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Cefzil

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Cefzil

CLINICAL PHARMACOLOGY

The pharmacokinetic data were derived from the capsule formulation; however, bioequivalence has been demonstrated for the oral solution, capsule, tablet, and suspension formulations under fasting conditions.

Following oral administration of cefprozil to fasting subjects, approximately 95% of the dose was absorbed. The average plasma half-life in normal subjects was 1.3 hours, while the steady-state volume of distribution was estimated to be 0.23 L/kg. The total body clearance and renal clearance rates were approximately 3 mL/min/kg and 2.3 mL/min/kg, respectively.

Average peak plasma concentrations after administration of 250 mg, 500 mg, or 1 g doses of cefprozil to fasting subjects were approximately 6.1, 10.5, and 18.3 g/mL, respectively, and were obtained within 1.5 hours after dosing. Urinary recovery accounted for approximately 60% of the administered dose. (See Table.)


Dosage (mg) Mean Plasma Cefprozil
Concentrations (g/mL)*
8-hour Urinary
Excretion (%)
  Peak appx. 1.5 h 4 h 8 h  
250 mg 6.1 1.7 0.2 60%
500 mg 10.5 3.2 0.4 62%
1000 mg 18.3 8.4 1.0 54%
*Data represent mean values of 12 healthy volunteers.

During the first 4-hour period after drug administration, the average urine concentrations following 250 mg, 500 mg, and 1 g doses were approximately 700 g/mL, 1000 g/mL, and 2900 g /mL, respectively.

Administration of CEFZIL (cefprozil) tablet or suspension formulation with food did not affect the extent of absorption (AUC) or the peak plasma concentration (Cmax) of cefprozil. However, there was an increase of 0.25 to 0.75 hours in the time to maximum plasma concentration of cefprozil (Tmax).

The bioavailability of the capsule formulation of cefprozil was not affected when administered 5 minutes following an antacid.

Plasma protein binding is approximately 36% and is independent of concentration in the range of 2 g/mL to 20 g/mL.

There was no evidence of accumulation of cefprozil in the plasma in individuals with normal renal function following multiple oral doses of up to 1000 mg every 8 hours for 10 days.

In patients with reduced renal function, the plasma half-life may be prolonged up to 5.2 hours depending on the degree of the renal dysfunction. In patients with complete absence of renal function, the plasma half-life of cefprozil has been shown to be as long as 5.9 hours. The half-life is shortened during hemodialysis. Excretion pathways in patients with markedly impaired renal function have not been determined. (See PRECAUTIONS and DOSAGE AND ADMINISTRATION.)

In patients with impaired hepatic function, the half-life increases to approximately 2 hours. The magnitude of the changes does not warrant a dosage adjustment for patients with impaired hepatic function.

Healthy geriatric volunteers ( ≥ 65 years old) who received a single 1-g dose of cefprozil had 35% to 60% higher AUC and 40% lower renal clearance values compared with healthy adult volunteers 20 to 40 years of age. The average AUC in young and elderly female subjects was approximately 15% to 20% higher than in young and elderly male subjects. The magnitude of these age- and gender-related changes in the pharmacokinetics of cefprozil is not sufficient to necessitate dosage adjustments.

Adequate data on CSF levels of cefprozil are not available.

Comparable pharmacokinetic parameters of cefprozil are observed between pediatric patients (6 months to 12 years) and adults following oral administration of selected matched doses. The maximum concentrations are achieved at 1 to 2 hours after dosing. The plasma elimination half-life is approximately 1.5 hours. In general, the observed plasma concentrations of cefprozil in pediatric patients at the 7.5, 15, and 30 mg/kg doses are similar to those observed within the same time frame in normal adult subjects at the 250, 500, and 1000 mg doses, respectively. The comparative plasma concentrations of cefprozil in pediatric patients and adult subjects at the equivalent dose level are presented in the table below.


