CLINICAL PHARMACOLOGY
Absorption and Metabolism
After oral administration, cefuroxime axetil is absorbed from the gastrointestinal tract and rapidly hydrolyzed by nonspecific esterases in the intestinal mucosa and blood to cefuroxime. Cefuroxime is subsequently distributed throughout the extracellular fluids. The axetil moiety is metabolized to acetaldehyde and acetic acid.
Pharmacokinetics
Approximately 50% of serum cefuroxime is bound to protein. Serum pharmacokinetic parameters for CEFTIN Tablets and CEFTIN for Oral Suspension are shown in Tables 1 and 2.
Table 1. Postprandial Pharmacokinetics of Cefuroxime Administered as CEFTIN Tablets to Adultsa
Doseb
(Cefuroxime
Equivalent)
|
Peak Plasma Concentration
(mcg/mL)
|
Time of Peak Plasma Concentration (hr)
|
Mean
Elimination
Half-life (hr)
|
AUC
(mcg•hr/mL)
|
125 mg
|
2.1
|
2.2
|
1.2
|
6.7
|
250 mg
|
4.1
|
2.5
|
1.2
|
12.9
|
500 mg
|
7.0
|
3.0
|
1.2
|
27.4
|
1,000 mg
|
13.6
|
2.5
|
1.3
|
50.0
|
a Mean values of 12 healthy adult volunteers.
b Drug administered immediately after a meal.
Table 2. Postprandial Pharmacokinetics of Cefuroxime Administered as CEFTIN for Oral Suspension to Pediatric Patientsa
Doseb
(Cefuroxime
Equivalent)
|
n
|
Peak Plasma
Concentration
(mcg/mL)
|
Time of Peak
Plasma
Concentration (hr)
|
Mean
Elimination
Half-life
(hr)
|
AUC
(mcg•hr/mL)
|
10 mg/kg
|
8
|
3.3
|
3.6
|
1.4
|
12.4
|
15 mg/kg
|
12
|
5.1
|
2.7
|
1.9
|
22.5
|
20 mg/kg
|
8
|
7.0
|
3.1
|
1.9
|
32.8
|
a Mean age = 23 months.
b Drug administered with milk or milk products.
Comparative Pharmacokinetic Properties
A 250 mg/5 mL-dose of CEFTIN Suspension is bioequivalent to 2 times 125 mg/5 mL-dose of CEFTIN Suspension when administered with food (see Table 3). CEFTIN for Oral Suspension was not bioequivalent to CEFTIN Tablets when tested in healthy adults. The tablet and powder for oral suspension formulations are NOT substitutable on a milligram-per-milligram basis. The area under the curve for the suspension averaged 91% of that for the tablet, and the peak plasma concentration for the suspension averaged 71% of the peak plasma concentration of the tablets. Therefore, the safety and effectiveness of both the tablet and oral suspension formulations had to be established in separate clinical trials.
Table 3. Pharmacokinetics of Cefuroxime Administered as 250 mg/5 mL or 2 x 125 mg/5 mL CEFTIN for Oral Suspension to Adultsa With Food
Dose
(Cefuroxime
Equivalent)
|
Peak Plasma Concentration
(mcg/mL)
|
Time of Peak
Plasma
Concentration (hr)
|
Mean Elimination
Half-life (hr)
|
AUC
(mcg•hr/mL)
|
250 mg/5 mL
|
2.23
|
3
|
1.40
|
8.92
|
2 x 125 mg/5 mL
|
2.37
|
3
|
1.44
|
9.75
|
a Mean values of 18 healthy adult volunteers.
Food Effect on Pharmacokinetics
Absorption of the tablet is greater when taken after food (absolute bioavailability of CEFTIN Tablets increases from 37% to 52%). Despite this difference in absorption, the clinical and bacteriologic responses of patients were independent of food intake at the time of tablet administration in 2 studies where this was assessed.
All pharmacokinetic and clinical effectiveness and safety studies in pediatric patients using the suspension formulation were conducted in the fed state. No data are available on the absorption kinetics of the suspension formulation when administered to fasted pediatric patients.
Renal Excretion
Cefuroxime is excreted unchanged in the urine; in adults, approximately 50% of the administered dose is recovered in the urine within 12 hours. The pharmacokinetics of cefuroxime in the urine of pediatric patients have not been studied at this time. Until further data are available, the renal pharmacokinetic properties of cefuroxime axetil established in adults should not be extrapolated to pediatric patients.
Because cefuroxime is renally excreted, the serum half-life is prolonged in patients with reduced renal function. In a study of 20 elderly patients (mean age = 83.9 years) having a mean creatinine clearance of 34.9 mL/min, the mean serum elimination half-life was 3.5 hours. Despite the lower elimination of cefuroxime in geriatric patients, dosage adjustment based on age is not necessary (see PRECAUTIONS: Geriatric Use).
