To reduce the development of drug-resistant bacteria and maintain the effectiveness of cefpodoxime proxetil and other antibacterial drugs, cefpodoxime proxetil should be used only to treat or prevent infections that are proven or strongly suspected to be caused by bacteria.
DESCRIPTION
Cefpodoxime proxetil is an orally administered, extended spectrum, semi-synthetic antibiotic of the cephalosporin class. The chemical name is (RS)-1(isopropoxycarbonyloxy) ethyl (+)-(6R,7R)-7-[2-(2-amino-4-thiazolyl)-2-{(Z)methoxyimino}acetamido]-3-methoxymethyl-8-oxo-5-thia-1-azabicyclo [4.2.0]oct-2-ene- 2-carboxylate.
Its molecular formula is C
21H
27N
5O
9S
2 and its structural formula is represented below:
The molecular weight of cefpodoxime proxetil is 557.6.
Cefpodoxime proxetil is a prodrug; its active metabolite is cefpodoxime. All doses of cefpodoxime proxetil in this insert are expressed in terms of the active cefpodoxime moiety. The drug is supplied as flavored granules for oral suspension.
Each 5 mL of cefpodoxime proxetil for oral suspension contains cefpodoxime proxetil equivalent to 50 mg or 100 mg of cefpodoxime activity after constitution and the following inactive ingredients: lactose monohydrate, corn starch, croscarmellose sodium, ferric oxide yellow, hydroxypropyl cellulose, microcrystalline cellulose and carboxymethyl cellulose sodium, colloidal silicon dioxide, citric acid anhydrous, sodium citrate, sodium benzoate, sucrose, and citron & vanille flavorings.
CLINICAL PHARMACOLOGY
Absorption and Excretion
Cefpodoxime proxetil is a prodrug that is absorbed from the gastrointestinal tract and de-esterified to its active metabolite, cefpodoxime. Following oral administration of 100 mg of cefpodoxime proxetil to fasting subjects, approximately 50% of the administered cefpodoxime dose was absorbed systemically. Over the recommended dosing range (100 to 400 mg), approximately 29 to 33% of the administered cefpodoxime dose was excreted unchanged in the urine in 12 hours. There is minimal metabolism of cefpodoxime
in vivo.
Effects of Food
When a 200 mg dose of the suspension was taken with food, the extent of absorption (mean AUC) and mean peak plasma concentration in fed subjects were not significantly different from fasted subjects, but the rate of absorption was slower with food (48% increase in T
max).
Pharmacokinetics of Cefpodoxime Proxetil Suspension
In adult subjects, a 100 mg dose of oral suspension produced an average peak cefpodoxime concentration of approximately 1.5 mcg/mL (range: 1.1 to 2.1 mcg/mL), which is equivalent to that reported following administration of the 100 mg tablet. Time to peak plasma concentration and area under the plasma concentration-time curve (AUC) for the oral suspension were also equivalent to those produced with film-coated tablets in adults following a 100 mg oral dose.
The pharmacokinetics of cefpodoxime were investigated in 29 patients aged 1 to 17 years. Each patient received a single, oral, 5 mg/kg dose of cefpodoxime oral suspension. Plasma and urine samples were collected for 12 hours after dosing. The plasma levels reported from this study are as follows:
CEFPODOXIME PLASMA LEVELS (mcg/mL) IN FASTED PATIENTS (1 to 17 YEARS OF AGE) AFTER SUSPENSION ADMINISTRATION
Dose
(cefpodoxime equivalents) |
Time after oral ingestion |
|
1hr |
2hr |
3hr |
4hr |
6hr |
8hr |
12hr |
|
1 Dose did not exceed 200 mg. |
|
5 mg/kg1 |
1.4 |
2.1 |
2.1 |
1.7 |
0.90 |
0.40 |
0.090 |
Distribution
Protein binding of cefpodoxime ranges from 22 to 33% in serum and from 21 to 29% in plasma.
Skin Blister
Following multiple-dose administration every 12 hours for 5 days of 200 mg or 400 mg cefpodoxime proxetil, the mean maximum cefpodoxime concentration in skin blister fluid averaged 1.6 and 2.8 mcg/mL, respectively. Skin blister fluid cefpodoxime levels at 12 hours after dosing averaged 0.2 and 0.4 mcg/mL for the 200 mg and 400 mg multiple-dose regimens, respectively.
