Pediatric Infectious Disease Journal:
Pharmacodynamics and pharmacokinetics of cefdinir, an oral extended spectrum cephalosporin
GUAY, DAVID R. P. PHARMD, FCP, FCCP, FASCP, CGP
From the Department of Experimental and Clinical Pharmacology, College of Pharmacy, University of Minnesota and HealthPartners, Inc., Minneapolis, MN.
Reprints not available.
Background. Oral second and third generation cephalosporins are undergoing continuing research and development in the arena of pediatric infectious disease in an attempt to fill voids created by existing agents in the quest for the “ideal” antimicrobial. This paper reviews the in vitro antimicrobial activity (pharmacodynamics) and pharmacokinetics of cefdinir, an extended spectrum oral cephalosporin, with an emphasis on those aspects relevant to the pediatric patient population.
Methods. A MEDLINE literature search was conducted for the years 1985 through 2000, identifying all English language papers examining the in vitro antimicrobial activity and human pharmacokinetics of cefdinir. Bibliographies of these papers were reviewed, as were relevant data on file with the manufacturer.
Cefdinir exhibits broad range in vitro activity against Gram-positive and Gram-negative aerobes. It exhibits superior activity against Gram-positive aerobes, compared with drugs like cefixime, ceftibuten, cefuroxime and cefpodoxime. In addition it is stable to hydrolysis by many of the common beta-lactamases. The pharmacokinetic parameters of cefdinir in children are similar to those obtained in adults using similar milligram per m2 doses (300, 600 mg in adults = 7, 14 mg/kg in children, respectively).
Conclusions. The pharmacodynamic and pharmacokinetic characteristics of cefdinir as described in this paper, as well as the results of the clinical trials program, support the use of this agent in the treatment of a wide variety of pediatric infectious diseases.
The “ideal” antimicrobial for ambulatory pediatric patients would encompass the following characteristics: clinical efficacy; bactericidal activity; appropriate antimicrobial spectrum, including activity against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pyogenes; optimal pharmacokinetic properties, including excellent oral absorption, good penetration to infection sites, long terminal disposition half-life and stability in serum; low adverse event potential, including low impact on colonic microflora; patient convenience, including once or twice daily dosing and a palatable, pleasant-tasting suspension formulation. Unfortunately no oral antimicrobial fulfills all of these characteristics, thus prompting continuing research and development in this field.
The oral second and third generation cephalosporins have been developed in an attempt to fill this void. Although drugs such as penicillin for streptococcal pharyngotonsillitis or amoxicillin or trimethoprim-sulfamethoxazole for acute otitis media are generally considered first line therapy, 1–3 cephalosporins may be useful agents in areas where local susceptibility patterns reveal a high prevalence of organisms resistant to traditional first line agents 1, 4, 5 or in patients with sulfonamide or nonimmediate penicillin allergies. 1, 2, 6 In addition cephalosporins may be useful when less frequent dosing or shorter duration of therapy may be viewed as significant benefits, from the patient’s or family’s perspective. 7
Available cephalosporins and carbacephems have certain liabilities. Cefprozil has modest in vitro activity against M. catarrhalis and H. influenzae and lesser clinical performance than comparators in some studies. 8–10 Cefuroxime is limited by poor palatability. 8–10 Loracarbef exhibits marginal activity against H. influenzae, and its bioavailability is reduced by food. 9, 10 Cefixime has marginal to modest activity against S. pneumoniae and no activity against Staphylococcus aureus as well as a high risk of antibiotic-associated diarrhea. 8–10 Ceftibuten has liabilities similar to those of cefixime with the exception of diarrhea. 8, 9 Cefpodoxime has only modest activity against Staphylococcus aureus when standard doses are utilized; in addition palatability of the suspension formulation is inferior to that of many other agents. 8–10
The purpose of this paper is to review the in vitro antimicrobial activity (pharmacodynamics) and pharmacokinetics of cefdinir, an oral expanded spectrum cephalosporin (Omnicef; Abbott Laboratories, Chicago, IL), with an emphasis on application to pediatric patients.
