This report was reviewed for medical and scientific accuracy by James M. Oleske, MD, MPH, Francois-Xavier Bagnoud Professor of Pediatrics, Director, Division of Pulmonary, Allergy, Immunology & Infectious Diseases, Department of Pediatrics, University of Medicine & Dentistry of New Jersey-New Jersey Medical School, Newark, New Jersey

Introduction

According to the results of a meta-analysis published in the April 2004 issue of Pediatrics, antibiotic therapy with cephalosporins was associated with significantly higher bacteriologic and clinical cure rates when compared to penicillin therapy in the treatment of Group A β-hemolytic streptococcal pharyngitis in children.¹ These findings confirm previously published meta-analyses^2,3 and reviews^4-7 that found cephalosporin therapy to be superior to penicillin in the treatment of Group A β-hemolytic streptococcal pharyngitis. The results of this meta-analysis will generate extensive debate because they contradict well-established practice guidelines from the American Academy of Pediatrics,⁸ the American Heart Association,⁹ the World Health Organization,¹⁰ and the Infectious Diseases Society of America recommending penicillin as the agent of choice for Group A β-hemolytic streptococcal pharyngitis.¹¹

Group A β-hemolytic streptococcus is the most common cause of bacterial pharyngitis and is responsible for 15% to 30% and 5% to 15% of all cases in children and adults, respectively.^12,13 The primary goal of antibiotic therapy is eradication of the bacterial pathogen. Eradication is necessary to prevent nonsuppurative and suppurative sequelae,¹⁴ eliminate contagion,¹⁵ and produce a more rapid resolution of patient symptoms.¹⁶

Due to its proven efficacy, relative safety, narrow spectrum and low cost, oral penicillin administered for 10 days has remained the agent of choice.^8-11 However, since the early 1980s, clinical studies have shown an increasing incidence of Group A β-hemolytic streptococcus not cured by penicillin treatment.^17-19 In 2001, Kaplan and Johnson found that intramuscular benzathine penicillin failed to eradicate Group A β-hemolytic streptococcus in 37% to 42% of children; oral penicillin failed in 35% of children.²⁰

Cephalosporins have been used successfully for the treatment of Group A β-hemolytic streptococcus since the early 1970s. Two previous meta-analyses have concluded that cephalosporin treatment was superior to penicillin therapy for Group A β-hemolytic streptococcal tonsillopharyngitis.^2,3 Since the publication of the last meta-analysis, a number of well-designed, controlled, randomized, comparative clinical trials have been conducted and published. Using updated and rigorous meta-analysis methodology, investigators compared the relative efficacy of cephalosporin and penicillin in treating Group A β-hemolytic tonsillopharyngitis in children. This Pediatric Press Newsletter reviews the methodology and results of their meta-analysis.

Superiority of Cephalosporins versus Penicillin for Group A β-hemolytic Streptococcus

A total of 140 citations of randomized, controlled trials comparing a cephalosporin and penicillin in the treatment of Group A β-hemolytic streptococcus were identified from Medline (1966-2000) and Embase (1974-2000) searches. Using stringent inclusion/exclusion criteria, an independent review identified 40 clinical trials of which 35 published trials that enrolled 7,125 pediatric subjects were included in the meta-analysis. The Jadad scale [0 to 5 (best quality trial) based on random- ization, being double-blinded, and accounting for study withdrawals] was used to assess the quality of the clinical trials.²¹ The 5 remaining unpublished trials were selected for inclusion in a sensitivity analysis that assessed publication bias.

