CLINICAL PHARMACOLOGY
Pharmacokinetics
The cefaclor extended-release tablet formulation of cefaclor is pharmacokinetically different from the cefaclor immediate-release capsule formulation of cefaclor. (See TABLE 1.) No direct comparisons with the suspension formulation of cefaclor have been conducted; therefore, there are no data with which to compare the pharmacokinetic properties of the extended-release tablet formulation and the suspension formulation. Until further data are available, the pharmacokinetic equivalence of the extended-release tablet and the suspension formulations should NOT be assumed.
Absorption and Metabolism
The extent of absorption (AUC) and the maximum plasma concentration (Cmax) of cefaclor from cefaclor extended-release tablets are greater when the extended-release tablet is taken with food.
[NOTE: The extent of absorption (AUC) of cefaclor from cefaclor immediate-release capsules is unaffected by food intake; however, when cefaclor immediate-release capsules are taken with food, the C max is decreased.]
There is no evidence of metabolism of cefaclor in humans.
Comparative Serum Pharmacokinetics
Serum pharmacokinetic parameters for cefaclor extended-release tablets and cefaclor immediate-release capsules are shown in the table below.
TABLE 1: COMPARATIVE PHARMACOKINETICS OF CEFACLOR IMMEDIATE-RELEASE CAPSULES VS. CEFACLOR EXTENDED-RELEASE TABLETSIN FASTING AND FED STATES |
(± 1 standard deviation)
NA = data not available
|
| Parameter | Cefaclor Extended- Release Tablets | Cefaclor Extended- Release Tablets | Cefaclor Immediate- Release Capsules |
| | 375 mg | 500 mg | 2 x 250 mg |
| | fed | fast | fed | fast | fed | fast |
| | n = 10 | | n = 16 | n = 16 | n = 15 | n = 16 |
| Cmax | 3.7 (1.1) | NA | 8.2 (4.2) | 5.4 (1.6) | 9.3 (2.7) | 16.8 (4.7) |
| Tmax | 2.7 (1.0) | NA | 2.5 (0.8) | 1.5 (0.7) | 1.5 (0.6) | 0.9 (0.4) |
| AUC | 9.9 (2.2) | NA | 18.1 (4.2) | 14.8 (4.0) | 20.5 (2.8) | 19.2 (5.0) |
No drug accumulation was noted when cefaclor extended-release tablets were given twice daily.
The plasma half-life in healthy subjects is independent of dosage form and averages approximately 1 hour.
Food Effect on Pharmacokinetics
When cefaclor extended-release tablets are taken with food, the AUC is 10% lower while the C max is 12% lower and occurs 1 hour later compared to cefaclor immediate-release capsules. In contrast, when cefaclor extended-release tablets are taken without food, the AUC is 23% lower while the Cmax is 67% lower and occurs 0.6 hours later, using an equivalent milligram dose of cefaclor immediate-release capsules as a reference. Therefore, cefaclor extended-release tablets should be taken with food.
Special Populations
Renal Insufficiency
In patients with reduced renal function, the serum half-life of cefaclor is slightly prolonged. In those with complete absence of renal function, the plasma half-life of the intact molecule is 2.3 to 2.8 hours. Excretion pathways in patients with markedly impaired renal function have not been determined. Hemodialysis shortens the half-life by 25% to 30%.
Geriatric Patients
In elderly subjects (over age 65) with normal serum creatinine values, higher peak plasma concentrations and AUCs have been observed. This is considered to be primarily a result of an age-related decrement in renal function, and has no apparent clinical significance. Therefore, dosage adjustment is not necessary in elderly subjects with normal serum creatinine values.
Microbiology
Cefaclor has in vitro activity against a broad range of gram-positive and gram-negative bacteria. The bactericidal action of cefaclor results from inhibition of cell-wall synthesis. Cefaclor is stable in the presence of some bacterial ß-lactamases; consequently, some ß-lactamase-producing organisms may be susceptible to cefaclor.
Cefaclor extended-release tablets have 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.
Gram-positive aerobes:
Staphylococcus aureu s
Streptococcus pneumonia e
Streptococcus pyogene s
NOTE: Cefaclor is inactive against methicillin-resistant staphylococci.
Gram-negative aerobes:
Haemophilus influenzae (non-ß-lactamase-producing strains only)
Moraxella catarrhalis (including ß-lactamase-producing strains)
The following in vitro data are available, but their clinical significance is unknown. Cefaclor exhibits in vitro minimum inhibitory concentrations (MICs) of 8 mcg/mL or less (systemic susceptibility breakpoint) against most (≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of cefaclor extended-release tablets in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled trials.
Gram-positive aerobes:
Staphylococcus epidermidis
Gram-negative aerobes:
Haemophilus parainfluenza e
Klebsiella pneumonia e
Anaerobic bacteria:
Peptococcus niger
Peptostreptococc i
Propionibacterium acne s
NOTE: Acinetobacter calcoaceticus, Enterobacter spp., Entercoccus spp., Morganella morganii, Proteus vulgaris, Providencia spp., Pseudomonas spp., and Serratia spp. are resistant to cefaclor.
Susceptibility Testing
Dilution Techniques
Quantitative methods are used to determine antimicrobial minimum 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 (broth, agar, or microdilution) or equivalent with standardized inoculum concentrations and standardized amounts of cefaclor powder. The MIC values should be interpreted according to the following criteria:
| MIC (mcg/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 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 cefaclor powder should provide the following MIC values:
|
*Broth microdilution tests performed using Haemophilus Test Medium (HTM)1
|
| Microorganism | MIC range (mcg/mL) |
| E. coli | ATCC 25922 | 1 to 4 |
| E. faecalis | ATCC 29212 | > 32 |
| S. aureus | ATCC 29213 | 1 to 4 |
| H. influenzae | ATCC 49766* | 1 to 4 |
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 2 requires the use of standardized inoculum concentrations. This procedure uses paper disks impregnated with 30 mcg cefaclor to test the susceptibility of microorganisms to cefaclor.
Reports from the laboratory providing results of the standard single-disk susceptibility test with a 30 mcg cefaclor disk should be interpreted according to the following criteria:
| Zone diameter (mm) | Interpretation |
| ≥ 18 | Susceptible (S) |
| 15-17 | Intermediate (I) |
| ≤ 14 | Resistant (R) |
When testing* H. Influenzae, the following interpretive criteria should be used:
| Zone diameter (mm) | Interpretation |
| ≥ 20 | Susceptible (S) |
| 17-19 | Intermediate (I) |
| ≤ 16 | Resistant (R) |
*Disk susceptibility tests performed using Haemophilus Test Medium (HTM) 2
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 cefaclor.
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 mcg cefaclor disk should provide the following zone diameters in these laboratory test quality control strains:
|
* Disk susceptibility tests performed using Haemophilus Test Medium (HTM) 2
|
| Microorganism | MIC range (mcg/mL) |
| E. coli | ATCC 25922 | 23-27 |
| S. aureus | ATCC 25923 | 27-31 |
| H. influenzae* | ATCC 49766 | 25-31 |
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