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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 (μg/mL) tmax (hr) AUC (μg•hr/mL)
300 mg 1.6 (0.55) 2.9 (0.89) 7.05 (2.17)
600 mg 2.87 (1.01) 3 (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(μg/mL) tmax(hr) AUC(μg•hr/mL)
7 mg/kg 2.3 (0.65) 2.2 (0.6) 8.31 (2.5)
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) μg/mL were observed 4 to 5 hours following administration of 300- and 600mg 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 (0.220.46) and 0.36 (0.22-0.80) μg/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) μg/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) μg/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) μg/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) μg/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 5fold, 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

Mechanism of Action

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.

Mechanism of Resistance

Resistance to cefdinir is primarily through hydrolysis by some β-lactamases, alteration of penicillin-binding proteins (PBPs) and decreased permeability. Cefdinir is inactive against most strains of Enterobacter spp., Pseudomonas spp., Enterococcus spp., penicillin-resistant streptococci, and methicillin-resistant staphylococci. β-lactamase negative, ampicillin-resistant (BLNAR) H. influenzae strains are typically non-susceptible to cefdinir.

Antimicrobial Activity

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 AND USAGE.

Gram-Positive Bacteria

Staphylococcus aureus (methicillin-susceptible strains only)
Streptococcus pneumoniae
(penicillin-susceptible strains only)
Streptococcus pyogenes

Gram-Negative Bacteria

Haemophilus influenzae
Haemophilus parainfluenzae

Moraxella catarrhalis

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

Cefdinir exhibits in vitro minimum inhibitory concentrations (MICs) of 1 mcg/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.

Gram-Positive Bacteria

Staphylococcus epidermidis (methicillin-susceptible strains only)
Streptococcus agalactiae

Viridans group streptococci

Gram-Negative Bacteria

Citrobacter koseri
Escherichia coli

Klebsiella pneumoniae

Proteus mirabilis

Susceptibility Test Methods

When available, the clinical microbiology laboratory should provide periodic reports that describe the regional/local susceptibility profile of potential nosocomial and community-acquired pathogens. These reports should aid the physician in selecting an antibacterial drug for treatment.

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 test method1 (broth and/or agar). The MIC values should be interpreted according to criteria provided in Table 1.

Diffusion Techniques

Quantitative methods that require measurement of zone diameters also provide reproducible estimates of the susceptibility of bacteria to antimicrobial compounds. The zone size should be determined using a standardized method.2 The procedure uses paper disks impregnated with 5 mcg cefdinir to test the susceptibility of bacteria. The disk diffusion interpretive criteria are provided in Table 1.

Table 1: Susceptibility Test Interpretive Criteria for Cefdinir

Microorganismsa Minimum Inhibitory Concentration (mcg/mL) Zone Diameter (mm)
S I R S I R
Haemophilus influenzae ≤ 1 ≥ 20
Haemophilus parainfluenzae ≤ 1 ≥ 20
Moraxella catarrhalis ≤ 1 2 ≥ 4 ≥ 20 17 - 19 ≤ 16
Streptococcus pneumoniaeb ≤ 0.5 1 ≥ 2
Streptococcus pyogenes ≤ 1 2 ≥ 4 ≥ 20 17 - 19 ≤ 16
aStreptococci other than S. pneumoniae that are susceptible to penicillin (MIC ≤ 0.12 mcg/mL), can be considered susceptible to cefdinir.
bS. pneumoniae that are susceptible to penicillin (MIC ≤ 0.06 mcg/mL) can be considered susceptible to cefdinir. Isolates of S. pneumoniae tested against a 1-μg oxacillin disk with oxacillin zone sizes ≥ 20 mm are susceptible to penicillin and 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.

Susceptibility of staphylococci to cefdinir may be deduced from testing penicillin and either cefoxitin or oxacillin. Staphylococci susceptible to oxacillin (cefoxitin) can be considered susceptible to cefdinir.3

A report of “Susceptible” indicates that antimicrobial is likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations at the site of infection necessary to inhibit growth of the pathogen. 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 a high dosage of drug can be used. This category also provides a buffer zone that prevents small uncontrolled technical factors from causing major discrepancies in interpretation. A report of “Resistant” indicates that the antimicrobial is not likely to inhibit growth of the pathogen if the antimicrobial compound reaches the concentrations usually achievable at the infection site; other therapy should be selected.

Quality Control

Standardized susceptibility test procedures require the use of laboratory controls to monitor and ensure the accuracy and precision of supplies and reagents used in the assay, and the techniques of the individual performing the test.1,2,3 Standard cefdinir powder should provide the following range of MIC values as noted in Table 2. For the diffusion technique using a 5 mcg disk the criteria in Table 2 should be achieved.

Table 2: Acceptable Quality Control Ranges for Cefdinir

QC Strain Minimum Inhibitory Concentration (mcg/mL) Zone Diameter (mm)
Escherichia coli ATCC 25922 0.12 - 0.5 24 - 28
Haemophilus influenzae ATCC 49766 0.12 - 0.5 24 - 31
Staphylococcus aureus ATCC 25923 -- 25 - 32
Staphylococcus aureus ATCC 29213 0.12 - 0.5 --
Streptococcus pneumoniae ATCC 49619 0.03 - 0.25 26 - 31

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 control

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. Clinical and Laboratory Standards Institute (CLSI). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard – Tenth Edition. CLSI Document M07-A10 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

2. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Disk Diffusion Susceptibility Tests; Approved Standard – Twelfth Edition. CLSI Document M02-A12 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

3. Clinical and Laboratory Standards Institute (CLSI). Performance Standards for Antimicrobial Susceptibility Testing; Twenty-fifth Informational Supplement, CLSI Document M100-S25 [2015], Clinical and Laboratory Standards Institute, 950 West Valley Road, Suite 2500, Wayne, Pennsylvania 19087, USA.

4. Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31-41.

5. Schwartz GJ, Haycock GB, Edelmann CM, Spitzer A. A simple estimate of glomerular filtration rate in children derived from body length and plasma creatinine. Pediatrics 1976;58:259-63.

6. Schwartz GJ, Feld LG, Langford DJ. A simple estimate of glomerular filtration rate in full-term infants during the first year of life. J Pediatrics 1984;104:849-54.

Last reviewed on RxList: 11/30/2015
This monograph has been modified to include the generic and brand name in many instances.

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