Microbiology
The in vivo bactericidal activity of cefuroxime axetil is due to cefuroxime's binding to essential target proteins and the resultant inhibition of cell-wall synthesis.
Cefuroxime has bactericidal activity against a wide range of common pathogens, including many beta-lactamase−producing strains. Cefuroxime is stable to many bacterial beta-lactamases, especially plasmid-mediated enzymes that are commonly found in enterobacteriaceae.
Cefuroxime has been demonstrated to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the INDICATIONS AND USAGE (see INDICATIONS AND USAGE).
Aerobic Gram-Positive Microorganisms
Staphylococcus
aureus (including betalactamase−producing strains)
Streptococcus
pneumoniae
Streptococcus
pyogenes
Aerobic Gram-Negative Microorganisms
Escherichia coli
Haemophilus
influenzae (including betalactamase−producing strains)
Haemophilus
parainfluenzae
Klebsiella
pneumoniae
Moraxella
catarrhalis (including betalactamase−producing strains)
Neisseria
gonorrhoeae (including betalactamase−producing strains)
Spirochetes
Borrelia
burgdorferi
Cefuroxime has been shown to be active in vitro against most strains of the following microorganisms; however, the clinical significance of these findings is unknown.
Cefuroxime exhibits in vitro minimum inhibitory concentrations (MICs) of 4.0 mcg/mL or less (systemic susceptible breakpoint) against most (≥90%) strains of the following microorganisms; however, the safety and effectiveness of cefuroxime in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.
Aerobic Gram-Positive Microorganisms
Staphylococcus
epidermidis
Staphylococcus
saprophyticus
Streptococcus
agalactiae
NOTE: Listeria
monocytogenes and certain strains of enterococci, e.g., Enterococcus
faecalis (formerly Streptococcus
faecalis), are resistant to cefuroxime. Methicillin-resistant staphylococci are resistant to cefuroxime.
Aerobic Gram-Negative Microorganisms
Morganella
morganii
Proteus
inconstans
Proteus mirabilis
Providencia
rettgeri
NOTE: Pseudomonas spp., Campylobacter spp., Acinetobacter
calcoaceticus, Legionella spp., and most strains of Serratia spp. and Proteus
vulgaris are resistant to most first- and second-generation cephalosporins. Some strains of Morganella
morganii, Enterobacter
cloacae, and Citrobacter
spp. have been shown by in vitro tests to be resistant to cefuroxime and other cephalosporins.
Anaerobic Microorganisms
Peptococcus
niger
NOTE: Most strains of Clostridium
difficile and Bacteroides
fragilis are resistant to cefuroxime.
Susceptibility Tests
Dilution Techniques
Quantitative methods that are used to determine MICs provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure uses a standardized dilution method1 (broth, agar, or microdilution) or equivalent with cefuroxime powder. The MIC values obtained should be interpreted according to the following criteria:
MIC (mcg/
mL
)
|
Interpretation
|
≤4
|
(S) Susceptible
|
8-16
|
(I) Intermediate
|
≥32
|
(R) Resistant
|
A report of "Susceptible" indicates that the pathogen, if in the blood, is likely to be inhibited by usually achievable concentrations of the antimicrobial compound in blood. A report of "Intermediate" indicates that inhibitory concentrations of the antibiotic may be achieved if high dosage is used or if the infection is confined to tissues or fluids in which high antibiotic concentrations are attained. This category also provides a buffer zone that prevents small, uncontrolled technical factors from causing major discrepancies in interpretation. A report of "Resistant" indicates that usually achievable concentrations of the antimicrobial compound in the blood are unlikely to be inhibitory and that other therapy should be selected.
Standardized susceptibility test procedures require the use of laboratory control microorganisms. Standard cefuroxime powder should give the following MIC values:
Microorganism
|
MIC (mcg/
mL
)
|
Escherichia coli ATCC 25922
|
2-8
|
Staphylococcus
aureus
ATCC 29213
|
0.5-2
|
Diffusion Techniques
Quantitative methods that require measurement of zone diameters provide estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure2 that has been recommended (for use with disks) to test the susceptibility of microorganisms to cefuroxime uses the 30-mcg cefuroxime disk. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefuroxime.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-mcg cefuroxime disk should be interpreted according to the following criteria:
Zone Diameter (mm)
|
Interpretation
|
≥23
|
(S) Susceptible
|
15-22
|
(I) Intermediate
|
≤14
|
(R) Resistant
|
Interpretation should be as stated above for results using dilution techniques.
As with standard dilution techniques, diffusion methods require the use of laboratory control microorganisms. The 30-mcg cefuroxime disk provides the following zone diameters in these laboratory test quality control strains:
Microorganism
|
Zone Diameter (mm)
|
Escherichia coli ATCC 25922
|
20-26
|
Staphylococcus
aureus ATCC 25923
|
27-35
|
|