IN VITRO ANTIMICROBIAL ACTIVITY
As with the older beta-lactam compounds, cefdinir binds to penicillin-binding proteins, thereby causing cell death by impairing cell wall formation. 11 Cefdinir binds to penicillin-binding proteins 1, 2, 3 and 4 of Staphylococcus aureus (strain 123-1-2) and 1A, 1B, 2, 3 and 4 of Escherichia coli (strains NIHJ JC-2 and K12). 12, 13
Table 1 illustrates the in vitro antibacterial activity of cefdinir and comparator cephalosporins against a wide variety of Gram-positive and Gram-negative aerobes and anaerobes. 12–42 Unlike several extended spectrum oral beta-lactams, cefdinir retains excellent activity against gram-positive aerobes, including staphylococci (except methicillin-resistant strains) and group A, B, C and G streptococci. It also exhibits excellent activity against Neisseriaceae, Haemophilus and Moraxella spp. and variable species-specific activity against the Enterobacteriaceae. In general cefdinir is inactive against Enterococcus and Listeria spp. and exhibits variable activity against S. pneumoniae, with increased MICs for penicillin-intermediate and -resistant vs. penicillin-susceptible strains. Cefdinir is generally inactive against Legionella spp. and anaerobes. 14, 15, 18, 26, 43
The minimum bactericidal concentration of cefdinir is usually <4 times the MIC. 14, 18 The presence of human serum or urine does not affect cefdinir MIC or minimum bactericidal concentration. 14, 15, 25, 44 The presence of CO2, magnesium ions and pH alterations (over a range of pH 5.5 to 8) similarly have no significant effect on cefdinir MIC. 13, 14, 18, 44 Cefdinir MIC increases with increasing inoculum size, but this increase is modest for most species. 14, 15, 18, 41, 44 Brief (up to 2 h) in vitro postantibiotic effect periods have been reported for S. pneumoniae, S. pyogenes, Staphylococcus aureus, Staphylococcus epidermidis, other coagulase-negative staphylococci, H. influenzae, M. catarrhalis and E. coli. 44–46 Cefdinir is stable to hydrolysis by numerous beta-lactamases, including TEM-1, TEM-2, TEM-6, TEM-7, TEM-9, TEM-10, CAZ-2, SHV-1, HMS-1, OXA-1, OXA-2, OXA-3 and P99 type 1a. 14, 15, 18, 40, 47–49 Cefdinir exhibits no deleterious effects on human immune system function ex vivo. 50–52
Cefdinir appears to exert little effect on normal human fecal flora. In a study involving seven pediatric patients (0.5 to 12.5 years old) treated with doses ranging from 9 to 11 mg/kg/day for 4 to 14 days, only modest effects on fecal flora were observed. Aerobic and anaerobic counts, except those of enterococci, varied little over time and in no case did glucose nonfermenters or fungi become predominant species for any length of time. 53
Interpretive criteria and quality control parameters have been published for broth microdilution and disk diffusion methods for cefdinir susceptibility testing of pneumococci, Neisseria gonorrhoeae, H. influenzae, E. coli, Staphylococcus aureus, Enterococcus faecalis and Pseudomonas aeruginosa. 17, 39, 54–60 The MIC breakpoint is 1 mg/l (sensitive, ≤1 mg/l; intermediate, 2 mg/l; resistant, ≥4 mg/l) and the zone size breakpoint for disk diffusion testing with a 5-mg disk is 20 mm (resistant, ≤16 mm; intermediate, 17 to 19 mm; sensitive, ≥20 mm) for organisms other than streptococci. 53, 61 MIC and disk diffusion breakpoints have been established for S. pneumoniae and streptococci other than S. pneumoniae. 53
Pharmacokinetic parameters for cefdinir in adults and children are illustrated in Table 2. Absorption appears to be reasonably rapid in children, with a time to peak plasma concentration (Tmax) of ∼2 h.
