This report was reviewed for medical and scientific accuracy by Frank P. Murphy, MD, Assistant Professor of Medicine, Division of Dermatology; Chief, Division of Dermatology,University of Medicine & Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey

Introduction

According to the results of a recent study, the use of cefdinir, an extended- spectrum cephalosporin, demonstrated a spectrum and potency comparable or superior to other orally administered β-lactam antibiotics on more than 400 isolates of community-acquired skin and skin-structure infections.¹ Cefdinir was the most active oral cephalosporin (4- to 16-fold more potent) when tested against oxacillin-susceptible Staphylococcus aureus (S. aureus) and 4- to 32-fold more potent than all other cephalo-sporins evaluated against coagulase-negative staphylococci. Only 0.5% of isolates were resistant to cefdinir, all among sampled Gram-negative species.

Uncomplicated skin and skin-structure infections represent one of the most commonly occurring community-acquired infections in patients of all ages. Pharmacologic therapy for the treatment of uncomplicated skin and skin-structure infections typically involves oral antibiotics with parenteral therapy reserved for more complex and complicated infections. When appropriately diagnosed and treated with early antibiotic intervention, these infections are almost always curable. However, if not treated appropriately, simple skin and skin-structure infections have the potential to cause serious complications such as septicemia, nephritis and carditis resulting in high morbidity and even mortality. Moreover, the development of drug-resistant organisms has made the selection of initial antibiotic therapy for uncomplicated skin and skin-structure infections more complex. Therefore, it is critically important to select the most appropriate antibiotic agent to fully eradicate the infection and avoid worsening of the infection or hospitalization of the patient.

For most uncomplicated skin and skin-structure infections, empiric antibiotic therapy is directed toward the most likely pathogens, typically S. aureus and Streptococcus pyogenes (S. pyogenes; group A beta-hemolytic streptococci). In rare cases, infections may have a polymicrobial origin. Consideration to the resistance profile of the target organism is a key factor to avoiding therapeutic failure from selecting an inappropriate antibiotic. For example, data indicate that the majority of skin isolates of S. aureus are now resistant to penicillin,² and are becoming increasingly resistant to erythromycin.³

Oral β-lactam antibiotics (eg, penicillins, cephalosporins) are one of the most widely used class of antibiotic agents for the treatment of uncomplicated skin and skin-structure infections,4 due to their broad spectrum, clinical efficacy and safety profiles. Due to increasing S. aureus resistance, β-lactamase stable penicillins (eg, dicloxacillin, amoxicillin/ clavulanate) are appropriate treatment options for uncomplicated skin and skin-structure infections. However, the use of amoxicillin/clavulanate is compromised by the occurrence of amoxicillin-induced rash and diarrhea.⁵ Cephalosporins offer excellent activity with a broad spectrum of coverage and are well tolerated.

First-generation cephalosporins (eg, cefadroxil, cephalexin) have generally been supplanted by second- and third-generation cephalosporins. New extended-spectrum cephalosporins such as cefdinir have a broad spectrum of activity against Gram-positive and Gram-negative aerobes, including most Gram-negative enteric organisms. Additionally, cefdinir offers a convenient dosage schedule for patients, low incidence of adverse events, and a favorable palatability,^6,7 which may enhance compliance in pediatric patients for whom taste and palatability are significant issues.

As a result of increased awareness of bacterial resistance and treatment guidelines calling for more judicious use of antibiotics, a study was conducted to re-evaluate the potency and spectrum of coverage of cefdinir as well as selected oral antibiotic agents against recent clinical isolates from community-acquired skin and skin-structure infections.¹ The antimicrobial susceptibility test results of this study, reviewed in this Dermatology Express Report^TM, provided the impetus for a recent meeting of nationally recognized experts in the treatment of uncomplicated skin and skin-structure infections.⁸ Utilizing the study results for antimicrobial susceptibility testing, the panelists sought to develop a treatment algorithm for use by primary care physicians, as well as other clinicians, that incorporated issues such as resistance, potency, spectrum of coverage, compliance, and appropriate antibiotic agents for the treatment of uncomplicated skin and skin-structure infections. The treatment algorithm will be published in the near future but the preliminary algorithm schematic is illustrated on the last page of this report for your benefit.

Potency and Spectrum of Selected Antimicrobial Agents against Pathogens Causing Uncomplicated Skin and Skin-structure Infections

A total of 415 isolates were collected from 34 medical centers located in the United States and 5 centers located in Canada. The vast majority of isolates (83%) including all S. aureus, Escherichia coli (E. coli) and Klebsiellaspp. were collected in 2002 with the remaining isolates collected from 1997 to 2000. Due to the non-sterile origin of the bacterial isolates, participant medical centers were directed to collect only isolates that were clinically relevant and considered responsible for the cutaneous infection. Confirmation of species identification was performed with conventional methods as required.

