Randomized, Double-Blind, Multicenter Comparison of Oral

CLINICAL THERAPEUTICS®/VOL. 24, NO. 7, 2002

Randomized, Double-Blind, Multicenter Comparison of Oral Cefditoren 200 or 400 mg BID with Either Cefuroxime 250 mg BID or Cefadroxil 500 mg BID for the Treatment of Uncomplicated Skin and Skin-Structure Infections

Alicia D. Bucko, DO, 1 Barbara J. Hunt, MS,2 Sarah L. Kidd, BS,2 and Richard Hom, MD, PhD z 1Academic Dermatology Associates, Albuquerque, New Mexico, and 2TAP Pharmaceutical Products Inc, Lake Forest, Illinois

ABSTRACT

Background: Uncomplicated skin and skin-structure infections are commonly observed in medical practice. Because these infections typically are confined to the super- ficial layers and seldom lead to the destruction of skin structures and resultant systemic dissemination, in general they can be treated with an oral antibiotic with potent microbiologic activity against gram-positive pathogens. Objective: This paper compares the efficacy and tolerability of 3 beta-lactam antibiotics in patients with uncomplicated skin and skin-structure infections. Methods: Two double-blind, multicenter, parallel-group studies were conducted, in which patients aged >12 years with uncomplicated skin and skin-structure infections were randomized to receive cefditoren 200 or 400 mg, cefuroxime 250 mg, or cefadroxil 500 mg, each BID for 10 days. Study 1 compared cefditoren with cefuroxime; Study 2 compared cefditoren with cefadroxil. Clinical and microbiologic responses were assessed at a posttreatment visit (within 48 hours of treatment completion) and test-of-cure visit (7-14 days after treatment completion). Patients were monitored closely throughout the study with the use of physical examinations, clinical laboratory tests, and assessment of adverse events. Results: A total of 1685 patients (855 males, 830 females; mean age, 41.1 years [range, 12-95 years]) were enrolled. Within both studies, the 3 treatment groups were similar at baseline based on demographic characteristics and types of infection. Cellulitis (26%), wound infection (25%), and simple abscess (15%) were the most common infections. Clin- ical cure rates at the test-of-cure visit were 85% (443/523) for cefditoren 200 rag, 83%

Presented in part at the 40th Interscience Conference on Antimicrobial Agents and Chemotherapy, September 17-20, 2000, Toronto, Ontario, Canada. Accepted for publication April 24, 2002. Printed in the USA. Reproduction in whole or part is not permitted,

1134 0149-2918/02/$19.00 A.D. BUCK0 ET AL.

(427/516) for cefditoren 400 mg, 88% infections, and simple abscesses, are com- (234/265) for cefuroxime, and 85% monly encountered in ambulatory set- (21 l/248) for cefadroxil. At the test-of- tings.’ Staphylococcus aureus, group A cure visit, cefditoren 200 mg had eradi- streptococci (ie, Streptococcus pyogenes), cated significantly fewer of the causative and occasionally other beta-hemolytic pathogens isolated before treatment in mi- streptococci cause most of these infec- crobiologically evaluable patients than did tions, although gram-negative organisms cefuroxime in Study 1 (P = 0.043) but sig- (eg, Pseudomonas aeruginosa, Esch- nificantly more of the pathogens than did erichia co/i) are also isolated.2 Because cefadroxil in Study 2 (P = 0.018). Eradi- uncomplicated skin and skin-structure in- cation rates for the most commonly iso- fections typically are confined to the su- lated pathogens were generally similar in perficial layers and seldom lead to the de- the 3 treatment groups in both studies, with struction of skin structures and resultant the only significant difference favoring systemic dissemination, in general they cefditoren 200 and 400 mg over cefadroxil can be treated with an oral antibiotic with for Peptostreptococcus species in Study 2 potent microbiologic activity against (P = 0.016 and P = 0.003, respectively). A gram-positive pathogens. In select cases, minority of patients (1.5% in any treatment local dibridement or incision and drainage group) discontinued study-drug treatment also are used to facilitate cure. prematurely due to a treatment-related ad- Among the antimicrobial agents used verse event, with statistically higher rates for treating uncomplicated skin and skin- for cefditoren 400 mg than for cefditoren structure infections, beta-lactams provide 200 mg and the comparator cephalosporins excellent coverage of methicillin-susceptible (each P < 0.05). All 3 cephalosporins were S aureus and streptococci. Oral beta-lactam generally well tolerated. Most adverse agents with proven clinical efficacy for events (~93%) were categorized as mild uncomplicated skin and skin-structure in- to moderate, with the most common being fections include cefprozil, cefpodoxime diarrhea, nausea, and headache. proxetil, cefuroxime axetil, cefadroxil mono- Conclusion: In this population of pa- hydrate, and penicillin-beta-lactamase tients with uncomplicated skin and skin- inhibitor combinations (eg, amoxicillin/ structure infections, including those due clavulanate).‘-6 to Staphylococcus aureus or Streptococcus Cefditoren pivoxil is an oral, beta- pyogenes, the clinical cure rate and toler- lactamase-stable cephalosporin with bal- ability of cefditoren were comparable to anced in vitro activity against both gram- those of cefuroxime and cefadroxil. positive and gram-negative organisms?-” Key words: cefditoren, cefadroxil, cef- In particular, it possesses excellent in vitro uroxime, skin and soft tissue infection. activity against S aureus (minimum in- (C&z Ther. 2002;24: 1134-l 147) hibitory concentration [MIC] at which 90% of isolates are inhibited [MIC,,] = 0.5 pg/mL) and Spyogenes (MIC,, = 0.03 INTRODUCTION pg/mL).9 After oral administration, cef- Uncomplicated skin and adjacent skin- ditoren pivoxil is absorbed by the gas- structure infections, including impetigo, trointestinal tract and hydrolyzed to cef- erysipelas, cellulitis, folliculitis, wound ditoren by esterases. The maximal plasma