  Mean (SD) Plasma Cefprozil Concentrations (g/mL)  
Population Dose 1 h 2 h 4 h 6 h T1/2 (h)
children (n=18) 7.5 mg/kg 4.70 (1.57) 3.99 (1.24) 0.91 (0.30) 0.23a
(0.13)
0.94 (0.32)
adults (n=12) 250 mg 4.82 (2.13) 4.92 (1.13) 1.70b (0.53) 0.53
(0.17)
1.28 (0.34)
children (n=19) 15 mg/kg 10.86 (2.55) 8.47 (2.03) 2.75 (1.07) 0.61c (0.27) 1.24 (0.43)
adults (n=12) 500 mg 8.39 (1.95) 9.42 (0.98) 3.18d (0.76) 1.00d (0.24) 1.29 (0.14)
children (n=10) 30 mg/kg 16.69 (4.26) 17.61 (6.39) 8.66 (2.70) - 2.06 (0.21)
adults (n=12) 1000 mg 11.99 (4.67) 16.95 (4.07) 8.36 (4.13) 2.79
(1.77)
1.27 (0.12)
an=11; bn=5; cn =9; dn=11.

Microbiology

Cefprozil has in vitro activity against a broad range of gram-positive and gram-negative bacteria. The bactericidal action of cefprozil results from inhibition of cell-wall synthesis. Cefprozil 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 β-lactamase-producing strains)
NOTE: Cefprozil is inactive against methicillin-resistant staphylococci.
Streptococcus pneumoniae
Streptococcus pyogenes
Aerobic gram-negative microorganisms:
Haemophilus influenzae (including β-lactamase-producing strains)
Moraxella (Branhamella) catarrhalis (including β-lactamase-producing strains)

The following in vitro data are available; however, their clinical significance is unknown. Cefprozil exhibits in vitro minimum inhibitory concentrations (MICs) of 8 g/mL or less against most ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of cefprozil in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.


Aerobic gram-positive microorganisms:
Enterococcus durans
Enterococcus faecalis
Listeria monocytogenes
Staphylococcus epidermidis
Staphylococcus saprophyticus
Staphylococcus warneri
Streptococcus agalactiae
Streptococci (Groups C, D, F, and G)
viridans group Streptococci
NOTE: Cefprozil is inactive against Enterococcus faecium.
Aerobic gram-negative microorganisms:
Citrobacter diversus
Escherichia coli
Klebsiella pneumoniae
Neisseria gonorrhoeae (including β-lactamase-producing strains)
Proteus mirabilis
Salmonella spp.
Shigella
spp.
Vibriospp.
NOTE: Cefprozil is inactive against most strains of Acinetobacter, Enterobacter, Morganella morganii, Proteus vulgaris, Providencia, Pseudomonas, and Serratia.
Anaerobic microorganisms:
Prevotella (Bacteroides) melaninogenicus
Clostridium difficile
Clostridium perfringens
Fusobacterium spp. Peptostreptococcus spp. Propionibacterium acnes
NOTE: Most strains of the Bacteroides fragilis group are resistant to cefprozil.

Susceptibility Tests

Dilution Techniques: Quantitative methods are used to determine antimicrobial minimal inhibitory concentrations (MICs). These MICs provide estimates of the susceptibility of bacteria to antimicrobial compounds. The MICs should be determined using a standardized procedure. Standardized procedures are based on a dilution method1,2 (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of cefprozil powder. The MIC values should be interpreted according to the following criteria:


MIC (g/mL) Interpretation
≤ 8 Susceptible (S)
16 Intermediate (I)
≥ 32 Resistant (R)

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentrations usually achievable. A report of "Intermediate" indicates that the result 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 uncontrolled 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.