Antimicrobial susceptibility testing was performed using reference broth microdilution methods as described by the National Committee for Clinical Laboratory Standards (NCCLS).⁹ Antimicrobial agents were obtained as reagent grade powder and included cefdinir, cephalexin, cefaclor, cefprozil, cefuroxime, cefpodoxime, amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, erythromycin, ciprofloxacin, levo-floxacin and penicillin. Bacterial pathogens included oxacillin- susceptible S. aureus (n = 242), oxacillin-susceptible coagulase-negative staphylococci (n = 21), S. pyogenes (n = 57), Streptococcus agalactiae (S. agalactiae) (n = 28), viridans group streptococci (n = 25), Klebsiella spp. (n = 21), and E. coli (n = 21). Breakpoint interpretative criteria used were those established by the NCCLS.¹⁰

Oxacillin-susceptible Staphylococcus aureus
Cefdinir was the most potent oral cephalosporin tested against oxacillin-susceptible S. aureus with 50% minimum inhibitory concentration (MIC₅₀) and MIC₉₀ of 0.5 µg/mL (Table 1). Cefdinir was found to be 4-fold more potent than cefprozil (MIC₉₀, 2 µg/mL) and 16-fold more potent than cephalexin (MIC₉₀, 8 µg/mL). Cefuroxime and amoxicillin/ clavulanate also showed excellent activity with >99% susceptibility, while susceptibility rates for ciprofloxacin and levofloxacin were slightly lower (95.5-96.3%). As previously documented,¹¹ cefpodoxime showed only marginal activity (MIC₅₀, 4 µg/mL) against oxacillin-susceptible S. aureus with 43.4% of strains considered susceptible and 55.6% showing intermediate-resistance. Resistance to erythromycin (MIC₅₀, 0.25 µg/mL) was also relatively high (21.1%) among oxacillin-susceptible S. aureus strains.

Oxacillin-susceptible coagulase-negative staphylococci
All oxacillin-susceptible coagulase-negative staphylococci isolates were 100% susceptible to oral cephalosporins and amoxicillin/clavulanate. Among the cephalosporins, cefdinir was 4- to 32-fold more potent than the other oral cephalosporins evaluated (MIC₅₀, 0.06 µg/mL). Susceptibility rates were lower for ciprofloxacin and levofloxacin (90.5-93.3%), trimethoprim/sulfamethoxazole (81.0%), and erythromycin (61.9%). Resistance rates were relatively high for erythromycin (38.1%) and trimethoprim/sulfamethoxazole (9.5%).

Streptococcus pyogenes
All isolates of S. pyogenes were 100% susceptible to all cephalosporins, amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, and levofloxacin. Cefdinir and cefpodoxime were the most potent cephalosporins (MIC₉₀, ≤0.03 µg/mL) being 32-fold more potent than cephalexin (MIC₉₀, 1 µg/mL). However, resistance to erythromycin was 10.6% (87.7% susceptible).

Streptococcus agalactiae
All isolates of S. agalactiae were 100% susceptible to all cephalosporins, amoxicillin/clavulanate, trimethoprim/sulfamethoxazole, and levofloxacin. Among the cephalosporins, cefdinir and cefuroxime showed comparable potency (MIC₉₀ for cefdinir and cefuroxime, respectively, was 0.06 µg/mL and ≤0.06 µg/mL). Resistance rates for erythromycin were high (32.1%) with only 67.9% of S. agalactiae isolates being susceptible.

Viridans Group Streptococci
Although no breakpoints have been established by the NCCLS for oral cephalosporins, cefdinir, cefuroxime, and cefpodoxime displayed an equivalent MIC₅₀ (0.25 µg/mL). Eighty-eight percent of isolates were inhibited by cefdinir at ≤1 µg/mL. Erythromycin showed the lowest MIC₅₀ (≤0.06 µg/mL) followed by penicillin (0.03 µg/mL) and amoxicillin/clavulanate (MIC₅₀, 0.12 µg/mL). However, resistance to erythromycin was 8.0% with 76.0% of isolates being susceptible to erythromycin.

Enterobacteriaceae
Among the Enterobacteriaceae isolates, cefdinir and cefpodoxime were the most active cephalosporins. Only the extended-spectrum beta-lact-amase (ESBL)-producing strains were resistant to cefdinir (one E. coliand one K. pneumoniae isolate). Among E. coliisolates, cefdinir (MIC₅₀, 0.25 µg/mL) was 16-fold more potent than cefuroxime (MIC₅₀, 4 µg/mL) and 8-fold more potent than cefaclor and cefprozil (MIC₅₀, 2 µg/mL). Both cefdinir and cefpodoxime were 32-fold more potent than cepha-lexin (MIC₅₀, 8 µg/mL). Among the cephalosporins, resistance rates varied from 4.8% for cefdinir and cefpodoxime to 42.9% for cefuroxime. Resistance to amoxicillin/clavulanate and trimethoprim/sulfamethoxazole for E. coliwas 14.3% and 23.8%, respectively. Among the Klebsiella isolates, cefdinir (MIC₅₀, 0.12 µg/mL) was 32-fold more potent than cefuroxime (MIC₅₀, 4 µg/mL) and 16-fold more potent than cefaclor and cefprozil (MIC₅₀, 2 µg/mL). Among the cephalosporins, resistance rates varied from 4.8% for cefdinir to 14.3% for cefuroxime. Only ciprofloxacin showed 100% susceptibility for Klebsiella. Resistance to amoxicillin/clavulanate for Klebsiella was 9.5%.

