PEDIATRICS Vol. 106 No. 2 August 2000, pp. 380-381

Eradication of Group A Streptococci

To the Editor.

In the interesting recent article by Gerber et al,¹ the primary outcomes originally sought in the study apparently were differences in  lactamase-producing pharyngeal flora and populations of pharyngeal bacteria interfering with the growth of group A -hemolytic streptococcus (GABHS) in unsuccessfully treated patients. For measurement they applied simple but elegant in vitro assay systems that failed to confirm in vivo observations made earlier by other groups.^2-4 However, we are concerned by the application of a posthoc definition to identify "likely bona fide" versus "likely carrier" patients enrolled in a prospective trial; we suspect the authors, reviewers, and editors also saw this as a methodologic flaw. The question then becomes: How serious is the flaw as flawless studies are rare? We are never told the symptoms and signs used as enrollment criteria. The authors suggest that 2 study sites (Valparaiso, IN and Albany, NY) "seemed to have had a lower threshold for obtaining throat cultures." Did they deviate from the prospective enrollment criteria? Is it as likely that the 2 other study sites (Danbury and Bristol, CT) preferentially enrolled patients with more severe GABHS symptoms and signs, consistent with greater tonsillopharyngeal inflammation? Penicillin may be more effective in such patients because inflammation may improve the generally low tonsillopharyngeal levels penicillin achieves after oral or injectable administration.^5,6 Duration of illness may also influence penicillin success,^7,8 and although the authors could not find a difference among the 4 study sites for this parameter, the statistical power to detect such a difference is not stated. So which were the more representative populations enrolled in this studythose from Valparaiso and Albany or those from Bristol and Danbury?

A second fact that raises a concern about the carrier definition applied and/or representativness of the study group relates to the final carrier rate determined. The 4 enrollment sites were all private practices, probably not too dissimilar from the Elmwood Pediatric Group in Rochester, New York. We recently showed that the carrier risk in our practice was 2.5% for well children and 4.4% for children with acute viral pharyngitis.⁹ Of 343 children classified by their definition, 44% were carriersa 10-fold higher prevalence than we observed.⁹ What could account for the carrier rate difference? We have observed that the carrier status more frequently follows penicillin therapy compared with cephalosporin or macrolide therapy.⁹ How many of the patients recently had GABHS pharyngitis, and how many were previously treated with penicillin versus other antibiotics? Patient age can be a factor in penicillin treatment success⁸; what was the distribution of age groups in the enrolled population by study site and overall?

In their discussion, Gerber et al restate a previously drawn conclusion that "there has been no consistent increase in the reported bacteriologic failure rate with orally administered penicillin therapy."¹⁰ Perhaps the authors were unaware of our recent publication documenting a clear rise in penicillin treatment failure from 6% to 10% in the 1970s to 20% to 25% in the 1980s and 1990s.¹¹ Edward Kaplan, MD, has also noted a rise in penicillin treatment failure.¹²

We agree that penicillin is the antibiotic of choice for most patients with GABHS pharyngitis. At the Elmwood Pediatric Group we continue to use penicillin for about two-thirds of our patients, but we do so because we still request a follow-up visit to verify clinical and bacteriologic cure.¹¹ Relying on severe symptoms in treatment-failure patients may not be wise, as fewer symptoms may occur in some who are at risk for acute rheumatic fever.¹³ When follow-up is unlikely in rapid antigen or culture-positive GABHS-infected individuals, selection of a cephalosporin, amoxicillin-clavulanate, or a macrolide may be a prudent choice.

Michael E. Pichichero
Department of Microbiology and Immunology, Pediatrics and Medicine
University of Rochester
Rochester, NY 14642

