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

Expert Commentary

James Q. Del Rosso, DO, FAOCD, Clinical Assistant Professor, Department of Dermatology, University of Nevada School of Medicine, Las Vegas, Nevada

According to data presented at the ACADEMY '04 Summer Meeting of the American Academy of Dermatology, cefdinir, an extended spectrum cephalosporin antibiotic, is the most effective oral cephalosporin against Staphylococcus aureus (S. aureus) and Streptococcus pyogenes (S. pyogenes), maintains broad coverage against Gram-negative organisms, and is highly effective for uncomplicated skin and skin-structure infections.^1,2 In addition, the preliminary results of an open observational assessment suggest that once-daily dosing of cefdinir for 7 days may effectively treat uncomplicated skin and skin-structure infections resulting in shorter duration of therapy, sustained efficacy, enhanced patient compliance, and decreased cost of therapy.¹

Uncomplicated skin and skin-structure infections represent one of the most commonly occurring community-acquired infections in patients of all ages. 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 in some patient populations, such as septicemia, nephritis, and carditis, resulting in high morbidity and even mortality. Inappropriate treatment can also lead to the development of bacterial resistance through natural selection. Therefore, it is critically important to select the most appropriate antibiotic agent to fully eradicate the infection, particularly in patients who are more susceptible to complications including children, the elderly, or in patients who are diabetic, immunocompromised, or neutropenic.

For most uncomplicated skin and skin-structure infections, empiricantibiotic therapy is directed toward the most likely pathogens, typically S. aureus or S. pyogenes; although infections can also be caused by coagulase-negative staphylococci, Streptococcus agalactiae (S. agalactiae), other β-hemolytic streptococci (Groups C, F, G), and enteric bacilli (eg, Escherichia coli [E. coli], Klebsiella spp.). Therefore, empiric antibiotic therapy must provide a broad spectrum of coverage against possible pathogens to insure adequate eradication of the pathogen.

In choosing an antibiotic, consideration must be given to pharmacokinetics, pharmacodynamics, antimicrobial spectrum and potency, current resistance patterns in the treated organism population, safety profile, patient compliance, tolerability, patient preference issues, and cost-effectiveness. Due to their clinical efficacy and excellent safety profiles, cephalosporins are one of the most widely used class of antibiotic agents for the treatment of uncomplicated skin and skin-structure infections. Indeed, a panel of nationally recognized thought leaders developed a treatment algorithm outlining the most appropriate antibiotic therapy for uncomplicated skin and skin-structure infections.³ The preliminary treatment algorithm is presented at the end of this report for your benefit. Other classes of antibiotic used for uncomplicated skin and skin-structure infections include β-lactamase stable penicillins, macrolides, and fluoroquinolones.

The purpose of this Dermatology Express Report^TM is to review data presented at the ACADEMY '04 Summer Meeting of the American Academy of Dermatology on the current role of cephalosporin therapy in the successful treatment of uncomplicated skin and skin-structure infections.

Cephalosporins: Generations and Spectrum of Activity

According to James Q. Del Rosso, DO, FAOCD, Clinical Assistant Professor, Department of Dermatology, University of Nevada School of Medicine, Las Vegas, Nevada, oral cephalosporins have sustained a reputation for safety and efficacy with a broad spectrum of antimicrobial coverage that has spanned over 4 decades. In addition to being well tolerated, the pharmacokinetic and pharmacodynamic profiles of many cephalosporins have allowed for effective use in a variety of clinical infections including respiratory, genitourinary, otologic, and dermatologic indications.

