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PEDIATRICS Vol. 109 No. 6 June 2002, pp. 1190-1192
Penicillin Failures?!
To the Editor.—I share the concern of Kaplan and Johnson1 that current formulations of benzathine penicillin G may not be up to the standards of the Wyeth product I originally investigated in the early 1950s. I do not, however, share their concerns about the reported low rate of "microbiological cure" of group A streptococcal (GAS) pharyngitis in the cohorts they studied. Their concerns are based on data obtained from the studies of the primary prevention of rheumatic fever by penicillin therapy in military epidemics. In those studies, the "bacteriologic cure" rate exceeded 90% in the selected cases of exudative pharyngitis caused by highly encapsulated, M protein-rich rheumatogenic strains.2 Subsequent studies of sporadic streptococcal pharyngitis in schoolchildren, however, revealed not only a high frequency of persistent group A streptococcal throat carriage but, compared with the virulent infections causing rheumatic fever, far lower virulence properties of the strains producing mild sporadic pharyngitis associated with only modest immunologic responses.3,4
In the absence of clinical relapse, therefore, expert committees do not advise reculturing the throat following the recommended treatment of nonepidemic GAS pharyngitis. Persistent convalescent carriage of such attenuated strains has not been associated with significant sequelae or with a significant secondary attack rate in contacts. Careful studies of infectivity of streptococci isolated during acute pharyngitis compared with those isolated during convalescence have clearly shown the latter’s diminished virulence.5,6
If the rate of "failure of microbiologic cure" of sporadic GAS pharyngitis by treatment with either oral penicillin or intramuscular injection of benzathine penicillin G is as high as 35% to 37% in the infections reported by Kaplan and Johnson, why has rheumatic fever completely disappeared in these cohorts? Doesn’t that alone confirm that higher bacteriologic cure rates of these attenuated infections are unnecessary where rheumatic fever is not prevalent? The term "unexplained failure" of penicillin treatment is misleading and ignores the wealth of clinical and experimental data relating GAS strain virulence to the attack rate of rheumatic fever or other significant sequelae.7 Rarely, for example, do current studies report such a readily observable marker of virulence as the highly encapsulated "mucoid" colonies formed on blood agar plates.
The genetic control of GAS virulence has been brilliantly elucidated in recent years. Virulent GAS mutants have been found to lack the gene that represses expression of hyaluronate capsules, streptolysin S, and other toxins.8,9 The "Control of Virulence" gene (covRS, also called csrRS) is also subject to as yet unexplained environmental factors that may influence its expression at different stages of infection. F1 and other surface proteins of unencapsulated GAS internalize such organisms within epithelial cells where they may remain dormant, colonizing the mucosa asymptomatically and resisting penicillin therapy.10 Mutations that inactivate covR result in encapsulation,11 and the hyaluronate capsule attaches to and disrupts the epithelium, resulting in invasion of deeper tissues.12 Actively proliferating, invading organisms are much easier to eradicate with penicillin!
Until we can conveniently and inexpensively identify really dangerous GAS strains, it is best that we continue to treat GAS pharyngitis with penicillin in the recommended fashion13 that has successfully driven such strains away. We should not insist on a "microbiological cure" for infections by attenuated strains that is neither feasible nor necessary, and that may eradicate protective normal flora and enhance the emergence of antibiotic-resistant pneumococci, staphylococci, and other pharyngeal pathogens. And because intramuscular injections of benzathine penicillin G are still brilliantly effective in terminating epidemics of rheumatic fever attributable to outbreaks of rheumatogenic GAS strains, the Food and Drug Administration should monitor the quality and efficacy of its current formulations so that it may be used with confidence if and when it is needed at home and abroad.