1135 CLINICAL THERAPEUTICS ® concentration of cefditoren averages legal guardians provided written informed 2.60 ± 0.65/~g/mL after a single 200-mg consent. dose and occurs 1.5 to 3.0 hours after dosing. Maximal concentrations of cefditoren Patients in blister fluid were observed 4 to 6 hours after administration of a 400-rag dose of Eligible patients included those aged cefditoren pivoxil, with a mean of 1.1 ± >12 years with mild to moderate uncom- 0.42 p g/mL.l 2 Mean cefditoren concentra- plicated skin or skin-structure bacterial tions in blister fluid at 12 hours after dos- infections that could be treated with an ing exceed 0.4/~g/mLJ 2 Because experi- oral antimicrobial agent. Eligible patients mental data with beta-lactams suggest that had at least 2 of the following local signs time above the MIC is related to outcome and symptoms: pain, tenderness, swelling, of infection 13 and concentrations of cefdi- erythema, associated warmth, purulent toren achieved in skin blister fluid exceed drainage/discharge, induration, and re- its MIC90 for the common gram-positive gional lymph node swelling or tenderness. skin pathogens over most of the 12-hour Women of childbearing potential were re- dosing interval, cefditoren is expected to quired to have a negative result of a have good clinical activity for treating skin prestudy serum or urine pregnancy test infections. In vitro data cannot substitute and agreed to use effective contraception for in vivo clinical data in humans. throughout the study. This article presents the results of 2 In addition to pregnancy or lactation, clinical trials that were designed to com- study exclusion criteria included a chronic pare the efficacy and tolerability of cefdi- or underlying skin condition at the site of toren with those of 2 comparator ceph- the infection(s) involving prosthetic mate- alosporins, cefuroxime and cefadroxil, rials; a wound caused by thermal injury or in patients with uncomplicated skin and acne vulgaris; a site that required surgical skin-structure infections. intervention; abscesses in an anatomic site at high risk for anaerobic infection (eg, rectal area); concomitant documented or PATIENTS AND METHODS suspected bacteremia; infections of the Study Design nail beds and scalp, as well as isolated fu- runculosis or folliculitis; immunodefi- Both multicenter studies (69 sites in the ciency; diabetes mellitus; significant vas- cefadroxil study and 63 sites in the cefur- cular disease; concomitant treatment with oxime study) were conducted in a double- oral or parenteral antibiotics or topical blind, randomized manner. The studies' agents (eg, corticosteroids or antimicro- protocols and procedures followed guide- bials) at the infection site; history of hy- lines established by the Infectious Dis- persensitivity reactions to beta-lactam eases Society of America and the US Food agents; known renal insufficiency (serum and Drug Administration for the evalua- creatinine concentration >2 mg/dL or tion of anti-infective agents. 14 Before pa- blood urea nitrogen >30 mg/dL); and clin- tient enrollment, the institutional review ically significant hepatic disease (alanine board of each site approved the study pro- aminotransferase, aspartate aminotrans- tocol, and all participating patients or their ferase, or total bilirubin >2 times the up-