REFERENCES

1. Gerber MA, Tanz RR, Kabat RS, Potential mechanisms for failure to eradicate group A streptococci from the pharynx. Pediatrics. 1999; 104:911-917 [Abstract/Free Full Text]
2. Brook I, Gober AE Role of bacterial interference and -lactamase-producing bacteria in the failure of penicillin to eradicate group A streptococcal pharyngotonsillitis. Arch Otolaryngol Head Neck Surg. 1995; 121:1405-1409
3. Roos K, Holm SE, Grahn E, Lind L Alpha-streptococci as supplementary treatment of recurrent streptococcal tonsillitis: a randomized placebo-controlled study. Scand J Infect Dis. 1993; 25:31-35 [Medline]
4. Brook I, Gober AE Interference by aerobic and anerobic bacteria in children with recurrent group A -hemolytic streptococcal tonsillitis. Arch Otolaryngol Head Neck Surg. 1999; 125:552-554
5. Stjernquist-Desatnik A, Samuelsson P, Walder M Penetration of penicillin V to tonsillar surface fluid in healthy individuals and in patients with acute tonsillitis. J Laryngol. Otol. 1993; 107:309-312 [Medline]
6. Bass JW, Longfield JN, Jones RG, Hartmann RA Serum levels of penicillin in basis trainees in the US Army who received intramuscular penicillin G benzathine. Clin Infect Dis. 1996; 22:727-728 [Medline]
7. Pichichero ME, Disney FA, Talpey WB, Adverse and beneficial effects of immediate treatment of group A -hemolytic streptococcal pharyngitis with penicillin. Pediatr Infect Dis J. 1987; 6:635-643 [Medline]
8. Pichichero ME, Hoeger W, Marsocci SM, Variables influencing penicillin treatment outcome in streptococcal tonsillopharyngitis. Arch Pediatr Adolesc Med. 1999; 153:565-570 [Abstract/Free Full Text]
9. Pichichero ME, Marsocci SM, Murphy ML, Incidence of streptococcal carriers in private pediatric practice. Arch Pediatr Adolesc Med. 1999; 153:624-628 [Abstract/Free Full Text]
10. Markowitz M, Gerber MA, Kaplan EL Treatment of streptococcal pharyngotonsillitis: reports of penicillin's demise are premature. J Pediatr. 1993; 123:679-685 [CrossRef][Medline]
11. Pichichero ME, Green JL, Francis AB, Recurrent group A streptococcal tonsillopharyngitis. Pediatr Infect Dis J. 1998; 17:809-815 [CrossRef][Medline]
12. Kaplan EL Benzathine penicillin G for treatment of group A streptococcal pharyngitis: a reappraisal in 1985. Pediatr Infect Dis J. 1985; 4:592-596
13. Lee JH, Ayoub E, Pichichero ME. Fewer symptoms occur in same-serotype recurrent streptococcal tonsillopharyngitis. Arch Otolaryngol Head Neck Surg. 2000. In press

In Reply.

We appreciate the opportunity to respond to Dr Pichichero's comments about our recent report.¹ Although our finding that neither -lactamase nor bacterial interference produced by normal pharyngeal flora is related to bacteriologic treatment failures in group A -hemolytic streptococcal (GABHS) pharyngitis is not consistent with reports cited by Dr Pichichero,^2-4 it is consistent with other reports.^5-7 As Dr Pichichero knows, bacteriologic treatment failure remains a very controversial issue that has defied simplistic explanations. Contrary to Dr Pichichero's characterization of the studies he cited as in vivo observations, they were, in fact, in vitro observations just as ours were.

Dr Pichichero is also concerned that our classification of patients as either more likely to be a chronic carrier of GABHS or as more likely to have bona fide acute GABHS pharyngitis was a posthoc analysis. This is not the case. The primary outcome of our study was bacteriologic treatment failure after either penicillin or cefadroxil therapy. The secondary outcomes were 1) the relationship between bacteriologic treatment failure and the presence of either -lactamase or bacterial interference produced by normal pharyngeal flora, and 2) the relationship between bacteriologic treatment failure and the clinical classification (carrier vs infected). As noted in the "Materials and Methods" section, the clinical classification (carrier vs infected) was established before the analysis of the bacteriologic outcomes.¹

The enrollment criteria in our study were clinical findings consistent with acute pharyngitis and a throat culture positive for GABHS.¹ Patients who had received systemic antimicrobial therapy within the week before enrollment or long-acting parenteral penicillin within 2 weeks before enrollment were excluded. Those with 3 or more confirmed episodes of GABHS pharyngitis in the previous year and those known to be chronic streptococcal carriers were not enrolled.

We are unaware of any published data that clearly establish age as an independent risk factor for penicillin treatment failures, and we have previously demonstrated that duration of illness does not have a significant impact on penicillin treatment failure rates.⁸ Nevertheless, the ages and durations of illness before enrollment in our study were similar for the patients in the treatment groups at each of the 4 study centers as well as for the entire study population.¹ The concept that patients with greater tonsillopharyngeal inflammation have higher concentrations of penicillin in tonsillar surface fluid, and, therefore, are more likely to respond to penicillin therapy is supported only by a single, preliminary investigation.⁹ The results of that investigation are not consistent with those of an earlier study¹⁰ and, to our knowledge, have not been corroborated by subsequent investigations. Therefore, this concept is primarily speculative at this time.