Gene H. Stollerman, MD
Hanover, NH 03755
REFERENCES
1. Kaplan EL, Johnson DR. Unexplained reduced microbiological efficacy of intramuscular benzathine penicillin G and oral penicillin V in eradication of group A streptococci from children with acute pharyngitis. Pediatrics.2001; 108 :1180 –1186[Abstract/Full Text]
2. Catanzaro FJ, Stetson CA, Morris AJ, et al. Symposium on rheumatic heart disease: the role of the streptococcus in the pathogenesis of rheumatic fever. Am J Med.1954; 17 :749 –756
3. Stollerman GH. Factors determining the attack rate of rheumatic fever. JAMA.1961; 177 :832 –828
4. Stollerman GH, Siegel AC, Johnson EE. Variable epidemiology of streptococcal disease and the changing pattern of rheumatic fever. Modern Concepts Cardiovasc Dis.1965; 34 :45 –48
5. Rothbard S, Watson RF. Variation occurring in group A streptococci during human infection. Progressive loss of M substance correlated with increasing susceptibility to bacteriostasis. J Exp Med.1948; 87 :521 –533
6. Krause RM, Rammelkamp CH Jr. Studies of the carrier state following infection with group A streptococci. II. Infectivity of streptococci isolated during acute pharyngitis and during the carrier state. J Clin Invest.1962; 41 :575 –578
7. Stollerman GH. Rheumatic fever in the 21st century. Clin Infect Dis.2001; 33 :806 –814[Medline]
8. Federle MJ, McIver KS, Scott JR. A response regulator that represses transcription of several virulence operons in the group A streptococcus. J Bacteriol.1999; 181 :3649 –3657[Abstract/Full Text]
9. Engelberg NC, Heath A, Miller A, Rivera C, DiRita VJ. Spontaneous mutations in the CsRS two-component regulatory system of Streptococcus pyogenes result in enhanced virulence in a murine model of skin and soft tissue infection. J Infect Dis.2001; 183 :1043 –1054[Medline]
10. Neeman R, Keller N, Barzalai A, Korenman Z, Sela S. Prevalence of internalization-associated gene, prtF1, among persisting group-A streptococcus strains isolated from asymptomatic carriers. Lancet.1998; 352 :1974 –1977[Medline]
11. Jadoun J, Sela S. Mutation in csrR global regulator reduces Streptococcus pyogenes internalization. Microbial Pathogenesis.2000; 29 :1 –7[Medline]
12. Cywes C, Wessels MR. Group A streptococcus tissue invasion by CD44-mediated cell signaling. Nature.2001; 414 :648 –652[Medline]
13. Bisno AL, Gerber MA, Gwaltney JM Jr, et al. Diagnosis and management of group A streptococcal pharyngitis: a practice guideline. Infectious Diseases Society of America. Clin Infect Dis.1997; 25 :574 –583[Medline]
In Reply.—
We are pleased to reply to the 4 letters received regarding our article published in the November 2001 issue of Pediatrics.1 We are delighted at this response because it means that the important questions that we have raised about both oral and intramuscular penicillin therapy for group A streptococcal upper respiratory tract infections have achieved their purpose: stimulating thought and discussion about this issue and about the implications. Our original report was never meant to be simply a description of a clinical trial.
These data have been bothersome for us also. After completion of this study, we analyzed and reanalyzed these data during a period of several years to search for an explanation for this "unexplained reduced microbiologic efficacy." In fact, we were sufficiently concerned to write a letter to the Director of the Division of Anti-infective Drug Products at the Food and Drug Administration (FDA) in Rockville, Maryland, in January 1997 to report the findings and to ask for advice and guidance. It was disappointing that we received neither an acknowledgment of receipt of our letter nor a reply. We even sent a second copy 1 month later; there was no response to that either. That letter to the FDA contained 3 different analyses of these data: an intent-to-treat analysis, a standard analysis, and the very stringent analysis that we later published in Pediatrics. Having completed multiple and extensive data analyses, and even having (unsuccessfully) attempted to enlist the advice and assistance of the FDA in further explaining these findings, we then felt an obligation to publish these data. This decision was made only after having reviewed the data with several colleagues with expertise in this subject for their suggestions. Because of the implications, we did not rush to publication.
The 4 letters to the editor that were received include almost 3000 words, and the issues raised are many, varied, and complex. We will, in this response, attempt to address the major issues, but space limitations dictate that our responses must, unfortunately, be less thorough than we would like.