Tonsil Tissue
Following a single, oral 100 mg cefpodoxime proxetil film-coated tablet, the mean maximum cefpodoxime concentration in tonsil tissue averaged 0.24 mcg/g at 4 hours post-dosing and 0.09 mcg/g at 7 hours post-dosing. Equilibrium was achieved between plasma and tonsil tissue within 4 hours of dosing. No detection of cefpodoxime in tonsillar tissue was reported 12 hours after dosing. These results demonstrated that concentrations of cefpodoxime exceeded the MIC
90of
S. pyogenes for at least 7 hours after dosing of 100 mg of cefpodoxime proxetil.
Lung Tissue
Following a single, oral 200 mg cefpodoxime proxetil film-coated tablet, the mean maximum cefpodoxime concentration in lung tissue averaged 0.63 mcg/g at 3 hours post-dosing, 0.52 mcg/g at 6 hours post-dosing, and 0.19 mcg/g at 12 hours post-dosing. The results of this study indicated that cefpodoxime penetrated into lung tissue and produced sustained drug concentrations for at least 12 hours after dosing at levels that exceeded the MIC
90 for S. pneumoniae and H. influenzae.
CSF
Adequate data on CSF levels of cefpodoxime are not available.
Effects of Decreased Renal Function
Elimination of cefpodoxime is reduced in patients with moderate to severe renal impairment (<50 mL/min creatinine clearance). (See
PRECAUTIONS and
DOSAGE AND ADMINISTRATION.) In subjects with mild impairment of renal function (50 to 80 mL/min creatinine clearance), the average plasma half-life of cefpodoxime was 3.5 hours. In subjects with moderate (30 to 49 mL/min creatinine clearance) or severe renal impairment (5 to 29 mL/min creatinine clearance), the half-life increased to 5.9 and 9.8 hours, respectively. Approximately 23% of the administered dose was cleared from the body during a standard 3-hour hemodialysis procedure.
Effect of Hepatic Impairment (cirrhosis)
Absorption was somewhat diminished and elimination unchanged in patients with cirrhosis. The mean cefpodoxime T
1/2 and renal clearance in cirrhotic patients were similar to those derived in studies of healthy subjects. Ascites did not appear to affect values in cirrhotic subjects. No dosage adjustment is recommended in this patient population.
Pharmacokinetics in Elderly Subjects
Elderly subjects do not require dosage adjustments unless they have diminished renal function. (See
PRECAUTIONS.) In healthy geriatric subjects, cefpodoxime half-life in plasma averaged 4.2 hours (Vs 3.3 in younger subjects) and urinary recovery averaged 21% after a 400 mg dose was administered every 12 hours. Other pharmacokinetic parameters (C
max, AUC, and T
max) were unchanged relative to those observed in healthy young subjects.
Microbiology
Cefpodoxime is active against a wide-spectrum of Gram-positive and Gram-negative bacteria. Cefpodoxime is stable in the presence of beta-lactamase enzymes. As a result, many organisms resistant to penicillins and cephalosporins, due to their production of beta lactamase, may be susceptible to cefpodoxime. Cefpodoxime is inactivated by certain extended spectrum beta-lactamases. The bactericidal activity of cefpodoxime results from its inhibition of cell wall synthesis.
Cefpodoxime has been shown to be active against most strains of the following microorganisms, both
in vitro and in clinical infections, as described in the
INDICATIONS AND USAGE section.
Aerobic Gram-positive microorganisms:
Staphylococcus aureus (including penicillinase-producing strains)
NOTE: Cefpodoxime is inactive against methicillin-resistant staphylococci
Staphylococcus saprophyticus
Streptococcus pneumoniae (excluding penicillin-resistant strains)
Streptococcus pyogenes
Aerobic Gram-negative microorganisms:
Escherichia coli
Klebsiella pneumoniae
Proteus mirabilis
Haemophilus influenzae (including beta-lactamase producing strains)
Moraxella (Branhamella) catarrhalis
Neisseria gonorrhoeae (including penicillinase-producing strains)
The following
in vitro data are available, but their clinical significance is unknown. Cefpodoxime exhibits
in vitro minimum inhibitory concentrations (MICs) of ≤ 2 mcg/mL against most (≥90%) of isolates of the following microorganisms. However, the safety and efficacy of cefpodoxime in treating clinical infections due to these microorganisms have not been established in adequate and well controlled clinical trials.
Aerobic Gram-positive microorganisms:
Streptococcus agalactiae
Streptococcus spp. (Groups C, F, G)
NOTE: Cefpodoxime is inactive against enterococci.