The primary outcomes of the meta-analysis were bacteriologic cure (defined as a failure to isolate Group A β-hemolytic streptococcus by throat culture obtained after completion of antibiotic therapy) and clinical cure (defined as the resolution of or improvement in presenting symptoms of Group A β-hemolytic streptococcal infection after completion of antibiotic therapy and continuing through follow-up). Additional sensitivity analyses were performed to assess the impact of compliance monitoring, exclusion of Group A β-hemolytic streptococcus carriers, careful clinical illness descriptions, and timing of the test-of-cure culture on the bacteriologic and clinical cure rates. Where possible, identification and elimination of Group A β-hemolytic streptococcus carriers was attempted with subsequent recalculation of bacteriologic and clinical cure rates. Bacteriologic and clinical cure rates were derived from the early follow-up test-of-cure data to minimize the inclusion of Group A β-hemolytic streptococcus reacquisitions or new infections in the final cure rates.

Differences in bacteriologic cure rates after cephalosporin treatment in comparison to penicillin therapy were calculated and expressed as an odds ratio (OR) with 95% Confidence Intervals (CI). An OR >1 indicated a higher bacteriologic cure rate for cephalosporin treatment compared to penicillin. A summary OR was determined by individual cephalosporin, by cephalosporin generation and by decade (1970-1979, 1980-1989, 1990-1999).

The mean quality score for all trials in the meta-analysis was 2.3, of a maximum of 5; 31% of the trials were of higher quality (Jadad score >2). The mean quality score increased from 1.8 (6 trials, 1970-1979) to 2.2 (11 trials, 1980-1989) to 2.6 (18 trials, 1990-1999), possibly attributed to improvements in study design.

Eleven different cephalosporins and one carbacephem were compared to penicillin in the 35 clinical trials. Antibiotics evaluated included the cephalosporins cefdinir (Omnicef), cephaloglycin (not available in United States), cefixime (Suprax), ceftibuten (Cedax), cephalexin (Keflex), cefadroxil (Duricef), cefaclor (Ceclor), cefuroxime (Ceftin), cefetamet (not available in United States), cefprozil (Cefzil), cefpodoxime (Vantin) and the carbacephem loracarbef (Lorabid).

Bacteriologic and Clinical Cure Rates
The summary OR for bacteriologic cure in all 35 clinical trials was 3.02 (95% CI, 2.49-3.67) favoring cephalosporin treatment (P<.00001). The summary ORs for trials performed in the 1970s, 1980s, and 1990s were respectively, 2.06 (95% CI, 1.27-3.34), 2.84 (95% CI, 1.97-4.09), and 3.25 (95% CI, 2.49-4.23) (Table 1).

Cephalosporin treatment showed a trend toward increasing superiority over penicillin over the past 3 decades; however, the trend did not reach statistical significance (P = .09). Of 35 clinical trials, 33 had ORs that favored cephalosporins. In 19 trials, cephalosporin treatment was significantly superior to penicillin therapy.

Five clinical trials did not report clinical cure rates. The summary OR for clinical cure rate in the remaining 30 clinical trials (n = 6448) was 2.34 (95% CI, 1.84-2.97) favoring cephalosporin treatment (P<.00001). The summary ORs for the 30 clinical trials performed in the 1970s, 1980s, and 1990s were, respectively, 2.19 (95% CI, 1.25-3.85), 2.36 (95% CI, 1.65-3.37), and 2.30 (95% CI, 1.62-3.26) (Table 2).

The clinical cure rate consistently favored cephalosporin treatment over penicillin therapy; however, there was not a statistically significant difference between decades (P = .5). Of 30 clinical trials, 23 had ORs that favored cephalo-sporins. In 11 clinical trials, the clinical cure rate reached statistical significance favoring cephalosporins.

To test the robustness of the summary ORs, sensitivity analyses were conducted for the bacteriologic and clinical cure rates. Sensitivity analyses for bacteriologic cure rates significantly favored cephalosporin treatment over penicillin when trials were grouped as double-blind (OR 2.31; 95% CI, 1.39-3.85; P<.001), high-quality (OR 2.50; 95% CI, 1.85-3.36; P<.00001), trials with well-defined clinical status at diagnosis (OR 2.12; 95% CI, 1.54-2.90; P<.00001), with detailed compliance monitoring (OR 2.85; 95% CI, 2.33-3.47; P<.00001), with Group A β-hemolytic streptococcus serotyping or genotyping (OR 3.10; 95% CI, 2.42-3.98; P<.00001), with carrier eliminated (OR 2.51; 95% CI, 1.55-4.08; P<.0002) and with test-of-cure 3 to 14 days post-treatment (OR 3.53; 95% CI, 2.75-4.54;P<.008). Similarly, sensitivity analyses for clinical cure rate significantly favored cephalosporin treatment over penicillin in all parameters with the exception of 6 double-blinded clinical trials, where the clinical cure rate did not significantly favor either cephalosporin or penicillin treatment (P = .5).