Standardized susceptibility test procedures require the use of laboratory control microorganisms to control the technical aspects of the laboratory procedures. Standard cefprozil powder should provide the following MIC values:


Microorganism MIC (g/mL)
Enterococcus faecalis ATCC 29212 4-16
Escherichia coli ATCC 25922 1-4
Haemophilus influenzae ATCC 49766 1-4
Staphylococcus aureus ATCC 29213 0.25-1
Streptococcus pneumoniae ATCC 49619 0.25-1

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 procedure3 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 g cefprozil to test the susceptibility of microorganisms to cefprozil.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30-g cefprozil disk should be interpreted according to the following criteria:


Zone diameter (mm) Interpretation
≥ 18 Susceptible (S)
15-17 Intermediate (I)
≤ 14 Resistant (R)

Interpretation should be as stated above for results using dilution techniques. Interpretation involves correlation of the diameter obtained in the disk test with the MIC for cefprozil.

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 30-g cefprozil disk should provide the following zone diameters in these laboratory test quality control strains.


Microorganism Zone diameter (mm)
Escherichia coli ATCC 25922 21-27
Haemophilus influenzae ATCC 49766 20-27
Staphylococcus aureus ATCC 25923 27-33
Streptococcus pneumoniae ATCC 49619 25-32

Clinical Studies

Study One

In a controlled clinical study of acute otitis media performed in the United States where significant rates of β-lactamase-producing organisms were found, cefprozil was compared to an oral antimicrobial agent that contained a specific β-lactamase inhibitor. In this study, using very strict evaluability criteria and microbiologic and clinical response criteria at the 10 to 16 days post-therapy follow-up, the following presumptive bacterial eradication/clinical cure outcomes (ie, clinical success) and safety results were obtained:

U.S. Acute Otitis Media Study Cefprozil vs β-lactamase inhibitor-containing control drug


EFFICACY:
Pathogen % of Cases with Pathogen
(n=155)
Outcome
S. pneumoniae 48.4% cefprozil success rate 5% better than control
H. influenzae 35.5% cefprozil success rate 17% less than control
M. catarrhalis 13.5% cefprozil success rate 12% less than control
S. pyogenes 2.6% cefprozil equivalent to control
Overall 100.0% cefprozil success rate 5% less than control
Safety

The incidences of adverse events, primarily diarrhea and rash*, were clinically and statistically significantly higher in the control arm versus the cefprozil arm.


Age Group Cefprozil Control
6 months-2 years 21% 41%
3-12 years 10% 19%
*The majority of these involved the diaper area in young children.
Study Two

In a controlled clinical study of acute otitis media performed in Europe, cefprozil was compared to an oral antimicrobial agent that contained a specific β-lactamase inhibitor. As expected in a European population, this study population had a lower incidence of β-lactamase-producing organisms than usually seen in U.S. trials. In this study, using very strict evaluability criteria and microbiologic and clinical response criteria at the 10 to 16 days post-therapy follow-up, the following presumptive bacterial eradication/clinical cure outcomes (ie, clinical success) were obtained:

European Acute Otitis Media Study Cefprozil vs β-lactamase inhibitor-containing control drug


EFFICACY
Pathogen % of Cases with Pathogen (n=47) Outcome
S. pneumoniae 51.0% cefprozil equivalent to control
H. influenzae 29.8% cefprozil equivalent to control
M. catarrhalis 6.4% cefprozil equivalent to control
S. pyogenes 12.8% cefprozil equivalent to control
Overall 100.0% cefprozil equivalent to control
Safety

The incidence of adverse events in the cefprozil arm was comparable to the incidence of adverse events in the control arm (agent that contained a specific β-lactamase inhibitor).

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically-Third Edition. Approved Standard NCCLS Document M7-A3, Vol. 13, No. 25, NCCLS, Villanova, PA, December 1993.

2. National Committee for Clinical Laboratory Standards. Methods for Antimicrobial Susceptibility Testing of Anaerobic Bacteria-Third Edition. Approved Standard NCCLS Document M11-A3, Vol. 13, No. 26, NCCLS, Villanova, PA, December 1993.

3. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests-Fifth Edition. Approved Standard NCCLS Document M2-A5, Vol. 13, No. 24, NCCLS, Villanova, PA, December 1993.

Last reviewed on RxList: 10/3/2007
This monograph has been modified to include the generic and brand name in many instances.

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