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 C
maxand 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 C
maxand 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 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:
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 (Vd
area) of cefdinir in adult subjects is 0.35 L/kg (±0.29); in pediatric subjects (age 6 months-12 years), cefdinir Vd
areais 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) mcg/mL were observed 4 to 5 hours following administration of 300 and 600 mg doses, respectively. Mean (±SD) blister C
maxand 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) mcg/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) mcg/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) mcg/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) mcg/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) mcg/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 (t
1/2) 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 (CL
cr). 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 CL
crbetween 30 and 60 mL/min, C
maxand t
1/2increased by approximately 2-fold and AUC by approximately 3-fold. In subjects with CL
cr<30 mL/min, C
maxincreased by approximately 2-fold, t
1/2by 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 t
1/2from 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), C
maxby 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 t
1/2were 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
Enterobacterspp.,
Pseudomonasspp.,
Enterococcusspp., penicillin-resistant streptococci, and methicillin-resistant staphylococci. β-lactamase negative, ampicillin-resistant (BLNAR)
H. influenzaestrains are typically non-susceptible to cefdinir.
Antimicrobial Activity:
Cefdinir has been shown to be active against most strains of the following microorganisms, both
in vitroand 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 vitrodata are available, but their clinical significance is unknown.
Cefdinir exhibits
in vitrominimum 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 method
1(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.
2The 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.
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.
1,2,3Standard 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.