Stratified Analysis of Cephalosporins
When compared to oral penicillin therapy, cefdinir, cephalexin, cefadroxil, cefuroxime, cefprozil, cefpodoxime, cefixime, and ceftibuten were statistically superior in bacterial and clinical eradication of Group A β-hemolytic streptococcus. The superiority of oral cephalo- sporin treatment over penicillin with respect to bacteriologic and clinical cure was consistent across first-, second-, and third generation cephalosporins. Individual cephalosporin bacteriologic and clinical cure rate analyses are illustrated in Tables 3 and 4.

Secondary Analyses
A secondary analysis to determine bacteriologic and clinical cure rates was conducted on 18 clinical trials (study described elimination of carriers) where, as best as possible, carriers of Group A β-hemolytic streptococcus were eliminated from analysis. The overall summary OR for recalculated bacteriologic cure rate was 2.65 (95% CI, 1.96-3.57), which still significantly favored cephalosporin treatment (P ≤.00001). A similar procedure was performed for a secondary analysis of the clinical cure rate with carriers eliminated from analysis. The overall summary OR for clinical cure rate was 2.61 (95% CI, 1.86-3.65), which still significantly favored cephalosporin treatment (P<.00001).

A sensitivity analysis was performed on the 5 abstracts that were never published. For the 5 abstracts, the summary ORs for bacteriologic and clinical cure rates were not significantly different from the summary ORs for the 35 clinical trials suggesting no evidence of publication bias.

Summary
This meta-analysis indicated that the likelihood of bacteriologic failure of Group A β-hemolytic streptococcal tonsillopharyngitis in children is significantly less (P<.00001) if an orally administered cephalosporin antibiotic (cefdinir, cephalexin, cefadroxil, cefuroxime, cefpodoxime, cefprozil, cefixime, or ceftibuten) is used for treatment compared with orally administered penicillin. Cefaclor, cephaloglycin, cefetamet and loracarbef were statistically equivalent to penicillin in bacteriologic eradication and clinical cure of Group A β-hemolytic streptococcus.

Conclusion

Cephalosporins have been used successfully for the treatment of Group A β-hemolytic streptococcus since the early 1970s. The results of a recently published meta-analysis confirm previous findings of the superiority of most cephalo-sporins over penicillin therapy for the treatment of Group A β-hemolytic streptococcal tonsillopharyngitis in children. Despite the proven superiority of cephalosporin treatment, penicillin has remained the agent of choice for Group A β-hemolytic streptococcal tonsillopharyngitis in multiple clinical practice guidelines. Based on superior bacteriologic eradication and clinical cure compared with penicillin, inclusion of cephalosporins as a first-line treatment choice for Group A β-hemolytic streptococcus seems warranted.