Cephalosporins are often classified according to generation (Table 1). This classification is often thought to correlate with spectrum of activity such that as cephalosporin agents increase in generation, antibacterial activity decreases against Gram-positive organisms and increases against Gram-negative organisms.^4,5 Although this generalization has some basis, exceptions exist, rendering this concept misleading to the clinician. For example, cefdinir and cefpodoxime proxetil are extended-spectrum third-generation cephalosporins with extensive activity against a wide range of both Gram-positive and Gram-negative organisms. Moreover, cefdinir has marked activity against S. aureus (including strains that produce β-lactamase), S. pyogenes, Haemophilus influenzae (H. influenzae), and Enterobacteriaceae, typical causative organisms in uncomplicated skin and skin-structure infections. Recent data have demonstrated that cefdinir is the most potent oral cephalosporin against oxacillin-susceptible S. aureus with a 50% minimum inhibitory concentration (MIC₅₀) and MIC₉₀ of 0.5 μg/mL.⁶ 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) while cefpodoxime showed only marginal activity (MIC₅₀, 4 μg/mL) against oxacillin-susceptible S. aureus with 43.4% of strains considered susceptible (99.6% susceptible with cefdinir). It is therefore essential to critically examine each cephalosporin individually to determine effectiveness against a particular organism.

Cephalosporin Efficacy in Uncomplicated Skin and Skin-structure Infections

Tack and colleagues evaluated the comparative safety and efficacy of cefdinir and cephalexin in adults and adolescents with skin and skin-structure infections.⁷ This multicenter, randomized, double-blind study was conducted in 952 adolescents and adults (ages 13 to 88 years) with acute skin and skin-structure infections (abscess, infected traumatic/surgical wound, paronychia, infected dermatitis, impetigo, cellulitis, furuncle, folliculitis, carbuncle, acutely infected cutaneous ulcer, or infected burn). Patients were randomized to treatment with either cefdinir (capsules) 300 mg twice daily for 10 days or cephalexin (capsules) 500 mg four times daily for 10 days.

Baseline cultures identified a total of 821 pathogens, of which S. aureus was the most common (present in 35% of cefdinir-treated patients and 32% of cephalexin-treated patients). Approximately one-fifth of patients (18% and 19% of patients in the cefdinir and cephalexin treatment groups, respectively) had polymicrobial infections, the most common of which involved S. aureus plus S. agalactiae and S. aureus plus S. pyogenes. Susceptibility testing at baseline demonstrated that significantly fewer pathogens were resistant to cefdinir than to cephalexin (88 vs 150, respectively; P<.001).

Both cefdinir and cephalexin eradicated the majority of pathogens (93% vs 89%, respectively) (Figure 1A). Cefdinir led to microbiologic cure (eradication) in 92% (131/143) of infections caused by S. aureus and 100% (17/17) of infections caused by S. pyogenes. Both agents demonstrated good clinical response (88% vs 87% were cured or improved in the cefdinir and cephalexin treatment groups, respectively) (Figure 1B). Statistical analyses (Cochran-Mantel-Haenzel test) confirmed that the microbiologic and clinical response rates were similar (P = .105 and P = .617 for microbiologic and clinical response rates, respectively).

Investigators concluded that cefdinir was as effective as cephalexin for the treatment of mild-to-moderate skin and skin-structure infections in adults and adolescents and was generally well-tolerated. Cefdinir was also found to be active against most cephalexin-resistant bacterial strains.

Cephalosporin Observational Experience in Private Practice

Dr. Del Rosso indicated that patient adherence to antibiotics was crucial in achieving successful eradication of an underlying infection. Factors such as shorter duration of therapy, reduced frequency of administration, and taste may contribute to enhanced patient adherence. In pediatric patients, the favorable palatability of cefdinir may enhance adherence in patients for whom taste and palatability are significant issues.^8,9 Improving adherence among the adult patients may involve strategies such as simpler dosing regimens, and administration without regard to food.

Dr. Del Rosso presented the results of an open observational assessment on the use of cefdinir in treating uncomplicated skin and skin-structure infections in his private practice.¹ The objective of the assessment was to evaluate shorter durations of therapy. Cefdinir is currently indicated for 10-day therapy in the treatment of uncomplicated skin and skin-structure infections.¹⁰ Once-daily and twice-daily dosing of cefdinir have demonstrated equivalent efficacy in acute otitis media, acute maxillary sinusitis, and pharyngitis/tonsillitis,¹⁰ but once-daily dosing of cefdinir has not been formally studied for uncomplicated skin and skin-structure infections. Dr. Del Rosso remarked, "It is possible that a duration of therapy shorter than 10 days may be adequate for clearance of infection or that once-daily administration may be effective for cutaneous infections where oral cefdinir would be appropriate."