Bioavailability of the capsule formulation ranges from 16 to 21%; bioavailability of the suspension formulation is 20% greater than that of the capsule formulation. 53 Food exerts no clinically significant effect on cefdinir bioavailability. 53
Few published data are available regarding tissue and body fluid penetration of cefdinir. In studies utilizing healthy adult volunteers, significant penetration was noted into suction-induced blister fluid (84 to 108%), bronchial mucosal tissue (31 to 41%), bronchial epithelial lining fluid (12 to 15%), tonsillar tissue (24%) and maxillary/ethmoid sinus mucosal tissue (16%). 53, 62, 63 In pediatric patients with acute bacterial otitis media, the mean middle ear fluid concentration 3 h after single 7- and 14-mg/kg doses of cefdinir was 15% that of the corresponding plasma concentration. 53
In adults cefdinir is primarily eliminated as unchanged drug via the renal route. 53, 62 This may not, however, be the case in children based on the low fractional elimination of unchanged drug in children (mean range, 2.7 to 12.7%) compared with that in adults (mean range, 12.7 to 23%). 53, 62 Terminal disposition half-life (t1/2) is ∼1.5 h in healthy adult and pediatric volunteers. 53, 62 Apparent total body clearance appears to be higher in younger (0- to 3-year-old) than in older (3- to 12-year-old) children, consistent with data obtained with other beta-lactam antimicrobials. 53 In adults with normal renal function, drug accumulation does not occur with multiple once or twice daily administration, and pharmacokinetic parameters are similar for multiple dose as compared with single dose administration. 53
Studies have been conducted in adults evaluating the effect of renal dysfunction and dialysis on cefdinir pharmacokinetics. 53 Decreases in apparent total body clearance and renal clearance of cefdinir were approximately proportional to the reduction in creatinine clearance (CrCl). For example in subjects with CrCl between 30 and 60 ml/min, peak plasma concentration (Cmax), t1/2 and area under the plasma concentration-vs.-time curve (AUC) increased ∼2-, 2- and 3-fold, respectively, compared with subjects who had normal renal function. Corresponding increases in subjects with CrCl <30 ml/min were 2-, 5- and 6-fold, respectively.
In hemodialysis patients studied on a nondialysis day, cefdinir Cmax, Tmax, AUC and t1/2 were elevated 3-, 2-, 17- and 11-fold, respectively, compared with healthy volunteers. Cefdinir appears to be hemodialyzable based on a comparison of inter-vs. intradialytic t1/2 and AUC. Fractional elimination in dialysate was 61%. 64 In continuous ambulatory peritoneal dialysis patients, cefdinir Cmax, t1/2 and AUC were elevated 6-, 11- and 24-fold, respectively, compared with healthy volunteers. In contrast to hemodialysis, continuous ambulatory peritoneal dialysis removal of the drug was minimal (<5 mg/24 h). 20
Simultaneous administration of magnesium-aluminum hydroxide antacid reduced cefdinir bioavailability by 38% (based on Cmax data) and 44% (based on AUC data). Separating the dose administrations by 2 h eliminated the interaction. 53
The effect of iron on cefdinir bioavailability is controversial. One study described a significant reduction in bioavailability when 1050 mg of ferrous sulfate were coadministered with or 3 h after cefdinir capsule administration. 65 Another study found that concomitant administration of ferrous sulfate (60 mg elemental iron) and multiple vitamins supplemented with iron (10 mg elemental iron) reduced cefdinir bioavailability by 79 and 38%, respectively (based on Cmax data) and 80 and 31%, respectively (based on AUC data). In contrast iron-fortified infant formula was not found to significantly affect cefdinir bioavailability from the suspension formulation in healthy infants. 53
Cefdinir is an extended spectrum oral cephalosporin with a broad range of activity against Gram-positive and Gram-negative aerobes. It exhibits superior activity against Gram-positive aerobes such as staphylococci and streptococci compared with drugs such as cefixime, cefpodoxime, cefuroxime and ceftibuten. The pharmacokinetic parameters of cefdinir in children are similar to those obtained in adults using similar milligram per m 2 doses (300 mg in adults = 7 mg/kg in children and 600 mg in adults = 14 mg/kg in children). Pharmacokinetic data have thus validated the use of 7 mg/kg twice daily and 14 mg/kg once daily dosing in the pediatric efficacy studies described in the literature 53, 66–68 and in this supplement.
I thank Kari Bunjer for administrative assistance in the preparation of the manuscript.
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Cefdinir; cephalosporins; pharmacokinetics; pharmacodynamics
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