1136 A.D. BUCKO ET AL. per limit of normal or alkaline phos- visits conducted at regular intervals phatase >1.25 times the upper limit of throughout the 2 studies: (1) before the normal). Exclusion criteria also included start of dosing on the first study day, (2) the use of a systemic antibiotic within 7 immediately after treatment (within 48 days (azithromycin, within 14 days) be- hours of treatment completion), and (3) at fore enrollment or concomitant use during a follow-up visit conducted 7 to 14 days the study for another type of infection. after treatment completion (test-of-cure visit). In addition, one of the investigators was to contact patients by telephone dur- Treatment ing treatment (study days 3-5), and a clinic Patients were instructed to receive the visit was to be scheduled if the patient's study drug BID, after meals, for 10 days. symptoms had not improved by that time. In both studies, patients were randomized Whenever possible, a specimen for cul- in a 1:1:1 ratio to receive cefditoren ture was to be obtained by the investiga- pivoxil* 200 or 400 mg or the comparator tors from the infection site within 48 hours cephalosporin (cefuroxime axetW 250 mg before the initiation of study drug and at in Study l and cefadroxil monohydrate$ any time thereafter, as clinically indicated. 500 mg in Study 2). Study-drug containers A specimen was considered acceptable if were dispensed in numeric sequence at it was obtained by swab of an infected le- each investigative site as patients were en- sion, discharge/drainage, blister fluid, or rolled to ensure random assignment of needle aspiration of abscesses or the lead- treatment regimens according to the ran- ing edge of cellulitis after cleansing with domization schedule. Therapy was admin- normal saline to prevent surface contam- istered in a double-blind, double-dummy ination. The pathogens isolated were fashion. Local adjunctive measures, such tested by a laboratory technician for sus- as daily dressing changes and the use of ceptibility to cefditoren and the compara- cleansing agents (eg, nonantibacterial soap, tor cephalosporin using standard National water, saline, and nonionic surfactants) Committee for Clinical Laboratory Stan- were permitted, whereas chronic anticoag- dards broth microdilution methods) 5 In ulant therapy and systemic steroids at a addition, isolates of S aureus were tested dose >10 mg/d of prednisone (or the equiv- for susceptibility to oxacillin. alent) were not allowed. The exception was long-term treatment with aspirin 325 mg/d. Outcome Measures

Efficacy Study Procedures Clinical and microbiologic responses The clinical status of patients was eval- were assessed by the investigators at the uated by the investigators during clinic posttreatment and test-of-cure visits. Pa- tients were considered clinical cares if *Trademark: Spectracef TM (TAP Pharmaceutical their pretreatment signs and symptoms of Products lnc, Lake Forest, Illinois). infection had improved or resolved and *Trademark: Ceftin® (GlaxoSmithKline, Research Triangle Park, North Carolina). they did not need additional antibiotic *Trademark: Duricef ® (Bristol-Myers Squibb Com- therapy for the treatment of the skin or skin- pany, Princeton, New Jersey). structure infection. Patients were consid-