Dr Rowe’s Letter
Recolonization is certainly a possibility, but only individuals with serotype concordant acute and convalescent cultures were considered "persistent," making this explanation a remote possibility in our view.
The question about negative cultures at 5 to 8 days after initiation of therapy is moot. Because 10 days of oral penicillin constitutes full therapy, patients receiving oral penicillin would have been incompletely treated at 5 to 8 days; it would make no difference whether the 5- to 8-day cultures were negative or positive. (The 5- to 8-day visit was included in the protocol as an "end of therapy" visit for those treated with ceftriaxone. See Fig 1 in the original article.) A negative culture at 5 to 8 days simply could reflect suppression of the organism without eradication. We originally included these 5- to 8-day values, but we were asked to remove them by a referee.
Dr Pichichero’s Letter
The issue of whether penicillin or the cephalosporins should be used for therapy of group A streptococcal upper respiratory tract infection has, we think, been adequately addressed in a thoughtful examination of this issue by Shulman et al.2 We agree with their conclusions, and we refer the readers to that discussion to allow them to judge for themselves.
We disagree with Dr Pichichero’s assertion that penicillin manufacturing differences should not be considered as a possible explanation. Penicillin is now manufactured in many places around the world. In fact, we have vials of benzathine penicillin G sold with a Wyeth label, which have been manufactured in Pakistan, in Mexico, and in at least one other place outside the United States. Data published by Zaher et al3 clearly document the potential for variability in bioavailability among benzathine penicillin G preparations. Admittedly, there is no direct evidence that manufacturing played a role in our results, but, until proven otherwise, this remains a distinct possibility.
It is not clear from Dr Pichichero’s comments how inclusion of clinical "results" would be relevant to our report. The study he refers to from his own group concludes: "Fewer symptoms occur during recurrent GABHS pharyngitis ... yet their infections put them at risk for sequelae."4 Therefore, Dr Pichichero’s own work suggests that what is important is not clinical symptoms but microbiologic cure!
Finally, the issues raised in Dr Pichichero’s last paragraph cannot be adequately discussed in the space available although we would welcome the opportunity to do so in a more appropriate venue. We disagree with his conjecture, and we would again call to the attention of the reader the article by Shulman et al.2
Dr Stollerman’s Letter
Dr Stollerman states that he is not concerned about the "reported low rate of microbiological cure" because studies he and his colleagues carried out in schoolchildren 40 years ago also revealed "a high frequency of persistent group A throat carriage." However, Dr Stollerman’s published data from those studies reveal a persistence rate of streptococci of the same serotype of only 1.0% at 9 days and 2.0% at 21 days; that article concludes: "In the penicillin-treated group suppression of Group A flora was almost complete for twenty-one days."5 His report is in dramatic contrast to the persistence rates we observed and supports the importance of continually re-evaluating this issue.
Respectfully, Dr Stollerman’s comments about so-called "attenuated" organisms are somewhat speculative. There is no hard evidence that we are aware of to support this supposition as it relates to our article. If one carefully examines data from patients who develop rheumatic fever, a significant percentage had mild preceding symptoms or were totally asymptomatic as Markowitz6 has recently pointed out. Therefore, to equate a lack of clinical severity with an inability of the organism to cause rheumatic fever is not universally true.
We also submit that Dr Stollerman’s statement that studies of strains isolated during convalescence "have clearly shown the latter’s diminished virulence" may be less "clear" than he has suggested. The referenced Rothbard and Watson study7 concludes that "the majority of strains do not lose their capacity to synthesize the M protein for relatively long periods after the onset of infection and are therefore potentially dangerous pathogens." The study by Krause and Rammelkamp examined infectivity (in monkeys) of isolates collected from a human over a 20-week period. When comparing the acute isolate with one collected after 10 weeks of harboring the organism, these investigators found that the 2 isolates "contained similar amounts of M protein" and that "no difference in infectivity for monkeys was detected between the two strains." Therefore, we are reluctant to dismiss the possible significance of the persistent positive cultures described in our report.
