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:

The extent of absorption (mean AUC) and the mean peak plasma concentration increased when film-coated tablets were administered with food. Following a 200 mg tablet dose taken with food, the AUC was 21 to 33% higher than under fasting conditions, and the peak plasma concentration averaged 3.1 mcg/mL in fed subjects versus 2.6 mcg/mL in fasted subjects. Time to peak concentration was not significantly different between fed and fasted subjects.

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 Tmax).

Pharmacokinetics of Cefpodoxime Proxetil Film-coated Tablets:

Over the recommended dosing range (100 to 400 mg), the rate and extent of cefpodoxime absorption exhibited dose-dependency; dose-normalized Cmax and AUC decreased by up to 32% with increasing dose. Over the recommended dosing range, the Tmax was approximately 2 to 3 hours and the T_½ ranged from 2.09 to 2.84 hours. Mean Cmax was 1.4 mcg/mL for the 100 mg dose, 2.3 mcg/mL for the 200 mg dose, and 3.9 mcg/mL for the 400 mg dose. In patients with normal renal function, neither accumulation nor significant changes in other pharmacokinetic parameters were noted following multiple oral doses of up to 400 mg Q 12 hours.

CEFPODOXIME PLASMA LEVELS (mcg/mL) IN FASTED ADULTS AFTER FILM-COATED TABLET ADMINISTRATION (Single Dose)

Dose	Time after oral ingestion
(cefpodoxime equivalents)	lhr	2hr	3hr	4hr	6hr	8hr	12hr
100 mg	0.98	1.4	1.3	1.0	0.59	0.29	0.08
200 mg	1.5	2.2	2.2	1.8	1.2	0.62	0.18
400 mg	2.2	3.7	3.8	3.3	2.3	1.3	0.38

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	Time after oral ingestion
(cefpodoxime equivalents)	Ihr	2hr	3hr	4hr	6hr	8hr	12hr
5 mg/kg1	1.4	2.1	2.1	1.7	0.90	0.40	0.090
1Dose did not exceed 200 mg.

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 MIC₉₀ of 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 MIC₉₀ 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_½ 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 (Cmax, AUC, and Tmax) 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 ≤ 2.0 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 Enterohacteriaceae and Staphylococcus spp.

MIC (mcg/mL")	Interpretation
≤ 2.0	Susceptible (S)
4.0	Intermediate (I)
≥ 8.0	Resistant (R)

For Susceptibility Testing of Haemophilus spp.^a

MIC (mcg/mL)	Interpretationb
≤ 2.0	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)
cThe 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)
1.0	Intermediate (I)
≥ .0	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) (2-5% 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.

^fThe 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) (2-5% 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 -1.0
Staphylococcus aureus (29213)	1.0 - 8.0
Haemophilus influenzae (49247)	0.25 -1.0g
Neisseria gonorrhoeae (49226)	0.03 - 0.12h
Streptococcus pneumoniae (49619)	0.03 - 0.12i
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 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 (S)
k The zone diameter for Haemophilus spp. is applicable only to tests performed on Haemophilus Test Medium (HTM) agar incubated under 5% C02.2 l"Intermediate" and "Resistant" criteria have not been determined.

For Susceptibility Testing of Neisseria gonorrhoeae.^m

Zone Diameter (mm)	Interpretationn
≥ 29	Susceptible (S)
m The zone diameter for N. gonorrhoeae is applicable only to tests performed on GC agar base and 1% defined growth supplement incubated under 5% CO2.2 n "Intermediate" and "Resistant" categories have not been determined.