1137 CLINICAL THERAPEUTICS ® ered clinical failures at the posttreatment ability rate was 50%, then ~280 patients visit if they experienced either persistent were to be enrolled in each treatment group. or worsening signs and symptoms or an This sample size provides at least 80% improvement only after the patient re- power to ensure that the 2-tailed 95% CI ceived additional antimicrobial therapy around the difference in response between for the infection. Patients were consid- treatments does not exceed 10%, which is ered clinical relapses at the test-of-cure the criterion to establish equivalence. visit if they experienced improvement in Patient evaluability and outcomes were their signs and symptoms at the posttreat- assessed under blinded conditions. To be ment visit and then worsening or the reap- considered clinically evaluable, patients pearance of signs and symptoms during were required to meet the study entry cri- the test-of-cure period. teria (including the hallmark signs and Microbiologic responses were classified symptoms within 4 days before the initi- as eradication (absence of the pretreat- ation of study drug); to have received at ment pathogen or the infection cleared to least 80% of their prescribed study regi- such an extent that no culturable material men (or :-2 consecutive days if the patient was available); persistence (growth of the was determined a clinical failure); to have pretreatment pathogen in a culture taken had posttreatment and test-of-cure assess- at the posttreatment visit); or recurrence ments to be evaluable at the respective (the pretreatment pathogen or the infec- time points; and, for patients with an tion cleared to such an extent that no cul- isolated pretreatment pathogen, to have turable material was available at the post- not received >1 dose of another anti- treatment visit but the same pathogen microbial agent during the period from reappeared during the follow-up period). the initiation of study-drug treatment (1 week before study enrollment for those Tolerability and Compliance with no pretreatment pathogen isolated) The investigators closely monitored the to the test-of-cure visit. Patients who dis- patients throughout the study using physi- continued study-drug treatment due to a cal examinations that included vital signs, drug-related adverse event or lack of clinical laboratory tests, and the assess- efficacy or who required incision and ment of adverse events. Before breaking of drainage during treatment were consid- the study blind, clinical adverse events were ered treatment failures. Clinically evalu- categorized by the investigators as mild, able patients with a pretreatment culture moderate, or severe. The investigators also (obtained within 4 days of study-drug classified the relationship of adverse events treatment initiation) that was positive for to the study drug as either definitely, prob- a bacterial pathogen were classified as mi- ably, possibly, or not drug related. The crobiologically evaluable. study coordinator counted unused study Within each study, pairwise compar- medication to assess treatment compliance. isons of the treatment groups were made for clinical cure rate and overall pathogen eradication rate using the Fisher exact test. Statistical Analysis Binomial 95% CIs, based on normal ap- Assuming the clinical cure rates for each proximation for the binomial distribution, treatment group were ~90% and the evalu- also were calculated for the difference

1138 A.D. BUCKO ET AL. between each pair of treatment groups for crobiologically nonevaluable was a lack clinical cure rate. of a pretreatment pathogen being isolated. Tolerability data were assessed for all patients who received at least 1 dose of Pretreatment Pathogens study drug. Adverse events that were definitely, probably, or possibly related to the One or more pretreatment pathogens study drug (hereafter called treatment were obtained from 834 patients: 573 in related) are presented in the "Results" the cefditoren-treated groups combined, section. 129 in the cefuroxime-treated group, and 132 in the cefadroxil-treated group. A total of 971 causative pathogens were iso- RESULTS lated, the most common being S aureus A total of 1685 patients were enrolled and (525 [54%]), Peptostreptococcus species treated in the 2 studies: 857 patients in the ( 154 [ 16%]; Peptostreptococcus asaccha- study comparing cefditoren with cefurox- rolyticus [39] and Peptostreptococcus ime (Study 1) and 828 patients in the study magnus [115]), streptococci (93 [10%]; comparing cefditoren with cefadroxil S pyogenes [53] and Streptococcus (Study 2). The mean age of these patients agalactiae [40]), and Enterococcus fae- was 41.1 years (range, 12-95 years). calis (63 [6%]). A total of 48 anaerobes Within both studies, the 3 groups were (5% of all pathogens) were isolated. well matched in terms of demographic MICg0 values of cefditoren were 1 characteristics and types of infection pg/mL against S aureus and 0.015/¢g/mL (Table I). Cellulitis (26%), wound infec- against S pyogenes. Higher MICg0 values tion (25%), and simple abscess (15%) ac- were determined for cefuroxime (2 and counted for most infections. Pretreat- 0.06/~g/mL, respectively) and cefadroxil ment signs and symptoms included some (8 and 0.25/zg/mL, respectively). The 525 combination of erythema, tenderness, S aureus isolates included 43 (8%) that swelling, pain, and warmth for most were resistant to oxacillin. patients. Overall Clinical Response Patient Disposition No statistically significant pairwise Of the 1685 enrolled patients, 88 pa- treatment differences based on clinical tients in Study 1 and 84 patients in Study cure rate were found in clinically evalu- 2 were classified as clinically nonevaluable patients at either the posttreatment or able at the posttreatment visit, as were 70 the test-of-cure visit. At the posttreatment and 63 patients in the respective studies at visit, the overall clinical cure rates were the test-of-cure visit (Table II). The rea- 89% for the groups treated with cefdi- sons for clinical nonevaluability were toren 200 and 400 mg and 90% for the equally divided among the treatment cefuroxime-treated group in Study 1. In groups, with no clinical response assess- Study 2, these rates were 89% for the ment being the most common reason. group treated with cefditoren 200 rag, Across the treatment groups, the primary 88% for the group treated with cefditoren reason for patients being classified as mi- 400 rag, and 90% for the group treated