Dr Stollerman’s discussion of genetic control of group A streptococcal virulence represents some of the numerous studies in this field, but we believe no direct relevance to the major issues discussed in our article.
Dr Stollerman indicates that "we should not insist on a ‘microbiological cure’ for infections by attenuated strains ... " but in the same paragraph admits that we cannot "conveniently and inexpensively identify really dangerous GAS strains... ." This is the clinical dilemma. He is quite correct that many virulent strains have a mucoid phenotype.8 However, we have previously reported that nearly 60% of rheumatic fever-associated isolates collected during the resurgence of these infections in the late 1980s were not mucoidal.8 Further, the mucoid phenotype, as he is aware, often is strongly influenced by culture conditions. Therefore, we do not agree that absence of mucoid phenotype is a universally reliable indicator of an attenuated organism.
Dr Burke’s Letter
We respectfully suggest that Dr Burke review the important paper by Catanzaro and colleagues,9 (published 50 years ago) which is the basis for the prevailing belief that eradication of the organism is necessary to prevent rheumatic fever. That report states: "The data clearly indicate that when the infecting organism is not eliminated from the patient by therapy, the attack rate of rheumatic fever is not reduced appreciably." If Dr Burke has data to the contrary, we would like very much to examine it.
We regret that, because of space limitations, our response to these 4 letters is not as complete as we would like. The issues raised in these letters as well as in our article have practical implications for practicing primary care physicians. That is why after having puzzled over these data for more than 4 years, after attempting to enlist the aid of the FDA, and after seeking advice from colleagues, we were still left with unresolved issues; we felt the obligation to raise the issues publicly. Through open dialogue, ideas may be generated that can lead to future studies directed toward providing useful answers, not only in everyday clinical practice, but also in understanding the sequelae of this unique bacterial infection.
Edward L. Kaplan, MD
Dwight R. Johnson, MD
University of Minnesota
Department of Pediatrics
Minneapolis, MN 55455
REFERENCES
1. Kaplan EL, Johnson DR. Unexplained reduced microbiological efficacy of intramuscular benzathine penicillin G and oral penicillin V in eradication of group A streptococci from children with acute pharyngitis. Pediatrics.2001; 108 :1180 –1186[Abstract/Full Text]
2. Shulman ST, Gerber MA, Tanz RR, Markowitz M. Streptococcal pharyngitis: the case for penicillin therapy. Pediatr Infect Dis J.1994; 13 :1 –7[Medline]
3. Zaher S, Kassem A, About-Shlieb H, Kholy AE, Kaplan E. Differences in serum penicillin concentrations following intramuscular injection of benzathine penicillin G from different manufacturers. J Pharm Med.1992; 2 :17 –23
4. Lee LH, Ayoub E, Pichichero ME. Fewer symptoms occur in same-serotype recurrent streptococcal tonsillopharyngitis. Arch Otolaryngol Head Neck Surg.2000; 126 :1359 –1362[Medline]
5. Siegel AC, Johnson EE, Stollerman GH. Controlled studies of streptococcal pharyngitis in a pediatric population. I. Factors related to the attack rate of rheumatic fever. N Engl J Med.1961; 265 :559 –566
6. Markowitz M. Rheumatic fever—a half-century perspective. Pediatrics.1998; 102(suppl) :272 –274
7. Rothbard S, Watson R. Variation occurring in group A streptococci during human infection. Progressive loss of M substance correlated with increasing susceptibility to bacteriostasis. J Exp Med.1948; 87 :521 –533
8. Johnson D, Stevens D, Kaplan E. Epidemiologic analysis of group A streptococcal serotypes associated with severe systemic infections, rheumatic fever, or uncomplicated pharyngitis. J Infect Dis.1992; 166 :374 –382[Medline]
9. Catanzaro F, Rammelkamp J, Chamovitz R. Prevention of rheumatic fever by treatment of streptococcal infections. II. Factors responsible for failures. N Engl J Med.1958; 259 :51 –57
PEDIATRICS (ISSN 1098-4275). ©2002 by the American Academy of Pediatrics
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