The pediatricians at each of the 4 study centers (all private pediatric offices) used their own judgment in deciding what signs and symptoms were "consistent with acute pharyngitis" and from whom to obtain a rapid strep test or throat culture. Therefore, the pediatricians at the sites in Valparaiso and Albany did not deviate from the enrollment criteria; they simply appeared to have had a lower threshold for obtaining a rapid strep test or throat culture than the pediatricians at the sites in Danbury and Bristol. The enrolled populations at all of the study sites were "representative," but varied with the clinical styles and practices of the specific physicians. In fact, it is just this kind of variability in the threshold for obtaining a throat swab that in turn results in a variable number of streptococcal carriers being identified and is responsible for much of the variability in the reported relative performances of penicillin and cephalosporins in the treatment of apparent GABHS pharyngitis.¹¹

Dr Pichichero expressed surprise that the apparent carrier rate in our study was 10-fold higher than that reported in a study from the Elmwood Pediatric Group.¹² However, these 2 studies are not comparable. Pichichero and coworkers determined the streptococcal carrier rate in asymptomatic children and in children with presumed or documented viral pharyngitis. We classified patients with acute pharyngitis as more likely streptococcal carriers or more likely infected after they were already known, on the basis of a rapid strep test or throat culture, to have GABHS present in their upper respiratory tract. Although the streptococcal carrier rate at the Elmwood Pediatric Group may be 2.5% to 4.4%, there is tremendous variability in this rate from one location to another and from 1 year to the next.^13,14 Streptococcal carrier rates as high as 29% have clearly been demonstrated in asymptomatic, school-aged children.^13,14

We continue to believe that there has been no consistent increase in the reported bacteriologic failure rates with orally administered penicillin therapy. We are very aware of the recent report by Dr Pichichero and coworkers¹⁵ in which they claim to have clearly demonstrated a marked increase in penicillin treatment failures in their practice from 1975 to 1996. However, to arrive at this conclusion requires that the population treated with penicillin over that period of time was consistent; unfortunately, in this retrospective chart review, this consistency could not be established. There is no evidence that the indications for obtaining a throat swab in 1975 were the same as in 1996. There are no data presented about the clinical findings of the patients who were cultured, the rate of culturing, or the proportion of the cultures taken that were positive. In 1975 to 1979, 91% of the patients were treated with penicillin/amoxicillin, but in 1995 to 1996, only 67% of the patients were treated with penicillin/amoxicillin. Clearly, in recent years, patients were selected to receive or not to receive penicillin/amoxicillin; how much bias resulted from this selection process is not clear. In addition, serotyping of the isolates of GABHS was not performed, and, therefore, treatment failures were not distinguished from acquisitions of new strains. Furthermore, there was no assessment of compliance to determine if the patients actually received the antimicrobial agents that were prescribed. In a review of 32 studies conducted between 1953 and 1993 in which no consistent increase in the bacteriologic failure rate with orally administered penicillin could be demonstrated, only studies in which serotyping was performed and in which compliance was assessed were included in the analysis.¹⁶

Finally, we strongly disagree with Dr Pichichero's practice of reculturing all patients treated for GABHS pharyngitis. This practice is not consistent with the current recommendations of the American Academy of Pediatrics, the American Heart Association, or the Infectious Diseases Society of America.^17-19 Of course, patients with recurrent clinical findings suggestive of GABHS after completing a course of antimicrobial therapy for GABHS pharyngitis should be evaluated. However, patients who are asymptomatic after completing a course of antimicrobial therapy and who continue to harbor GABHS in their upper respiratory tracts are likely to be streptococcal carriers. Because the streptococcal carrier state is a relatively benign condition for both carriers as well as their contacts, there is usually no need to identify or treat these patients except in unique epidemiologic settings (eg, communities with high rates of acute rheumatic fever).²⁰

Michael A. Gerber
Robert R. Tanz
Edward L. Kaplan
Stanford T. Shulman
^* University of Connecticut School of Medicine
 Northwestern University Medical School
^§ University of Minnesota School of Medicine