Conclusion

Prompt and appropriate antimicrobial treatment of uncomplicated skin and skin-structure infections to prevent worsening infection is essential. Cephalosporins have become the most widely used class of oral antibiotic therapy for treating uncomplicated skin and skin-structure infections. Cephalosporins typically offer excellent activity against a broad spectrum of increasingly resistant strains of pathogens and are well tolerated.

However, due to increasing bacterial resistance, the selection of initial therapy for uncomplicated skin and skin-structure infections has become more complex and first-generation cephalosporins have been supplanted by second- and extended-spectrum third-generation cephalosporins. The results of this study indicate that cefdinir, an extended-spectrum cephalosporin, exhibits potency and spectrum coverage comparable or superior to cephalexin, cefaclor, cefprozil, cefuroxime and cefpodoxime. Additionally, cefdinir offers a convenient dosage schedule for patients, low incidence of adverse events and a favorable palatability, potentially enhancing compliance in pediatric patients.

Due to the complexities involved with the selection of antimicrobial therapy (eg, resistance, potency, spectrum of coverage), a panel of nationally recognized experts was recently convened to develop a treatment algorithm for use by primary care physicians, as well as other clinicians, for the treatment of uncomplicated skin and skin-structure infections. The treatment algorithm schematic is included in this report for your review and will be completed in the near future.

References

1. Sader HS, Streit JM, Fritsche TR, Jones RN. Potency and spectrum re-evaluation of cefdinir tested against pathogens causing skin and soft tissue infections: a sample of North American isolates. Diagn Microbiol Infect Dis. 2004 (in press).
2. Dagan R, Bar-David Y. Comparison of amoxicillin and clavulanic acid (Augmentin) for the treatment of nonbullous impetigo. Am J Dis Child. 1989;143:916-918.
3. Demidovich CW, Wittler RR, Ruff ME, et al. Impetigo. Current etiology and comparison of penicillin, erythromycin, and cephalexin for impetigo. Am J Dis Child. 1990;144:1313-1315.
4. Low DE. The new oral cephalosporins in community-acquired infections. Clin Microbiol Infect. 2000;6(Suppl 3):64-69.
5. Hedrick J. Acute bacterial skin infections in pediatric medicine. Pediatr Drugs. 2003;5(Suppl 1):35-46.
6. Powers JL, Gooch WM, Oddo LP. Comparison of the palatability of the oral suspension of cefdinir vs amoxicillin/clavulanate potassium, cefprozil and azithromycin in pediatric patients. Pediatr Infect Dis J. 2000;19:S174-S180.
7. Steele RW, Thomas MP, Begue RE. Compliance issues related to the selection of antibiotic suspensions for children. Pediatr Infect Dis J. 2001;20:1-5.
8. Scher R, Hedrick J, Murakawa G, Joseph WS, Maurer T. Dermatology Process of Care: Treatment Algorithm for Uncomplicated Skin and Skin-structure Infections. Convened May 6, 2004 in Chicago, Illinois.
9. National Committee for Clinical Laboratory Standards (2003). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria That Grow Aerobically; Approved Standard, 6th edition. M7-A6. NCCLS, Wayne, PA.
10. National Committee for Clinical Laboratory Standards (2004). Performance Standards for Antimicrobial Susceptibility Testing; Fourteenth Informational Supplement. M100-S14. NCCLS, Wayne, PA.
11. Fulton B, Perry CM. Cefpodoxime proxetil: a review of its use in the management of bacterial infections in paediatric patients. Paediatr Drugs. 2001;3:137-158.

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Disclosure

Frank P. Murphy, MD
No significant relationships to disclose.

This report contains no information on commercial products that are unlabeled for use or investigational uses of products not yet approved.

The opinions expressed in this publication are those of the participating faculty and do not necessarily reflect the opinions or the recommendations of their affiliated institutions: University of Medicine & Dentistry of New Jersey; MMC, Inc.; or any other persons. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this publication should not be used by clinicians without evaluation of their patients' conditions, assessment of possible contraindications or dangers in use, review of any applicable manufacturer's product information, and comparison with the recommendation of other authorities. This Dermatology Express Report^TM does not include discussion of treatment and indications outside of current approved labeling. This Dermatology Express Report^TM was made possible through an educational grant from Abbott Laboratories.

© 2004 Millennium Medical Communications, Inc. and UMDNJ-Center for Continuing and Outreach Education

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