Source: Health Sciences Authority (SG) Revision Year: 2020 Publisher: United Italian Trading Corporation (Pte) Ltd, 28 Tai Seng Street, #06-01 Singapore, 534106, Tel: +65 6284 8889 Name and adress of manufacturer: Pharma Vision San. Ve Tic. A.Ş., Davutpaşa Caddesi No: 145, ...
Pharmacotherapeutic group: other beta-lactam antibiotics
ATC code: J01DE01
Cefepime is an antibiotic with its broad spectrum that acts by inhibition of bacterial cell wall synthesis.
It shows effect on Gram-positive and Gram-negative bacteria including many strains resistant to aminoglycosides or third-generation cephalosporins. Cefepime is highly resistant to hydrolysis by most beta-lactamases and has a low affinity for chromosomally-encoded betalactamases. It exhibits rapid penetration into Gram-negative bacterial cells.
In studies using Escherichia coli and Enterobacter cloacae, cefepime bound with highest affinity to penicillin binding proteins (PBP) 3 followed by PBP 2, then it was followed by PBPs 1a and 1b. Binding to PBP 2 occurs with significantly higher affinity than that of other parenteral cephalosporins. This may enhance its antibacterial activity. The moderate affinity of cefepime for PBPs 1a and 1b probably also contribute to its overall bactericidal activity.
Cefepime has been shown to be bactericidal by time-kill analysis (killing-curves) and by determination of minimum bactericidal concentrations (MBC) for a wide variety of bacteria. The cefepime MBC/MIC ratio was ≤2 for more than 80% of isolates of all Gram-positive and Gram-negative species tested. Synergy with aminoglycosides has been demonstrated in vitro, primarily with Pseudomonas aeruginosa isolates.
Cefepime has been shown to be active against most strains of the following microorganisms:
Gram-Positive Aerobes:
Staphylococcus aureus (including beta-lactamase producing strains), Staphylococcus epidermidis (including beta-lactamase producing strains) and other staphycoccus including S. hominis and S. Saprophyticus, Streptococcus pyogenes (A class staphycoccus), Streptococcus agalactiae (B class staphycoccus), Streptococcus pneumoniae (including moderately penicillin resistant strains, between MIC 0.1 and 1 mg/ml), Other beta-hemolytic streptococcus (group C, F, G), S. bovis (group D) Viridans streptococci.
Note: Most strains of enterococci, e.g., Enterococcus faecalis, and methicillin-resistant staphylococci are resistant to many cephalosporins including cefepime.
Gram-Negative Aerobes:
Acinetobacter calcoaceticus (anitratus, lwoffi subspecies), Aeromonas hydrophila, Capnocytophage species, Citrobacter species including C. diversus and C. Freundü, Campylobaster jejuni, Enterobacter species including E. cloacae, E. Areogenes, E. Sakazakü, Escherichia coli, Gardnerella vaginalis, Haemophilus ducreyi, Haemophilus influenzae (including beta-lactamase producing strains), Haemophilus parainfluenzae, Hafnia alvei, Klebsiella species including K. pneumoniae, K. Oxytoca, K. Ozaenae, Legionella species, Morganella morganii, Moraxella catarrhalis (Branhamella catarrhalis) (including beta-lactamase producing strains), Neisseria gonorrhoeae (including beta-lactamase producing strains), Neisseria meningitidis, Pantoea agglormerans (Known as Enterobacter agglomerans), Proteus species including P. mirabilis, P. Vulgaris, Providencia species including P.rettgeri, P. Stuartü, Pseudomonas species including P. aeruginosa, P. putida, P. stutzeri, Salmonella species, Serratia species including S. marcescens, S. Liquefaciense, Shigella species, Yersinia enterocolitica.
Note: Cefepime is inactive against many strains of Xanthomonas maltophilia (Pseudomonas maltophilia).
Anaerobes:
Bacteroides species, Clostridium perfringens, Fusobacterium species, Mobiluncus species, Peptostreptococcus species, Veillonella species and Prevotella melaninogenica known as Bacteroides melaninogenicus
Note: Cefepime is inactive against Bacteroides fragilis and Clostridium difficile. Synergy with Aminoglycoside antibiotics has been demonstrated.
Cefepime that is active substance of ROXIPIME is a broad spectrum cephalosporin antibiotic.
The average plasma concentrations of Cefepime observed in normal male adults at various times following single 30-minutes infusions (IV) or 500 mg, 1 g, and 2 g infusions (I.M.) are summarized in Table 3.
TABLE 3. Average Plasma Concentrations of Cefepime (mcg/mL) in healthy adult male volunteers:
| Cefepime Dose | 0.5 hr | 1 hr | 2 hr | 4 hr | 8 hr | 12 hr |
|---|---|---|---|---|---|---|
| 500 mg I.V. | 38.2 | 21.6 | 11.6 | 5.0 | 1.4 | 0.2 |
| 1 g I.V. | 78.7 | 44.5 | 24.3 | 10.5 | 2.4 | 0.6 |
| 2 g I.V. | 163.1 | 85.8 | 44.8 | 19.2 | 3.9 | 1.1 |
Concentrations of Cefepime achieved in specific tissues and body fluids are listed in Table 4. The ratio of binding to serum proteins is approximately 16.4% and is independent of its concentration in serum.
