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CLINICAL PHARMACOLOGY

Pharmacokinetics and Drug Metabolism

Absorption

Oral Bioavailability

Maximal plasma cefdinir concentrations occur 2 to 4 hours postdose following capsule or suspension administration. Plasma cefdinir concentrations increase with dose, but the increases are less than dose-proportional from 300 mg (7 mg/kg) to 600 mg (14 mg/kg). Following administration of suspension to healthy adults, cefdinir bioavailability is 120% relative to capsules. Estimated bioavailability of cefdinir capsules is 21% following administration of a 300 mg capsule dose, and 16% following administration of a 600 mg capsule dose. Estimated absolute bioavailability of cefdinir suspension is 25%. Cefdinir oral suspension of 250 mg/5 mL strength was shown to be bioequivalent to the 125 mg/5 mL strength in healthy adults under fasting conditions.

Effect of Food

The Cmax and AUC of cefdinir from the capsules are reduced by 16% and 10%, respectively, when given with a high-fat meal. In adults given the 250 mg/5 mL oral suspension with a high-fat meal, the Cmax and AUC of cefdinir are reduced by 44% and 33%, respectively. The magnitude of these reductions is not likely to be clinically significant because the safety and efficacy studies of oral suspension in pediatric patients were conducted without regard to food intake. Therefore, cefdinir may be taken without regard to food.

Cefdinir Capsules

Cefdinir plasma concentrations and pharmacokinetic parameter values following administration of single 300- and 600-mg oral doses of cefdinir to adult subjects are presented in the following table:

Mean (± SD) Plasma Cefdinir Pharmacokinetic Parameter Values Following Administration of Capsules to Adult Subjects

Dose Cmax
(g/mL)
tmax
(hr)
AUC
(g•hr/mL)
300 mg 1.60
(0.55)
2.9
(0.89)
7.05
(2.17)
600 mg 2.87
(1.01)
3.0
(0.66)
11.1
(3.87)

Cefdinir Suspension

Cefdinir plasma concentrations and pharmacokinetic parameter values following administration of single 7- and 14-mg/kg oral doses of cefdinir to pediatric subjects (age 6 months-12 years) are presented in the following table:

Mean (± SD) Plasma Cefdinir Pharmacokinetic Parameter Values Following Administration of Suspension to Pediatric Subjects

Dose Cmax
(g/mL)
tmax
(hr)
AUC
(g•hr/mL)
7 mg/kg 2.30
(0.65)
2.2
(0.6)
8.31
(2.50)
14 mg/kg 3.86
(0.62)
1.8
(0.4)
13.4
(2.64)

Multiple Dosing

Cefdinir does not accumulate in plasma following once- or twice-daily administration to subjects with normal renal function.

Distribution

The mean volume of distribution (Vdarea) of cefdinir in adult subjects is 0.35 L/kg (± 0.29); in pediatric subjects (age 6 months-12 years), cefdinir Vdarea is 0.67 L/kg (± 0.38). Cefdinir is 60% to 70% bound to plasma proteins in both adult and pediatric subjects; binding is independent of concentration.

Skin Blister

In adult subjects, median (range) maximal blister fluid cefdinir concentrations of 0.65 (0.33-1.1) and 1.1 (0.49-1.9) g/mL were observed 4 to 5 hours following administration of 300- and 600-mg doses, respectively. Mean (± SD) blister Cmax and AUC (0-∞) values were 48% (± 13) and 91% (± 18) of corresponding plasma values.

Tonsil Tissue

In adult patients undergoing elective tonsillectomy, respective median tonsil tissue cefdinir concentrations 4 hours after administration of single 300- and 600-mg doses were 0.25 (0.22-0.46) and 0.36 (0.22-0.80) g/g. Mean tonsil tissue concentrations were 24% (± 8) of corresponding plasma concentrations.

Sinus Tissue

In adult patients undergoing elective maxillary and ethmoid sinus surgery, respective median sinus tissue cefdinir concentrations 4 hours after administration of single 300- and 600-mg doses were < 0.12 ( < 0.12-0.46) and 0.21 ( < 0.12-2.0) g/g. Mean sinus tissue concentrations were 16% (± 20) of corresponding plasma concentrations.

Lung Tissue

In adult patients undergoing diagnostic bronchoscopy, respective median bronchial mucosa cefdinir concentrations 4 hours after administration of single 300- and 600-mg doses were 0.78 ( < 0.06-1.33) and 1.14 ( < 0.06-1.92) g/mL, and were 31% (± 18) of corresponding plasma concentrations. Respective median epithelial lining fluid concentrations were 0.29 ( < 0.3-4.73) and 0.49 ( < 0.3-0.59) g/mL, and were 35% (± 83) of corresponding plasma concentrations.