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1141 CLINICAL THERAPEUTICS® with cefadroxil. A similar trend, with and S pyogenes, respectively, were 83% slightly lower cure rates, was observed at and 90% for the group treated with cefdi- the test-of-cure visit (Table III). Clinical toren 200 mg, 87% and 90% for the group cure rates were similar among the treat- treated with cefditoren 400 mg, and 88% ment groups for each infection. At the and 100% for the group treated with cef- test-of-cure visit, the overall clinical cure uroxime in Study 1. In Study 2, these erad- rates for wound infections and simple ab- ication rates were 83% and 91% for the scesses, respectively, were as follows in group treated with cefditoren 200 mg, Study 1: 91% and 91% for the group 78% and 100% for the group treated with treated with cefditoren 200 rag; 89% and cefditoren 400 mg, and 81% and 100% 83% for the group treated with cefditoren for the group treated with cefadroxil. The 400 mg; and 88% and 90% for the group eradication rate for Peptostreptococcus treated with cefuroxime. In Study 2, these species was significantly higher with values were 94% and 85% for the group cefditoren 200 and 400 mg versus cefa- treated with cefditoren 200 mg; 82% and droxil in Study 2 (95% and 100% vs 59%; 88% for the group treated with cefditoren P = 0.016 and P = 0.003, respectively). 400 mg; and 90% and 85% for the group Otherwise, no statistically significant dif- treated with cefadroxil. ferences were found between treatment groups for eradication rate for a specific pathogen. Microbiologic Response Thirteen patients (2%) in Study 1 and Clinical cure rates were not consistent 22 patients (3%) in Study 2 had both pre- with eradication rates. Clinical cure rates treatment and follow-up cultures growing between the cefditoren-treated groups and S aureus. None of the follow-up cultures comparators were not statistically signifi- had a cefditoren MIC that differed from cant; however, statistically significant dif- the pretherapy cultures by a 2-fold dilu- ferences were found between treatment tion. One patient in Study 1 had a pre- groups based on eradication rates. Of the treatment isolate with an MIC of 4.0 causative pathogens isolated before the pg/mL, whereas an isolate at follow-up initiation of study drug from microbiolog- was obtained with an MIC of 0.5/~g/mL. ically evaluable patients, 81%, 85%, and No other organism in which pretreatment 89% were eradicated with cefditoren 200 and follow-up isolates were obtained dem- mg, cefditoren 400 mg, and cefuroxime, onstrated any significant increase in MIC respectively, at the test-of-cure visit in (by >2-fold dilution). Study 1 (P = 0.043 for cefditoren 200 mg vs cefuroxime; Table IV). In Study 2, 87%, Tolerability 82%, and 77% were eradicated with cefditoren 200 mg, cefditoren 400 rag, and The most common treatment-related cefadroxil, respectively (P = 0.018 for adverse events were diarrhea (14%, 19%, cefditoren 200 mg vs cefadroxil). 7%, and 8% for cefditoren 200 mg [across Eradication rates for the most com- studies], cefditoren 400 mg [across stud- monly isolated pathogens were generally ies], cefuroxime, and cefadroxil, respec- similar in the 3 treatment groups of each tively; P < 0.05 for cefditoren 200 vs 400 study. The eradication rates for S aureus rag; P < 0.001 for cefditoren 200 and 400

