, and moraxella catarrhalis (including β-lactamase producing strains) (see clinical studies). acute exacerbations of chronic bronchitis caused by haemophilusinfluenzae (including β-lactamase producing strains), haemophilusparainfluenzae (including β-lactamase producing strains), streptococcus pneumoniae(penicillin-susceptible strains only), and moraxella catarrhalis (including β-lactamase producing strains). acute maxillary sinusitis caused by haemophilusinfluenzae (including β-lactamase producing strains), streptococcus pneumoniae (penicillin-susceptible strains only), and moraxella catarrhalis (including β-lactamase producing strains). note: for information on use in pediatric patients, see pediatric use and dosage and administration. pharyngitis/tonsillitis caused by streptococcus pyogenes (see clinical studies). note: cefdinir is effective in the eradication of s. pyogenes from the oropharynx. cefdinir has not, however, been studied for the prevention of rheumatic fever following s. pyogenespharyngitis/tonsillitis. only intramuscular penicillin has been demonstrated to be effective for the prevention of rheumatic fever. uncomplicated skin and skin structure infections caused by staphylococcus aureus (including β-lactamase producing strains) and streptococcus pyogenes. pediatric patients acute bacterial otitis media caused by haemophilusinfluenzae (including β-lactamase producing strains), streptococcus pneumoniae (penicillin-susceptible strains only), and moraxella catarrhalis (including β-lactamase producing strains). pharyngitis/tonsillitis caused by streptococcus pyogenes (see clinical studies). note: cefdinir is effective in the eradication of s. pyogenes from the oropharynx. cefdinir has not, however, been studied for the prevention of rheumatic fever following s. pyogenespharyngitis/tonsillitis. only intramuscular penicillin has been demonstrated to be effective for the prevention of rheumatic fever. uncomplicated skin and skin structure infections caused by staphylococcus aureus (including β-lactamase producing strains) and streptococcus pyogenes.

colitis. treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of c. difficile. c. difficile produces toxins a and b which contribute to the development of cdad. hypertoxin producing strains of c. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. cdad must be considered in all patients who present with diarrhea following antibacterial use. careful medical history is necessary since cdad has been reported to occur over two months after the administration of antibacterial agents. if cdad is suspected or confirmed, ongoing antibacterial use not directed against c. difficile may need to be discontinued. appropriate fluid and electrolyte management, protein supplementation, antibacterial treatment of c. difficile, and surgical evaluation should be instituted as clinically indicated.

or adult patients with creatinine clearance < 30 ml/min, the dose of cefdinir should be 300 mg given once daily. creatinine clearance is difficult to measure in outpatients. however, the following formula may be used to estimate creatinine clearance (clcr) in adult patients. for estimates to be valid, serum creatinine levels should reflect steady-state levels of renal function. males: clcr = (weight) (140 – age) (72) (serum creatinine) females: clcr = 0.85 x above value where creatinine clearance is in ml/min, age is in years, weight is in kilograms, and serum creatinine is in mg/dl.4 the following formula may be used to estimate creatinine clearance in pediatric patients: clcr = k x body length or height serum creatinine where k=0.55 for pediatric patients older than 1 year5 and 0.45 for infants (up to 1 year).6 in the above equation, creatinine clearance is in ml/min/1.73 m2, body length or height is in centimeters, and serum creatinine is in mg/dl. for pediatric patients with a creatinine clearance of < 30 ml/min/1.73 m2, the dose of cefdinir should be 7 mg/kg (up to 300 mg) given once daily. patients on hemodialysis hemodialysis removes cefdinir from the body. in patients maintained on chronic hemodialysis, the recommended initial dosage regimen is a 300 mg or 7 mg/kg dose every other day. at the conclusion of each hemodialysis session, 300 mg (or 7 mg/kg) should be given. subsequent doses (300 mg or 7 mg/kg) are then administered every other day.

e 250 mg/5 ml oral suspension with a high-fat meal, the cmaxand 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 (mcg/ml) tmax (hr) auc (mcg•hr/ml) 300 mg 1.60 2.9 7.05 (0.55) (0.89) (2.17) 600 mg 2.87 3.0 11.1 (1.01) (0.66) (3.87) 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 to 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 to 1.1) and 1.1 (0.49 to 1.9) mcg/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 to 0.46) and 0.36 (0.22 to 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 to 0.46) and 0.21 (< 0.12 to 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 to 1.33) and 1.14 (< 0.06 to 1.92) mcg/ml, and were 31% (±18) of corresponding plasma concentrations. respective median epithelial lining fluid concentrations were 0.29 (< 0.3 to 4.73) and 0.49 (< 0.3 to 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 to 0.94) and 0.72 (0.14 to 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 (t1/2) 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 (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 t1/2increased by approximately 2-fold and auc by approximately 3-fold. in subjects with clcr< 30 ml/min, cmax increased by approximately 2-fold, t1/2 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 t1/2 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 t1/2 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. 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 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 haemophilusinfluenzae haemophilusparainfluenzae 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 microorganisms* minimum inhibitory concentration (mcg/ml) zone diameter (mm) s i r s i r * streptococci other than s. pneumoniae that are susceptible to penicillin (mic ≤ 0.12 mcg/ml), can be considered susceptible to cefdinir. † s. 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-mcg 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 haemophilusinfluenzae ≤ 1 -­ -­ ≥ 20 -­ -- haemophilusparainfluenzae ≤ 1 -­ -­ ≥ 20 -­ -- moraxella catarrhalis ≤ 1 2 ≥ 4 ≥ 20 17 - 19 ≤ 16 streptococcus pneumoniae† ≤ 0.5 1 ≥ 2 -­ -­ -­ streptococcus pyogenes ≤ 1 2 ≥ 4 ≥ 20 17 - 19 ≤ 16 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 haemophilusinfluenzae 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

ate 500/125 mg t.i.d. 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 cefdinirb.i.d. amoxicillin/ clavulanatet.i.d. 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 q.d. or b.i.d. to penicillin 250 mg or 10 mg/kg q.i.d. 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 q.d. cefdinir b.i.d. penicillin q.i.d. outcome adults/ adolescents eradication of s. pyogenesclinical cure rates 192/210 (91%) 199/217 (92%) 181/217 (83%) cefdinir superior to control 199/210 (95%) 209/217 (96%) 193/217 (89%) cefdinir superior to control pediatric patients eradication of s. pyogenesclinical cure rates 215/228 (94%) 214/227 (94%) 159/227 (70%) cefdinir superior to control 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 b.i.d. to 10 days of penicillin 250 mg or 10 mg/kg q.i.d.. 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 b.i.d. penicillin q.i.d. outcome adults/ adolescents eradication of s. pyogenes clinical cure rates 193/218 (89%) 176/214 (82%) cefdinir equivalent to control 194/218 (89%) 181/214 (85%) cefdinir equivalent to control pediatric patients eradication of s. pyogenes clinical cure rates 176/196 (90%) 135/193 (70%) cefdinir superior to control 179/196 (91%) 173/193 (90%) cefdinir equivalent to control