Middle Ear Fluid

In 14 pediatric patients with acute bacterial otitis media, respective median middle ear fluid cefdinir concentrations 3 hours after administration of single 7- and 14-mg/kg doses were 0.21 ( < 0.09-0.94) and 0.72 (0.14-1.42) g/mL. Mean middle ear fluid concentrations were 15% (± 15) of corresponding plasma concentrations.

CSF

Data on cefdinir penetration into human cerebrospinal fluid are not available.

Metabolism and Excretion

Cefdinir is not appreciably metabolized. Activity is primarily due to parent drug. Cefdinir is eliminated principally via renal excretion with a mean plasma elimination half-life (t½) of 1.7 (± 0.6) hours. In healthy subjects with normal renal function, renal clearance is 2.0 (± 1.0) mL/min/kg, and apparent oral clearance is 11.6 (± 6.0) and 15.5 (± 5.4) mL/min/kg following doses of 300- and 600-mg, respectively. Mean percent of dose recovered unchanged in the urine following 300- and 600-mg doses is 18.4% (± 6.4) and 11.6% (± 4.6), respectively. Cefdinir clearance is reduced in patients with renal dysfunction (see Special Populations - Patients with Renal Insufficiency).

Because renal excretion is the predominant pathway of elimination, dosage should be adjusted in patients with markedly compromised renal function or who are undergoing hemodialysis (see DOSAGE AND ADMINISTRATION).

Special Populations

Patients with Renal Insufficiency

Cefdinir pharmacokinetics were investigated in 21 adult subjects with varying degrees of renal function. Decreases in cefdinir elimination rate, apparent oral clearance (CL/F), and renal clearance were approximately proportional to the reduction in creatinine clearance (CLcr). As a result, plasma cefdinir concentrations were higher and persisted longer in subjects with renal impairment than in those without renal impairment. In subjects with CLcr between 30 and 60 mL/min, Cmax and t½ increased by approximately 2-fold and AUC by approximately 3-fold. In subjects with CLcr < 30 mL/min, Cmax increased by approximately 2-fold, t½ by approximately 5-fold, and AUC by approximately 6-fold. Dosage adjustment is recommended in patients with markedly compromised renal function (creatinine clearance < 30 mL/min; see DOSAGE AND ADMINISTRATION).

Hemodialysis

Cefdinir pharmacokinetics were studied in 8 adult subjects undergoing hemodialysis. Dialysis (4 hours duration) removed 63% of cefdinir from the body and reduced apparent elimination t½ from 16 (± 3.5) to 3.2 (± 1.2) hours. Dosage adjustment is recommended in this patient population (see DOSAGE AND ADMINISTRATION).

Hepatic Disease

Because cefdinir is predominantly renally eliminated and not appreciably metabolized, studies in patients with hepatic impairment were not conducted. It is not expected that dosage adjustment will be required in this population.

Geriatric Patients

The effect of age on cefdinir pharmacokinetics after a single 300-mg dose was evaluated in 32 subjects 19 to 91 years of age. Systemic exposure to cefdinir was substantially increased in older subjects (N = 16), Cmax by 44% and AUC by 86%. This increase was due to a reduction in cefdinir clearance. The apparent volume of distribution was also reduced, thus no appreciable alterations in apparent elimination t½ were observed (elderly: 2.2 ± 0.6 hours vs young: 1.8 ± 0.4 hours). Since cefdinir clearance has been shown to be primarily related to changes in renal function rather than age, elderly patients do not require dosage adjustment unless they have markedly compromised renal function (creatinine clearance < 30 mL/min, see Patients with Renal Insufficiency, above).

Gender and Race

The results of a meta-analysis of clinical pharmacokinetics (N = 217) indicated no significant impact of either gender or race on cefdinir pharmacokinetics.

Microbiology

As with other cephalosporins, bactericidal activity of cefdinir results from inhibition of cell wall synthesis. Cefdinir is stable in the presence of some, but not all, β-lactamase enzymes. As a result, many organisms resistant to penicillins and some cephalosporins are susceptible to cefdinir.

Cefdinir has been shown to be active against most strains of the following microorganisms, both in vitro and in clinical infections as described in INDICATIONS.

Aerobic Gram-Positive Microorganisms

Staphylococcus aureus (including β-lactamase producing strains)

NOTE: Cefdinir is inactive against methicillin-resistant staphylococci.

Streptococcus pneumoniae (penicillin-susceptible strains only)
Streptococcus pyogenes

Aerobic Gram-Negative Microorganisms

Haemophilus influenzae (including β-lactamase producing strains)
Haemophilus parainfluenzae
(including β-lactamase producing strains)
Moraxella catarrhalis
(including β-lactamase producing strains)

The following in vitro data are available, but their clinical significance is unknown.

