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 cefuroxime axetil
tablets and oral suspension are shown in TABLE 1 and TABLE
2.
| TABLE 1
Postprandial Pharmacokinetics of Cefuroxime Administered
as Cefuroxime Axetil Tablets to Adults* |
| Dose† (Cefuroxime Equivalent) |
Peak Plasma Concentration (mcg/ml) |
Time of Peak Plasma Concentration
(h) |
Mean Elimination Half-Life (h) |
AUC (mcg·h 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 |
|
1000 mg
|
13.6 |
2.5 |
1.3 |
50.0 |
| * Mean
values of 12 healthy adult volunteers. |
| † Drug
administered immediately after a meal. |
|
TABLE 2 Postprandial Pharmacokinetics of
Cefuroxime Administered as Cefuroxime Axetil Powder for Oral Suspension
to Pediatric Patients*
|
| Dose† (Cefuroxime Equivalent) |
n |
Peak Plasma Concentration
(mcg/ml) |
Time of Peak Plasma Concentration
(h) |
Mean Elimination Half-Life
(h) |
AUC (mcg·h 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 |
| * Mean
age=23 months. |
| † Drug
administered with milk or milk products. |
Comparative Pharmacokinetic Properties
A 250 mg/5 ml-dose of cefuroxime axetil suspension is
bioequivalent to two times 125 mg/5 ml-dose of cefuroxime
axetil suspension when administered with food (see TABLE
3). Cefuroxime axetil powder for oral suspension
was not bioequivalent to cefuroxime axetil tablets when
tested in healthy adults. The tablet and powder for oral
suspension formulations are NOT substitutable on a mg/mg
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 ´
125 mg/5 ml Cefuroxime
Axetil Powder for Oral Suspension to Adults* With Food
|
| Dose (Cefuroxime Equivalent) |
Peak Plasma Concentration
(mcg/ml) |
Time of Peak Plasma Concentration
(h) |
Mean Elimination Half-Life
(h) |
AUC (mcg·h ml) |
|
250 mg/5 ml
|
2.23
|
3
|
1.40
|
8.92
|
|
2 ´ 125 mg/5
ml
|
2.37
|
3
|
1.44
|
9.75
|
| * Mean
values of 18 healthy adult volunteers. |
Food Effect on Pharmacokinetics
Absorption of the tablet is greater when taken after
food (absolute bioavailability of cefuroxime axetil 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 two 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-lactamase¾producing
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 INDICATIONS
AND USAGE.
Aerobic Gram-positive Microorganisms:
Staphylococcus aureus (including beta-lactamase¾producing
strains).
Streptococcus pneumoniae.
Streptococcus pyogenes.
Aerobic Gram-negative Microorganisms:
Escherichia coli.
Haemophilus influenzae (including beta-lactamase-producing
strains).
Haemophilus parainfluenzae.
Klebsiella pneumoniae.
Moraxella catarrhalis (including beta-lactamase-producing
strains).
Neisseria gonorrhoeae (including beta-lactamase-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 (³90%) 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: 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, 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 Testing
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 criteria found in TABLE
4.
|
TABLE 4
|
| MIC (mcg/ml) |
Interpretation |
| £4 |
(S) Susceptible |
| 8-16 |
(I) Intermediate |
| ³32 |
(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 MIC values found in TABLE 5.
|
TABLE 5
|
| 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 procedure 2 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
criteria found in TABLE 6.
|
TABLE 6
|
| Zone diameter (mm) |
Interpretation |
| ³23 |
(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
(see TABLE 7).
|
TABLE 7
|
| Microorganism |
Zone Diameter (mm) |
| Escherichia coli ATCC
25922 |
20-26 |
| Staphylococcus aureus
ATCC 25923 |
27-35 |
CLINICAL STUDIES
Cefuroxime Axetil Tablets
Acute Bacterial Maxillary Sinusitis
One adequate and well-controlled study was performed
in patients with acute bacterial maxillary sinusitis.
In this study each patient had a maxillary sinus aspirate
collected by sinus puncture before treatment was initiated
for presumptive acute bacterial sinusitis. All patients
had to have radiographic and clinical evidence of acute
maxillary sinusitis. As shown in the following summary
of the study, the general clinical effectiveness of cefuroxime
axetil tablets was comparable to an oral antimicrobial
agent that contained a specific beta-lactamase inhibitor
in treating acute maxillary sinusitis. However, sufficient
microbiology data were obtained to demonstrate the effectiveness
of cefuroxime axetil tablets in treating acute bacterial
maxillary sinusitis due only to Streptococcus pneumoniae
or non-beta-lactamase-producing Haemophilus influenzae.