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1144 A.D. BUCKO ET AL. mg vs comparator cephalosporins), nau- tococcus species (16%) and streptococci sea (5%, 7%, 4%, and 7%, respectively), (10%). Based on MICs for isolates ob- and headache (4%, 4%, 2%, and 4%, re- tained before treatment and at follow-up spectively). More than 80% of the patients in these 2 studies, no evidence suggested who reported diarrhea required no med- that treatment with cefditoren may result ication to treat the adverse event and con- in the acquisition of resistance by the or- tinued taking study drug. ganism involved in the infection. Most (>93%) adverse events were cat- Results from these 2 multicenter stud- egorized as mild to moderate. Fourteen ies, in which all major forms of uncom- patients (<1%; 5 in each of the cefditoren- plicated skin and skin-structure infection treated groups and 2 each in the cefuroxime- were well represented, indicate that cefdi- treated and cefadroxil-treated groups) ex- toren was comparable to the reference perienced at least 1 severe adverse event, cephalosporins based on clinical cure rates. according to FDA regulatory definitions, The cure rates among clinically evaluable none of which was considered treatment re- patients at the test-of-cure visit were 85% lated. A minority of patients discontinued for the group treated with cefditoren 200 treatment prematurely due to a treatment- mg, 83% for the group treated with cefdi- related adverse event (2%, 5%, 2%, and toren 400 mg, 88% for the group treated 3% of patients in the respective treatment with cefuroxime, and 85% for the group groups [each P < 0.05 for cefditoren 400 mg treated with cefadroxil. Clinical cure rates vs cefditoren 200 mg and comparator were inconsistent with eradication rates. cephalosporins]). The overall pathogen eradication rate with cefditoren 200 mg was significantly higher than that with cefadroxil and significantly DISCUSSION lower than that with cefuroxime. In con- Cephalosporins are a mainstay for treat- trast, the overall pathogen eradication rates ing uncomplicated skin and skin-structure with cefuroxime and cefadroxil were sim- infections because these agents possess ilar to that observed with cefditoren 400 microbiologic activity against the major mg. In general, eradication rates for the gram-positive pathogens that cause the in- most commonly isolated pathogens were fection, achieve adequate penetration to similar for the 3 treatment groups of each skin sites, and have a well-established study, with the only significant difference safety profile, j6 In previous studies 17-23 favoring cefditoren over cefadroxil for of uncomplicated skin and skin-structure Peptostreptococcus species. infections, clinical success rates of >90% All 3 cephalosporins were generally have been documented at the posttreat- well tolerated by study enrollees, with ment visit with cefuroxime and cefadroxil, ~5% in any treatment group prematurely the comparator agents used here. discontinuing their participation in the Microbiologic findings in these 2 stud- study due to a treatment-related adverse ies were characteristic of uncomplicated event. Statistically significant higher rates skin and skin-structure infections. The of premature discontinuation due to a pathogens most commonly isolated be- treatment-related adverse event were ob- fore the initiation of study drug were served for cefditoren 400 mg versus 200 S aureus (54%) followed by Peptostrep- mg and comparator cephalosporins (each

1145 CLINICAL THERAPEUTICS ®

P < 0.05). The most common treatment- America). Bacterial pathogens isolated related adverse events for all 3 ceph- from patients with skin and soft tissue in- alosporins involved the gastrointestinal fections: Frequency of occurrence and antimicrobial susceptibility patterns from the tract, a common finding across studies SENTRY Antimicrobial Surveillance Pro- of beta-lactam drugs} 6 A dose response gram (United States and Canada, 1997). was observed for cefditoren, with a signif- Diagn Microbiol Infect Dis. 1999;34:65- icant difference between each of the dose 72. groups and the comparator cephalosporin- treated group based on incidence of diar- 2. Swartz MN. Cellulitis and subcutaneous rhea. The diarrhea was self-limited in tissue infections. In: Mandell GL, Bennett >80% of the patients (ie, patients did not JE, Dolan R, eds. Mandell, Douglas, and require medication to treat the diarrhea, Bennett's Principles and Practice of In- and patients continued receiving study fectious Diseases. 5th ed. New York: Churchill Livingstone; 2000:1037-1057. drug). 3. Nolen T. Comparative studies of cefprozil CONCLUSIONS in the management of skin and soft-tissue infections. Eur J Clin Microbiol Infect Findings from these studies suggest that Dis. 1994;13:866-871. the clinical cure rate and tolerability of cefditoren were comparable to those of 4. Schatz BS, Karavokiros KT, Taeubel MA, cefuroxime and cefadroxil. Therefore, Itokazu GS. Comparison of cefprozil, cefpodoxime proxetil, loracarbef, cefixime, cefditoren is a viable option for the treat- and ceftibuten. Ann Pharmacother. 1996; ment of patients with uncomplicated skin 30:258-268. and skin-structure infections, including those due to S aureus or S pyogenes. 5. Wilson SE. The management of skin and skin structure infections in children, ado- lescents and adults: A review of empiric ACKNOWLEDGMENTS antimicrobial therapy, lnt J Clin Pract. This research was supported by a grant 1998;52:414-417. from TAP Pharmaceutical Products Inc, 6. Wiseman LR, Benfield P. Cefprozil: A re- Lake Forest, Illinois. view of its antibacterial activity, pharma- Dr. Bucko is an investigator who has cokinetic properties, and therapeutic po- enrolled patients into studies supported tential. Drugs. 1993;45:295-317. by TAP Pharmaceutical Products Inc; she has no commercial or other association 7. Dubois J, St-Pierre C. In vitro study of the that would pose a conflict of interest in postantibiotic effect and the bactericidal the writing of this article. Ms. Hunt, Ms. activity of cefditoren and ten other oral Kidd, and Dr. Horn are employees of TAP antimicrobial agents against upper and lower respiratory tract pathogens. Diagn Pharmaceutical Products Inc. Microbiol Inject Dis. 2000;37:187-193.