TABLE 4. Average Concentrations of Cefepime in Different Body Fluids (mcg/mL) or Tissues (mcg/g) in Healthy adult male volunteers:
| Tissue or Fluid | Dose (I.V.) | Average Time of Sampling Post-Dose (h) | Average Concentration |
|---|---|---|---|
| Urine | 500 mg | 0-4 | 292 |
| 1 g | 0-4 | 926 | |
| 2 g | 0-4 | 3120 | |
| Bile | 2 g | 9.4 | 17.8 |
| Peritoneal Fluid | 2 g | 4.4 | 18.3 |
| Blister Fluid | 2 g | 1.5 | 81.4 |
| Bronchial Mucosa | 2 g | 4.8 | 24.1 |
| Sputum | 2 g | 4.0 | 7.4 |
| Prostate | 2 g | 1.0 | 31.5 |
| Appendix | 2 g | 5.7 | 5.2 |
| Gallbladder | 2 g | 8.9 | 11.9 |
Cefepime is metabolized to N-methylpyrolidine which is rapidly converted to the N-oxide. Approximately 85% of the administered dose is excreted as unchanged in the urine; cefepime is found in urine in high concentrations. Less than 1% of the administered dose exits in urine as N-methylpyrolidine, 6.8% of it as N-oxide, and 2.5% of it as an epimer of Cefepime.
Average elimination half-life of cefepime in blood is 2 hours and 250 mg – 2 g. In healthy individuals, accumulation was not observed in body at 2 g intravenous solutions administered every 8 hours during 9 days. Average total body clearance is 120 mL/min. Average renal clearance of cefepime is 110 mL/min, cefepime is mainly excreted by the kidneys mainly by glomerular filtration.
Average elimination half-life of cefepime in the blood does not show changes according to the dosage.
Cefepime single and multiple doses pharmacokinetics have been evaluated in patients between 2.1 months to 11.2 years of age and 50 mg/kg doses administered with I.V. infusion or I.M. injection; multiple doses has been applied for at least 48 hours every 8 or 12 hours.
Following a single intravenous dose in children, total body clearance is average 3.3 mL/min/kg; average volume of distribution is 0.3 l / kg, and average elimination half-life is 1.7 hours. 60.4% of the administered dose is excreted as unchanged in the urine, renal clearance is the major route of excretion as 2.0 ml/min/kg.
Following Multiple IV doses, the mean plasma concentrations of cefepime after the first dose were similar to those at steady state, with only slight accumulation seen upon repeated dosing.
In healthy volunteers 65 years and older, AUC value of cefepime that is administered as single dose of 1 g IV, is higher and renal clearance value is lower compared to young volunteers. If renal function is suppressed, dose adjustment is recommended for elderly patients (see, section 4.2 and 4.4).
The pharmacokinetics of cefepime were unaltered in patients with hepatic impairment who received a single 1 g dose. The pharmacokinetics of cefepime were unaltered significantly in cystic fibrosis patients. In these patient populations, changing of ROXIPIME dosage is not necessary.
The half-life in patients with varying degrees of renal impairment is prolonged, there is a linear relationship between creatinine clearance and body clearance. Therefore, dosage adjustment is recommended for patients in this group. The average half-life in patients requiring hemodialysis was 13 hours and in patients requiring continuous peritoneal dialysis was 19 hours.
The pharmacokinetics of cefepime do not change to a clinically significant degree in patients with cystic fibrosis.
The safety and efficacy of 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 5 describes the characteristics of the evaluable patient population.
TABLE 5. Demographic properties of Evaluable Patients (First Episodes Only):
| Cefepime | Ceftrazidime | |
|---|---|---|
| Total Median age (yr) Male | 164 56.0 (range, 18 to 82) 86 (52%) | 153 55.0 (range 16 to 84) 85 (56%) |
| Female | 78 (48%) | 68 (44%) |
| Leukemia | 65 (40%) | 52 (34%) |
| Other hematologic malignancies | 43 (26%) | 36 (24%) |
| Solid tumor Median ANC nadir (cells/microliter) Median duration of neutropenia (days) Indwelling venous catheter | 54 (33%) 20 (range, 0 to 500) 6 (range, 0 to 39) 97 (59%) | 56 (37%) 20.0 (range 0 to 500) 6.0 (range, 0 to 32) 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
The clinical response rates have been given on Table 6. For all outcome measures, Cefepime was found as therapeutically equivalent to ceftazidime:
TABLE 6. Pooled Response Rates for Empiric Therapy of Febrile Neutropenic Patients:
| % Response | ||
|---|---|---|
| Result Measures | Cefepime | Ceftazidime |
| (n=164) | (n=153) | |
| First attack was resolved with no treatment modification, no new febrile episodes or infection, and oral antibiotics were used for completion of treatment | ||
| First attack was resolved with no treatment modification, no new febrile episodes or infection and oral antibiotics were not used after treatment. | ||
| Survival, treatment modification was allowed. | 93 | 97 |
| First attack was resolved with no treatment modification and oral antibiotics were used for completion of treatment | 62 | 67 |
| First attack was resolved with no treatment modification and oral antibiotics were not used after treatment. | 46 | 51 |
Insufficient data exist to support the efficacy of Cefepime monotherapy in patients at high risk for severe infection (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.
For evaluating the carcinogenic potential, long-term study have not been conducted in animals. In vitro and in vivo genotoxicity tests showed that cefepime is not genotoxic. No lack of fertility was observed in rats.
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