In order to evaluate his hypothesis, Dr. Del Rosso compiled a list of patients from his practice with varying dosing regimens of cefdinir (Table 2). "All of the patients were adults with confirmed, cutaneous infections and without underlying immunosuppression or diabetes," explained Dr. Del Rosso. Oral cefdinir was used as monotherapy without the use of topical antimicrobial or incision and drainage interventions.

Although successful outcomes were observed in all cases, Dr. Del Rosso cautioned, "The data reflect a small patient number, are preliminary, and warrant far more extensive study. However, the results do suggest that shorter durations of therapy and/or once-daily dosing may be viable options that sustain efficacy, allow for reduced treatment time, enhance compliance, and decrease cost of therapy." Dr. Del Rosso advised further studies were warranted.

Conclusion

Cephalosporin antibiotics are highly effective against a broad range of Gram-positive and Gram-negative organisms. When determining the optimal cephalosporin to treat uncomplicated skin and skin-structure infections, consideration should be given to various factors including safety, efficacy, adherence, frequency of administration, and duration of therapy. Data suggest that cefdinir is the most potent oral cephalosporin against S. aureus and S. pyogenes, the two primary causative organisms in uncomplicated skin and skin-structure infections. Additionally, the twice-daily dosing and favorable palatability of cefdinir may enhance adherence in patients for whom taste is a significant issue.

References

1. Del Rosso JQ. Cephalosporin therapy in the management of uncomplicated skin and soft tissue infections: focus on clinical applications and dosing schedules with oral cefdinir. Presented at the ACADEMY '04 Summer Meeting of the American Academy of Dermatology, July 28-August 1, 2004, New York, New York. P20.

2. Murakawa GJ. The Use of Cephalosporins to Treat Uncomplicated Skin and Skin-structure Infections. Presented during the CME symposium, "Dependable Antibiotic Treatment for Uncomplicated Skin and Skin-structure Infections in Diverse Patient Populations: Safety & Efficacy of Cephalosporin Therapy" held during the ACADEMY '04 Summer Meeting of the American Academy of Dermatology, July 28-August 1, 2004, New York, New York.

3. Scher RK, Murakawa GJ, Elston D, Hedrick JA, Joseph WS, Maurer T. Dermatology Process of Care: Treatment options in the management of uncomplicated skin and skin-structure infections. National thought leader panel discussion conducted May 6, 2004, Chicago, Illinois.

4. Sadick NS. Systemic antibiotic agents. Dermatol Clin. 2001;19:1-21.

5. Marshall WF, Blair JE. The cephalosporins. Mayo Clin Proc. 1999;74:187-195.

6. Sader HS, Streit JM, Fritsche TR, Jones RN. Potency and spectrum re-evaluation of cefdinir test against pathogens causing skin and soft tissue infections: a sample of North American isolates. Diagn Microbiol Infect Dis. 2004;49:283-287.

7. Tack KJ, Littlejohn TW, Mailloux G, Wolf MM, Keyserling CH, for the Cefdinir Adult Skin Infection Study Group. Cefdinir versus cephalexin for the treatment of skin and skin-structure infections. Clin Ther. 1998;20:244-256.

8. Steele RW, Thomas MP, Begue RE. Compliance issues related to the selection of anti-biotic suspensions for children. Pediatr Infect Dis J. 2001;20:1-5.

9. 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.

10. Omnicef prescribing information [package insert]. Available at http://www.omnicef.com. Accessed August 5, 2004.

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Disclosure

James Q. Del Rosso, DO, FAOCD

Consultant—Medicis; Speakers Bureau—Medicis

Frank P. Murphy, MD

No significant relationships to disclose

This report contains 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; Millennium CME Institute, 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 includes 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 CME Institute, Inc. and UMDNJ—Center for Continuing and Outreach Education

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