An insufficient number of beta-lactamase-producing Haemophilus
influenzae and Moraxella catarrhalis isolates were obtained
in this trial to adequately evaluate the effectiveness
of cefuroxime axetil tablets in the treatment of acute
bacterial maxillary sinusitis due to these two organisms.
This study enrolled 317 adult patients, 132 patients
in the United States and 185 patients in South America.
Patients were randomized in a 1:1 ratio to cefuroxime
axetil 250 mg bid or an oral antimicrobial agent that
contained a specific beta-lactamase inhibitor. An intent-to-treat
analysis of the submitted clinical data yielded the results
in TABLE 8.
TABLE 8 Clinical Effectiveness of Cefuroxime Axetil Tablets
Compared to Beta-Lactamase Inhibitor-Containing Control Drug
in the Treatment of Acute Bacterial Maxillary Sinusitis
|
| |
U.S. Patients* |
South American
Patients† |
| |
Cefuroxime Axetil (n=49) |
Control (n=43) |
Cefuroxime Axetil (n=87) |
Control (n=89) |
| Clinical success
(cure + improvement) |
65% |
53% |
77% |
74% |
| Clinical cure |
53% |
44% |
72% |
64% |
| Clinical improvement |
12% |
9% |
5% |
10% |
| * 95%
Confidence interval around the success difference
[-0.08, +0.32]. |
| † 95%
Confidence interval around the success difference
[-0.10, +0.16]. |
In this trial and in a supporting maxillary puncture trial,
15 evaluable patients had non-beta-lactamase-producing Haemophilus
influenzae as the identified pathogen. Ten (10) of these
15 patients (67%) had their pathogen (non-beta-lactamase-producing
Haemophilus influenzae) eradicated. Eighteen (18) evaluable
patients had Streptococcus pneumoniae as the identified
pathogen. Fifteen (15) of these 18 patients (83%) had their
pathogen (Streptococcus pneumoniae) eradicated.
Safety: The incidence of drug-related
gastrointestinal adverse events was statistically significantly
higher in the control arm (an oral antimicrobial agent
that contained a specific beta-lactamase inhibitor) versus
the cefuroxime axetil arm (12% versus 1%, respectively;
P<0.001), particularly drug-related diarrhea (8% versus
1%, respectively; P=0.001).
Early Lyme Disease
Two adequate and well-controlled studies were performed
in patients with early Lyme disease. In these studies
all patients had to present with physician-documented
erythema migrans, with or without systemic manifestations
of infection. Patients were randomized in a 1:1 ratio
to a 20-day course of treatment with cefuroxime axetil
500 mg bid or doxycycline 100 mg tid. Patients were assessed
at 1 month posttreatment for success in treating early
Lyme disease (Part I) and at 1 year posttreatment for
success in preventing the progression to the sequelae
of late Lyme disease (Part II).
A total of 355 adult patients (181 treated with cefuroxime
axetil and 174 treated with doxycycline) were enrolled
in the two studies. In order to objectively validate the
clinical diagnosis of early Lyme disease in these patients,
two approaches were used:
1. Blinded expert reading of photographs,
when available, of the pretreatment erythema migrans skin
lesion; and
2. Serologic confirmation (using enzyme-linked
immunosorbent assay [ELISA] and immunoblot assay ["Western"
blot]) of the presence of anitbodies specific to Borrelia
burgdorferi, the etiologic agent of Lyme disease.
By these procedures, it was possible to confirm the physician
diagnosis of early Lyme disease in 281 (79%) of the 355
study patients. The efficacy data summarized in TABLE
9 are specific to this "validated" patient subset,
while the safety data summarized in TABLE 9 reflect the
entire patient population for the two studies.
Analysis of the submitted clinical data for evaluable
patients in the "validated" patient subset yielded
the results listed in TABLE 9.