Aerobic Gram-negative microorganisms:
Citrobacter diversus
Klebsiella oxytoca
Proteus vulgaris
Providencia rettgeri
Haemophilus parainfluenzae
NOTE: Cefpodoxime is inactive against most strains of
Pseudomonas and
Enterobacter.
Anaerobic Gram-positive microorganisms:
Peptostreptococcus magnus
SUSCEPTIBILITY TESTING
Dilution Techniques: Quantitative methods are used to determine antimicrobial inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of microorganisms to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on dilution methods
1,2 (broth or agar) or equivalent using standardized inoculum concentrations, and standardized concentrations of cefpodoxime from a powder of known potency. The MIC values should be interpreted according to the following criteria:
For Susceptibility Testing of Enterobacteriaceae and Staphylococcus spp.
MIC (mcg/mL) Interpretation
≤2 Susceptible (S)
4 Intermediate (I)
≥8 Resistant (R)
For Susceptibility Testing of Haemophilus spp.a
MIC (mcg/mL) Interpretationb
≤2 Susceptible (S)
a The interpretive criteria for
Haemophilus spp. is applicable only to broth microdilution susceptibility testing done with Haemophilus Test Medium (HTM) broth.
2
b “Intermediate” and “Resistant” categories have not been determined.
For Susceptibility Testing of Neisseria gonorrhoeae.c
MIC (mcg/mL) Interpretationd
≤0.5 Susceptible (S)
c The interpretive value for
N. gonorroheae is applicable only to agar dilution susceptibility testing done with
Neisseria gonorrhoeae susceptibility test medium.
2
d “Intermediate” and “Resistant” categories have not been determined.
For Susceptibility Testing of Streptococcus pneumoniae.
MIC (mcg/mL) Interpretatione
≤0.5 Susceptible (S)
1 Intermediate (I)
≥2 Resistant (R)
e The interpretive value for
S. pneumoniae is applicable only to broth microdilution susceptibility testing done with cation-adjusted Mueller-Hinton broth with lysed horse blood (LHB) (2 to 5% v/v).
2
For Susceptibility Testing of Streptococcus spp. other than Streptococcus pneumoniae.f
A streptococcal isolate that is susceptible to penicillin (MIC ≤0.12 mcg/mL) can be considered susceptible to cefpodoxime for approved indications, and need not be tested against cefpodoxime.
f The interpretive value for
Streptococcus spp. is applicable only to broth microdilution susceptibility testing done with cation-adjusted Mueller-Hinton broth with lysed horse blood (LHB) (2 to 5% v/v).
2
A report of “Susceptible” indicates that the pathogen is likely to be inhibited if the concentration of the antimicrobial compound in the blood reaches usually achievable levels. A report of “Intermediate” indicates that the results 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 high dosage of drug can be used. This category also provides a buffer zone which prevents small technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the pathogen is not likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable; other therapy should be selected.
Quality Control
A standardized susceptibility test procedure requires the use of laboratory control organisms to control the technical aspects of the laboratory procedures. Standard cefpodoxime powder should provide the following MIC values with the indicated quality control strains:
Microorganism (ATCC®#) MIC Range (mcg/mL)
Escherichia coli (25922) 0.25 - 1
Staphylococcus aureus (29213) 1 - 8
Haemophilus influenzae (49247) 0.25 - 1
g
Neisseria gonorrhoeae (49226) 0.03 - 0.12
h
Streptococcus pneumoniae (49619)
j 0.03 - 0.12
i
g These quality control ranges are applicable to tests performed by a broth microdilution procedure using Haemophilus Test Medium (HTM).
h These quality control ranges are applicable to tests performed by agar dilution only using GC agar base with 1% defined growth supplement.
i These quality control ranges are applicable to tests performed by the broth microdilution method only using cation-adjusted Mueller-Hinton broth with 2 to 5% lysed horse blood.
j When susceptibility testing
Streptococcus pneumoniae or
Streptococcus spp. this quality control strain should be tested.
Diffusion Techniques: Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. One such standardized procedure
3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 10 mcg cefpodoxime to test the susceptibility of microorganisms to cefpodoxime. Reports from the laboratory providing results of the standard single-disk susceptibility test with a 10 mcg cefpodoxime disk should be interpreted according to the following criteria:
For Susceptibility Testing of Enterobacteriaceae and Staphylococcus spp.
Zone Diameter (mm) Interpretation
≥21 Susceptible (S)
18-20 Intermediate (I)
≤17 Resistant (R)
For Susceptibility Testing of Haemophilus spp.k
Zone Diameter (mm) Interpretationl
≥21 Susceptible