REFERENCES 8. Felmingham D, Robbins M J, Ghosh G, et al. An in vitro characterization of cefdi- 1. Doern GV, Jones RN, Pfaller MA, et al, toren, a new oral cephalosporin. Drugs for the SENTRY Study Group (North Exp Clin Res. 1994;20:127-147.

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9. Dubois J, St-Pierre C. Superior inhibitory 16. Nightingale CH. Old and new cephalo- and bactericidal activity of cefditoren sporins: Clinical utility and benefits. JRespir against respiratory tract pathogens. In: Dis. 2001 ;22(Suppl):S8-S 18. Program and abstracts of the 40th Inter- science Conference on Antimicrobial 17. Ballantyne FN. Comparative efficacy of Agents and Chemotherapy (ICAAC); Sep- cefadroxil and cefaclor in the treatment of tember 17-20, 2000; Toronto, Ontario, skin and soft-tissue infections. Clin Ther. Canada. Abstract 370. 1985 ;7:487-491.

10. Chin NX, Zhang YX, Neu HC. In vitro 18. Jacobs RF, Brown WD, Chartrand S, et al. activity of a new cephalosporin ME- 1206 Evaluation of cefuroxime axetil and cefa- compared with other agents. Diagn Mi- droxil suspensions for treatment of pedi- crobiol Infect Dis. 1991 ; 14:417-424. atric skin infections. Antimicrob Agents Chemother. 1992;36:1614-1618. 11. Miyazaki S, Mayazaki Y, Tsuji A, et al. In vitro antibacterial activity of ME1207, a 19. Gooch WM 3rd, Kaminester L, Cole GW, new cephalosporin. Antimicrob Agents et al. Clinical comparison of cefuroxime Chemother. 1991 ;35:1691-1694. axetil and cefadroxil in the treatment of patients with primary infections of the skin 12. Mulford D, Mayer M, Witt G. Pharmaco- or skin structures. Dermatologica. 1991 ; kinetics of cefditoren pivoxil in blister 183:36-43. fluid and plasma. In: Program and abstracts of the 40th Interscience Confer- 20. Parish LC, Cocchetto DM, Werner K, et ence on Antimicrobial Agents and al. Cefuroxime axetil in the treatment of Chemotherapy (ICAAC); September 17- cutaneous infections. Int J Dermatol. 20, 2000; Toronto, Ontario, Canada. 1987;26:389-393. Abstract 656. 21. Hebert AA, Still JG, Reuman PD. Com- 13. Drusano GL. Human pharmacodynamics parative safety and efficacy of clarithro- of beta-lactams, aminoglycosides, and mycin and cefadroxil suspensions in the their combination. Scand J Infect Dis treatment of mild to moderate skin and Suppl. 1990;74:235-248. skin structure infections in children. Pedi- atr Infect Dis J. 1993;12(Suppl 3):S 112- 14. Guidelines for clinical evaluation of anti- S117. infective drugs. Document HEW (FDA) 77-3046. Available at: http://www.fda.gov/ 22. Heskel NS, Siepman NC, Pichotta PJ, et cder/guidance/guidance.htm. Accessed al. Erythromycin versus cefadroxil in the March 2, 1998. treatment of skin infections, Int J Derma- tol. 1992;31:131-133. 15. National Committee for Clinical Labora- tory Standards. Methods for Dilution 23. Lipsky BA, Yarbrough DR 3rd, Walker Antimicrobial Susceptibility Tests for Bac- FB 4th, et al. Ofloxacin versus cephalexin teria That Grow Aerobically. Wayne, Pa: for treating skin and soft tissue infections. NCCLS; 2000. Approved Standard M7-A5. Int J Dermatol. 1992;31:443-445.

Address correspondence to: Alicia D. Bucko, DO, Academic Dermatology Associates, 1203 Coal SE, Suites B and C, Albuquerque, NM 87106-5239. E-mail: [email protected]

1147