TABLE 9 Clinical Effectiveness of Cefuroxime Axetil Tablets
Compared to Doxycycline in the Treatment of Early Lime Disease
|
| |
Part I |
Part II |
| |
(1 Month Posttreatment)* |
(1 Year Posttreatment)† |
| |
Cefuroxime Axetil (n=125) |
Doxycycline (n=108) |
Cefuroxime Axetil (n=105‡) |
Doxycycline (n=83‡) |
| Satisfactory clinical outcome§ |
91% |
93% |
84% |
87% |
| Clinical cure/success |
72% |
73% |
73% |
73% |
| Clinical improvement |
19% |
19% |
10% |
13% |
| * 95% confidence interval
around the satisfactory difference for Part I (-0.08,
+0.05). |
| † 95% confidence interval
around the satisfactory difference for Part II (-0.13,
+0.07). |
| ‡ n's include patients
assessed as unsatisfactory clinical outcomes (failure
+ recurrence) in Part I (cefuroxime axetil¾11
[5 failure, 6 recurrence]; doxycycline¾8
[6 failure, 2 recurrence]). |
| § Satisfactory
clinical outcome includes cure + improvement (Part
I) and success + improvement (Part II). |
Cefuroxime axetil and doxycycline were effective in prevention
of the development of sequelae of late Lyme disease.
Safety: Drug-related adverse events
affecting the skin were reported significantly more frequently
by patients treated with doxycycline than by patients
treated with cefuroxime axetil (12% versus 3%, respectively;
P = 0.002), primarily reflecting the statistically significantly
higher incidence of drug-related photosensitivity reactions
in the doxycycline arm versus the cefuroxime axetil arm
(9% versus 0%, respectively; P< 0.001). While the incidence
of drug-related gastrointestinal adverse events was similar
in the two treatment groups (cefuroxime axetil¾13%;
doxycycline¾11%), the incidence of drug-related
diarrhea was statistically significantly higher in the
cefuroxime axetil arm versus the doxycycline arm (11%
versus 3%, respectively; P=0.005).
Secondary Bacterial Infections of Acute Bronchitis
Four randomized, controlled clinical studies were performed
comparing 5 days versus 10 days of cefuroxime axetil for
the treatment of patients with secondary bacterial infections
of acute bronchitis. These studies enrolled a total of
1253 patients (CAE-516 n=360; CAE-517 n=177; CAEA4001
n=362; CAEA4002 n=354). The protocols for CAE-516 and
CAE-517 were identical and compared cefuroxime axetil
250 mg bid for 5 days, cefuroxime axetil 250 mg bid for
10 days, and amoxicillin and clavulanate potassium 500
mg tid for 10 days. These two studies were conducted simultaneously.
CAEA4001 and CAEA4002 compared cefuroxime axetil 250 mg
bid for 5 days, cefuroxime axetil 250 mg bid for 10 days,
and cefaclor 250 mg tid for 10 days. They were otherwise
identical to CAE-516 and CAE-517 and were conducted over
the following two years. Patients were required to have
polymorphonuclear cells present on the Gram stain of their
screening sputum specimen, but isolation of a bacterial
pathogen from the sputum culture was not required for
inclusion. TABLE 10 demonstrates the results of the clinical
outcome analysis of the pooled studies CAE-516/CAE-517
and CAEA4001/CAEA4002, respectively.
TABLE 10 Clinical Effectiveness of Cefuroxime Axetil Tablets
250 mg bid in Secondary
Bacterial Infections of Acute Bronchitis
|
Comparisons of 5 Versus 10 Days' Treatment Duration
|
| |
CAE-516 and CAE-517* |
CAEA4001 and
CAEA4002† |
| |
5 Day |
10 Day |
5 Day |
10 Day |
| |
(n=127) |
(n=139) |
(n=173) |
(n=192) |
| Clinical Success
(cure + improvement) |
80% |
87% |
84% |
82% |
| Clinical cure |
61% |
70% |
73% |
72% |
| Clinical improvement |
19% |
17% |
11% |
10% |
| * 95%
Confidence interval around the success difference
[-0.164, +0.029]. |
| † 95%
Confidence interval around the success difference
[-0.061, +0.103]. |
The response rates for patients who were both clinically
and bacteriologically evaluable were consistent with those
reported for the clinically evaluable patients.
Safety: In these clinical trials, 399 patients
were treated with cefuroxime axetil for 5 days and 402 patients
with cefuroxime axetil for 10 days. No difference in the
occurrence of adverse events was observed between the two
regimens.
| |