References

1. Casey JR, Pichichero ME. Meta-analysis of cephalosporin versus penicillin treatment of Group A Streptococcal tonsillopharyngitis in children. Pediatrics. 2004;113:866-882.
2. Pichichero ME, Margolis PA. A comparison of cephalosporins and penicillins in the treatment of Group A beta-hemolytic streptococcal pharyngitis: a meta-analysis supporting the concept of microbial copathogenicity. Pediatr Infect Dis J. 1991;10:275-281.
3. Deeter RG, Kalman DL, Rogan MP, Chow SC. Therapy for pharyngitis and tonsillitis caused by Group A beta-hemolytic streptococci: a meta-analysis comparing the efficacy and safety of cefadroxil monohydrate versus oral penicillin V. Clin Ther. 1992;14:740-754.
4. Pichichero ME. Cephalosporins are superior to penicillin for treatment of streptococcal tonsillopharyngitis: is the difference worth it? Pediatr Infect Dis J. 1993;12:268-274.
5. Blumer JL, Goldfarb J. Meta-analysis in the evaluation of treatment for streptococcal pharyngitis: a review. Clin Ther. 1994;16:604-620.
6. Group A streptococcal infections: an era of growing concern. Proceedings of a symposium. May 31 and June 1, 1991. Pediatr Infect Dis J. 1991;10(10 Suppl):S3-S78.
7. Pichichero ME. The rising incidence of penicillin treatment failures in group A streptococcal tonsillopharyngitis: an emerging role for the cephalosporins? Pediatr Infect Dis J. 1991;10(10 Suppl):S50-S55.
8. American Academy of Pediatrics, Committee on Infectious Diseases. Red Book; Report of the Committee on Infectious Disease. 25th ed. Elk Grove Village, IL: American Academy of Pediatrics; 2000.
9. Dajani A, Taubert K, Ferrieri P, Peter G, Shulman S. Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: a statement for health professionals. Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, the American Heart Association. Pediatrics. 1995;96:758-764.
10. World Health Organization. Rheumatic fever and rheumatic heart disease. Report of a WHO Study Group. World Health Organ Tech Rep Ser. 1988;764:1-58.
11. Bisno AL, Gerber MA, Gwaltney JM Jr, Kaplan EL, Schwartz RH. Practice guidelines for the diagnosis and management of Group A streptococcal pharyngitis. Clin Infect Dis. 2002;35:113-125.
12. Dowell SF, Schwartz B, Phillips WR. Appropriate use of antibiotics for URIs in children: Part II. Cough, pharyngitis and the common cold. The Pediatric URI Consensus Team. Am Fam Physician. 1998;58:1335-1342,1345.
13. Snow V, Mottur-Pilson C, Cooper RJ, Hoffman JR for the American College of Physicians-American Society of Internal Medicine. Principles of appropriate antibiotic use for acute pharyngitis in adults. Ann Intern Med. 2001;134:506-508.
14. Delmar C. Managing sore throat: a literature review. II. Do antibiotics confer benefit? Med J Aust. 1992;156:644-649.
15. Bisno AL. Acute pharyngitis. N Engl J Med. 2001;344:205-211.
16. Pichichero ME, Disney FA, Talpey WB, et al. Adverse and beneficial effects of immediate treatment of Group A beta-hemolytic streptococcal pharyngitis with penicillin. Pediatr Infect Dis J. 1987;6:635-643.
17. Stillerman M. Comparison of oral cephalosporins with penicillin therapy for group A streptococcal pharyngitis. Pediatr Infect Dis J. 1986;5:649-654.
18. Holm S, Henning C, Grahn E, Lomberg H, Staley H. Is penicillin the appropriate treatment for recurrent tonsillopharyngitis? Results from a comparative randomized blind study of cefuroxime axetil and phenoxymethylpenicillin in children. The Swedish Study Group. Scand J Infect Dis. 1995;27:221-228.
19. Pichichero ME, Casey JR, Mayes T, et al. Penicillin failure in streptococcal tonsillopharyngitis: causes and remedies. Pediatr Infect Dis J. 2000;19:917-923.
20. Kaplan EL, Johnson DR. Unexplained reduced microbiological efficacy of intramuscular benzathine penicillin G and of oral penicillin V in eradication of group A streptococci from children with acute pharyngitis. Pediatrics. 2001;108:1180-1186.
21. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials. 1996;17:1-12.

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Disclosure
James M. Oleske, MD, MPH
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 Pediatric Press Newsletter does not include discussion of treatment and indications outside of current approved labeling. This Pediatric Press Newsletter was made possible through an educational grant from Abbott Laboratories.

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