillin.
A report of Susceptible (S) indicates that the antimicrobial drug is likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the site of infection. A report of Intermediate (I) indicates that the result should be considered equivocal, and, if the microorganism is not fully susceptible to alternative, clinically feasible drugs, the test should be repeated. This category implies possible clinical applicability in body sites where the drug is physiologically concentrated or in situations where a high dosage of the drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of Resistant (R) indicates that the antimicrobial drug is not likely to inhibit growth of the pathogen if the antimicrobial drug reaches the concentration usually achievable at the infection site; other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test 1,2,3. Standard cefepime powder should provide the following range of MIC values noted in Table 11. For the diffusion technique using the 30 mcg disc, the criteria in Table 11 should be achieved.
Table 11: Acceptable Quality Control Ranges for Cefepime
Minimum Inhibitory Concentrations
(zone diameters in mm)
|Escherichia coli ATCC 25922||0.015 to 0.12||31 to 37|
|Staphylococcus aureus ATCC 29213||1 to 4||-|
|Staphylococcus aureus ATCC 25923||-||23 to 29|
|0.5 to 4||24 to 30|
|0.03 to 0.25||28 to 35|
|0.5 to 2||25 to 31|
|0.015 to 0.06||37 to 46|
Febrile Neutropenic Patients
The safety and efficacy of empiric cefepime monotherapy of febrile neutropenic patients have been assessed in two multicenter, randomized trials comparing cefepime monotherapy (at a dose of 2 g intravenously every 8 hours) to ceftazidime monotherapy (at a dose of 2 g intravenously every 8 hours). These studies comprised 317 evaluable patients. Table 12 describes the characteristics of the evaluable patient population.
Table 12: Demographics of Evaluable Patients (First Episodes Only)
|Median age (yr)||56 (range, 18 to 82)||55 (range, 16 to 84)|
|Male||86 (52%)||85 (56%)|
|Female||78 (48%)||68 (44%)|
|Leukemia||65 (40%)||52 (34%)|
|Other hematologic malignancies||43 (26%)||36 (24%)|
|Solid tumor||54 (33%)||56 (37%)|
Median ANC nadir (cells/microliter)
||20 (range, 0 to 500)||20 (range, 0 to 500)|
|Median duration of neutropenia (days)||6 (range, 0 to 39)||6 (range, 0 to 32)|
|Indwelling venous catheter||97 (59%)||86 (56%)|
|Prophylactic antibiotics||62 (38%)||64 (42%)|
|Bone marrow graft||9 (5%)||7 (5%)|
|SBP less than 90 mm Hg at entry||7 (4%)||2 (1%)|
|ANC = absolute neutrophil count; SBP = systolic blood pressure|
Table 13 describes the clinical response rates observed. For all outcome measures, cefepime was therapeutically equivalent to ceftazidime.
Table 13: Pooled Response Rates for Empiric Therapy of Febrile Neutropenic Patients
|Primary episode resolved with no treatment modification, no new febrile episodes or infection, and oral antibiotics allowed for completion of treatment||51||55|
|Primary episode resolved with no treatment modification, no new febrile episodes or infection and no post-treatment oral antibiotics||34||39|
|Survival, any treatment modification allowed||93||97|
|Primary episode resolved with no treatment modification and oral antibiotics allowed for completion of treatment||62||67|
|Primary episode resolved with no treatment modification and no post-treatment oral antibiotics||46||51|
Insufficient data exist to support the efficacy of cefepime monotherapy in patients at high risk for severe infection (including patients with a history of recent bone marrow transplantation, with hypotension at presentation, with an underlying hematologic malignancy, or with severe or prolonged neutropenia). No data are available in patients with septic shock.
Complicated Intra-Abdominal Infections
Patients hospitalized with complicated intra-abdominal infections participated in a randomized, double-blind, multicenter trial comparing the combination of cefepime (2 g every 12 hours) plus intravenous metronidazole (500 mg every 6 hours) versus imipenem/cilastatin (500 mg every 6 hours) for a maximum duration of 14 days of therapy. The study was designed to demonstrate equivalence of the two therapies. The primary analyses were conducted on the population consisting of those with a surgically confirmed complicated infection, at least one pathogen isolated pretreatment, at least 5 days of treatment, and a 4 to 6 week follow-up assessment for cured patients. Subjects in the imipenem/cilastatin arm had higher APACHE II scores at baseline. The treatment groups were otherwise generally comparable with regard to their pretreatment characteristics. The overall clinical cure rate among the primary analysis patients was 81% (51 cured/63 evaluable patients) in the cefepime plus metronidazole group and 66% (62/94) in the imipenem/cilastatin group. The observed differences in efficacy may have been due to a greater proportion of patients with high APACHE II scores in the imipenem/cilastatin group.
1. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically; Approved Standard - Tenth Edition. CLSI document M07-10, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-sixth Informational Supplement, CLSI document M100-S26. CLSI document M100-S26, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2016.
3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI document M02-A12, Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA, 2015.
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