Cefdinir exhibits in vitro minimum inhibitory concentrations (MICs) of 1 g/mL or less against ( ≥ 90%) strains of the following microorganisms; however, the safety and effectiveness of cefdinir in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.

Aerobic Gram-Positive Microorganisms

Staphylococcus epidermidis (methicillin-susceptible strains only)
Streptococcus agalactiae

Viridans group streptococci
NOTE: Cefdinir is inactive against Enterococcus and methicillin-resistant Staphylococcus species.

Aerobic Gram-Negative Microorganisms

Citrobacter diversus
Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

NOTE: Cefdinir is inactive against Pseudomonas and Enterobacter species.

Susceptibility Tests

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 method(1) (broth or agar) or equivalent with standardized inoculum concentrations and standardized concentrations of cefdinir powder. The MIC values should be interpreted according to the following criteria:

For organisms other than Haemophilus spp. and Streptococcus spp:

MIC (µg/mL) Interpretation
≤ 1 Susceptible (S)
2 Intermediate (I)
≥ 4 Resistant (R)

For Haemophilus spp:a

MIC (µg/mL) Interpretation b
≤ 1 Susceptible (S)
a These interpretive standards are applicable only to broth microdilution susceptibility tests with Haemophilus spp. using Haemophilus Test Medium (HTM).(1)
b The current absence of data on resistant strains precludes defining any results other than "Susceptible." Strains yielding MIC results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.

For Streptococcus spp:

Streptococcus pneumoniae that are susceptible to penicillin (MIC ≤ 0.06 g/mL), or streptococci other than S. pneumoniae that are susceptible to penicillin (MIC ≤ 0.12 g/mL), can be considered susceptible to cefdinir. Testing of cefdinir against penicillin-intermediate or penicillin-resistant isolates is not recommended. Reliable interpretive criteria for cefdinir are not available.

A report of "Susceptible" indicates that the pathogen is likely to be inhibited if the antimicrobial compound in the blood reaches the concentration 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 laboratory procedures. Standard cefdinir powder should provide the following MIC values:

Microorganism MIC Range (g/mL)
Escherichia coli ATCC 25922 0.12-0.5
Haemophilus influenzae ATCC 49766c 0.12-0.5
Staphylococcus aureus ATCC 29213 0.12-0.5
c This quality control range is applicable only to H. influenzae ATCC 49766 tested by a broth microdilution procedure using HTM.

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 5-g cefdinir to test the susceptibility of microorganisms to cefdinir.

Reports from the laboratory providing results of the standard single-disk susceptibility test with a 5-g cefdinir disk should be interpreted according to the following criteria:

For organisms other than Haemophilus spp. and Streptococcus spp:d

Zone Diameter (mm) Interpretation
≥ 20 Susceptible (S)
17-19 Intermediate (I)
≤ 16 Resistant (R)
d Because certain strains of Citrobacter, Providencia, and Enterobacter spp. have been reported to give false susceptible results with the cefdinir disk, strains of these genera should not be tested and reported with this disk.

For Haemophilus spp:e

Zone Diameter (mm) Interpretationf
≥ 20 Susceptible (S)
e These zone diameter standards are applicable only to tests with Haemophilus spp. using HTM.(2)
f The current absence of data on resistant strains precludes defining any results other than "Susceptible." Strains yielding MIC results suggestive of a "nonsusceptible" category should be submitted to a reference laboratory for further testing.

For Streptococcus spp:

Isolates of Streptococcus pneumoniae should be tested against a 1-g oxacillin disk.

Isolates with oxacillin zone sizes ≥ 20 mm are susceptible to penicillin and can be considered susceptible to cefdinir. Streptococci other than S. pneumoniae should be tested with a 10-unit penicillin disk. Isolates with penicillin zone sizes ≥ 28 mm are susceptible to penicillin and can be considered susceptible to cefdinir.

As with standardized dilution techniques, diffusion methods require the use of laboratory control microorganisms to control the technical aspects of laboratory procedures. For the diffusion technique, the 5-g cefdinir disk should provide the following zone diameters in these laboratory quality control strains:

Organism Zone Diameter (mm)
Escherichia coli ATCC 25922 24-28
Haemophilus influenzae ATCC 49766g 24-31
Staphylococcus aureus ATCC 25923 25-32
g This quality control range is applicable only to testing of H. influenzae ATCC 49766 using HTM.