For Susceptibility Testing of Streptococcus pneumoniae.⁰

Isolates of pneumococci with oxacillin zone sizes of ≥ 20 mm are susceptible (MIC ≤ 0.06 mcg/mL) to penicillin and can be considered susceptible to cefpodoxime for approved indications, and cefpodoxime need not be tested.
⁰ The zone diameter for S. pneumoniae is applicable only to tests performed on Mueller-Hinton agar with 5% sheep blood incubated in 5% C02.2

For Susceptibility Testing of Streptococcus spp. other than Streptococcus pneumoniae.^p

A streptococcal isolate that is susceptible to penicillin (zone diameter ≥ 28 mm) can be considered susceptible to cefpodoxime for approved indications, and cefpodoxime need not be tested.
^p The zone diameter for Streptococcus spp. is applicable only to tests performed on Mueller-Hinton agar with 5% sheep blood incubated in 5% CO₂.²

Quality Control

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms that are used to control the technical aspects of the laboratory procedures. For the diffusion technique, the 10 mcg cefpodoxime disk should provide the following zone diameters with the quality control strains listed below:

Microorganism (ATCC®#)	Zone Diameter Range (mm)
Escherichia coli (25922)	23-28
Staphylococcus aureus (25923)	19-25
Haemophilus influenzae (49247)	25-31q
Neisseria gonorrhoeae (49226)	35-43r
Streptococcus pneumoniae (49619)t	28-34s
q This zone diameter range is only applicable to tests performed on Haemophilus Test Medium (HTM) agar incubated in 5% C02. r This zone diameter range is only applicable to tests performed on GC agar base and 1% defined growth supplement incubated in 5% CO2. s This zone diameter range is only applicable to tests performed on Mueller-Hinton agar supplemented with 5% defibrinated sheep blood, incubated in 5% CO2. t This organism is to be used for quality control testing for both S. pneumoniae and Streptococcus spp.

ATCC® is a registered trademark of the American Type Culture Collection.

CLINICAL TRIALS

Cystitis

In two double-blind, 2:1 randomized, comparative trials performed in adults in the United States, cefpodoxime proxetil was compared to other beta-lactam antibiotics. In these studies, the following bacterial eradication rates were obtained at 5 to 9 days after therapy:

Pathogen	Cefpodoxime	Comparator
E. coli	200/243 (82%)	99/123 (80%)
Other pathogens	34/42 (81 %)	23/28 (82%)
K. pneumoniae
P. mirabilis
S. saprophyticus
TOTAL	234/285 (82%)	122/151 (81%)

 In these studies, clinical cure rates and bacterial eradication rates for cefpodoxime proxetil were comparable to the comparator agents; however, the clinical cure rates and bacteriologic eradication rates were lower than those observed with some other classes of approved agents for cystitis.

Acute Otitis Media Studies

In controlled studies of acute otitis media performed in the United States, where significant rates of beta-lactamase-producing organisms were found, cefpodoxime proxetil was compared to cefixime. In these studies, using very strict evaluability criteria and microbiologic and clinical response criteria at the 4 to 21 day post-therapy follow-up, the following presumptive bacterial eradication/clinical success outcomes (cured and improved) were obtained.

	Cefpodoxime Proxetil	Cefixime
Pathogen	5 mg/kg Q 12 h x 5 d
S. pneumoniae	88/122(72%)	72/124(58%)
H. influenzae	50/76(66%)	61/81(75%)
M. catarrhal	22/39 (56%)	23/41 (56%)
S. pyogenes	20/25(80%)	13/23(57%)
Clinical success rate	171/254(67%)	165/258(64%)

REFERENCES

1. NCCLS. Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically -fourth edition; Approved standard. NCCLS document M7-A4 (ISBN 1-56238-309-4). NCCLS, 940 West Valley Rd., Suite 1400, Wayne, PA 19087-1898, 1997.
2. NCCLS. Performance standards for antimicrobial susceptibility testing; Eighth informational supplement. NCCLS document M100-S8 (ISBN 1-56238-337-x). NCCLS, 940 West Valley Rd., Suite 1400, Wayne, PA 19087-1898, 1998.
3. NCCLS. Performance standards for antimicrobial disk susceptibility tests - sixth edition; Approved standard. NCCLS document M2-A6 (ISBN 1-56238-306-6). NCCLS, 940 West Valley Rd., Suite 1400, Wayne, PA 19087-1898, 1997.

Last reviewed on RxList: 6/26/2007
This monograph has been modified to include the generic and brand name in many instances.