REFERENCES

1. Gerber MA, Tanz RR, Kabat W, Potential mechanisms for failure to eradicate group A streptococci from the pharynx. Pediatrics. 1999; 104:911-917
2. Brook I, Grober AE Role of bacterial interference and -lactamase-producing bacteria in the failure of penicillin to eradicate group A streptococcal pharyngotonsillitis. Arch Otolaryngol Head Neck Surg. 1995; 121:1405-1409
3. Roos K, Holm SE, Grahn E, Lind L Alpha- streptococci as supplementary treatment of recurrent streptococcal tonsillitis: a randomized placebo-controlled study. Scand J Infect Dis. 1993; 25:31-35
4. Brook I, Grober AE Interference by aerobic and anerobic bacteria in children with recurrent group A -hemolytic streptococcal tonsillitis. Arch Otolaryngol Head Neck Surg. 1999; 125:552-554
5. Huskins WC, Kaplan EL Inhibitory substances produced by Streptococcus salivarius and colonization of the upper respiratory tract with group A streptococci. Epidemiol Infect. 1989; 102:401-412 [Medline]
6. Tanz RR, Shulman ST, Sroka PA, Marubio S, Brook I, Yogev R Lack of influence of beta-lactamase producing flora on recovery of group A streptococci after treatment of acute pharyngitis. J Pediatr. 1990; 117:859-863 [CrossRef][Medline]
7. Quie PG, Pierce HC, Wannamaker LW Influence of penicillinase producing staphylococci on the eradication of group A streptococci from the upper respiratory tract by penicillin treatment. Pediatrics. 1966; 37:467-476 [Abstract/Free Full Text]
8. Gerber MA, Randolph MF, DeMeo KK, Lack of impact of early antibiotic therapy for streptococcal pharyngitis on recurrence rates. J Pediatr. 1990; 117:853-858 [CrossRef][Medline]
9. Stjernquist-Desatnik A, Samuelson P, Walder M Penetration of penicillin V to tonsillar surface fluid in healthy individuals and in patients with acute tonsillitis. J Laryngol Otol. 1993; 107:309-312
10. Stromberg A, Friberg U, Cars O Concentrations of phenoxymethylpenicillin and cefadroxil in tonsillar tissue and tonsillar surface fluid. Eur J Clin Microbiol. 1987; 6:525-529 [CrossRef][Medline]
11. Shulman ST, Gerber MA, Tanz RR, Markowitz M Streptococcal pharyngitis: the case for penicillin therapy. Pediatr Infect Dis J. 1994; 13:1-7 [Medline]
12. Pichichero ME, Marsocci SM, Murphy ML, Hoeger W, Green JL, Sorrento A Incidence of streptococcal carriers in private pediatric practice. Arch Pediatr Adolesc Med. 1999; 153:624-628
13. Cornfeld D, Werner G, Weaver R, Bellows MT, Hubbard JP Streptococcal infection in a school population: preliminary report. Ann Intern Med. 1958; 49:1305-1319
14. Quinn RW Hemolytic streptococci in Nashville school children. South Med J. 1980; 73:288-296 [Medline]
15. Pichichero ME, Green JL, Francis AB, Recurrent group A streptococcal tonsillopharyngitis. Pediatr Infect Dis J. 1998; 17:809-815
16. Markowitz M, Gerber MA, Kaplan EL Treatment of streptococcal pharyngotonsilitis: reports of penicillin's demise are premature. J Pediatr. 1993; 123:679-685
17. American Academy of Pediatrics, Committee on Infectious Diseases. 1997 Red Book: Report of the Committee on Infectious Diseases. 24th ed. Elk Grove Village, IL: American Academy of Pediatrics; 1997
18. Dajani A, Taubert K, Ferrieri P, Treatment of acute streptococcal pharyngitis and prevention of rheumatic fever: a statement for health professionals. Pediatrics. 1995; 96:758-764 [Abstract/Free Full Text]
19. Bisno AL, Gerber MA, Gwaltney JM, Kaplan EL, Schwartz RH Diagnosis and management of group A streptococcal pharyngitis: a practice guideline. Clin Infect Dis. 1997; 25:574-583 [Medline]
20. Kaplan EL The group A streptococcal upper respiratory tract carrier state: an enigma. J Pediatr. 1980; 97:337-345 [CrossRef][Medline]