Clinical Studies

Community-Acquired Bacterial Pneumonia

In a controlled, double-blind study in adults and adolescents conducted in the US, cefdinir BID was compared with cefaclor 500 mg TID. Using strict evaluability and microbiologic/clinical response criteria 6 to 14 days posttherapy, the following clinical cure rates, presumptive microbiologic eradication rates, and statistical outcomes were obtained:

US Community-Acquired Pneumonia Study Cefdinir vs Cefaclor

  Cefdinir BID Cefaclor TID Outcome
Clinical Cure Rates 150/187 (80%) 147/186 (79%) Cefdinir equivalent to control
Eradication Rates Overall 177/195 (91%) 184/200 (92%) Cefdinir equivalent to control
S. pneumoniae 31/31 (100%) 35/35 (100%)  
H. influenzae 55/65 (85%) 60/72 (83%)  
M. catarrhalis 10/10 (100%) 11/11 (100%)  
H. parainfluenzae 81/89 (91%) 78/82 (95%)  

In a second controlled, investigator-blind study in adults and adolescents conducted primarily in Europe, cefdinir BID was compared with amoxicillin/clavulanate 500/125 mg TID. Using strict evaluability and clinical response criteria 6 to 14 days posttherapy, the following clinical cure rates, presumptive microbiologic eradication rates, and statistical outcomes were obtained:

European Community-Acquired Pneumonia Study Cefdinir vs Amoxicillin/Clavulanate

  Cefdinir BID Amoxicillin/ Clavulanate TID Outcome
Clinical Cure Rates 83/104 (80%) 86/97 (89%) Cefdinir not equivalent to control
Eradication Rates Overall 85/96 (89%) 84/90 (93%) Cefdinir equivalent to control
S. pneumoniae 42/44 (95%) 43/44 (98%)  
H. influenzae 26/35 (74%) 21/26 (81%)  
M. catarrhalis 6/6 (100%) 8/8 (100%)  
H. parainfluenzae 11/11 (100%) 12/12 (100%)  

Streptococcal Pharyngitis/Tonsillitis

In four controlled studies conducted in the United States, cefdinir was compared with 10 days of penicillin in adult, adolescent, and pediatric patients. Two studies (one in adults and adolescents, the other in pediatric patients) compared 10 days of cefdinir QD or BID to penicillin 250 mg or 10 mg/kg QID. Using strict evaluability and microbiologic/ clinical response criteria 5 to 10 days posttherapy, the following clinical cure rates, microbiologic eradication rates, and statistical outcomes were obtained:

Pharyngitis/Tonsillitis Studies Cefdinir (10 days) vs Penicillin (10 days)

Study Efficacy Parameter Cefdinir QD Cefdinir BID Penicillin QID Outcome
Adults/ Adolescents Eradication of S. pyogenes 192/210 (91%) 199/217 (92%) 181/217 (83%) Cefdinir superior to control
Clinical Cure Rates 199/210 (95%) 209/217 (96%) 193/217 (89%) Cefdinir superior to control
Pediatric Patients Eradication of S. pyogenes 215/228 (94%) 214/227 (94%) 159/227 (70%) Cefdinir superior to control
Clinical Cure Rates 222/228 (97%) 218/227 (96%) 196/227 (86%) Cefdinir superior to

Two studies (one in adults and adolescents, the other in pediatric patients) compared 5 days of cefdinir BID to 10 days of penicillin 250 mg or 10 mg/kg QID. Using strict evaluability and microbiologic/clinical response criteria 4 to 10 days posttherapy, the following clinical cure rates, microbiologic eradication rates, and statistical outcomes were obtained:

Pharyngitis/Tonsillitis Studies Cefdinir (5 days) vs Penicillin (10 days)

Study Efficacy Parameter Cefdinir BID Penicillin QID Outcome
Adults/ Adolescents Eradication of S. pyogenes 193/218 (89%) 176/214 (82%) Cefdinir equivalent to control
Clinical Cure Rates 194/218 (89%) 181/214 (85%) Cefdinir equivalent to control
Pediatric Patients Eradication of S. pyogenes 176/196 (90%) 135/193 (70%) Cefdinir superior to control
Clinical Cure Rates 179/196 (91%) 173/193(90%) Cefdinir equivalent to control

REFERENCES

1. National Committee for Clinical Laboratory Standards. Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically, 4th ed. Approved Standard, NCCLS Document M7-A4, Vol 17(2). NCCLS, Villanova, PA, Jan 1997.

2. National Committee for Clinical Laboratory Standards. Performance Standards for Antimicrobial Disk Susceptibility Tests, 6th ed. Approved Standard, NCCLS Document M2-A6, Vol 17(1). NCCLS, Villanova, PA, Jan 1997.

Last reviewed on RxList: 2/13/2009
This monograph has been modified to include the generic and brand name in many instances.

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