used this longer (12.9 vs 11.3 days) mean length of stay in the amoxicillin/tobramycin group as an explanation for the 18 times higher risk of colonization. Obviously a difference in stay of just more than one day can’t explain an 18 times higher risk. Secondly, the authors’ state that horizontal transmission of antibiotic-resis-tant Gram-negative bacilli is unusual, but we recently demon-strated that a large proportion of the antibiotic-resistant Enter-obacter strains was acquired through cross-transmission.4 Therefore, I propose that an antibiotic policy restricting the selec-tion of empirical, prophylactic, or directed therapy is an important potential control measure. Furthermore, giving the antibiotic at the optimum dose and for the recommended duration are essen-tial strategies for controlling antibiotic-resistant microorganisms. Infection-control policies remain a vital component in the surveil-lance and prevention of resistance and cannot be overemphasized. However, whether improvements in infection-control standards are of greater benefit than a manipulation of antibiotic policies is not known. Probably both will be necessary.
John N. van den Anker, MD, PhD
Section of Pediatric Clinical Pharmacology and Medical Toxicology
Children’s Hospital Columbus, OH 43205
REFERENCES
1. Toltzis P, Dul MJ, Hoyen C, et al. Molecular epidemiology of antibiotic-resistant gram-negative bacilli in a neonatal intensive care unit during a nonoutbreak period.Pediatrics.2001;108:1143–1148
2. De Man P, Verhoeven BA, Verbrugh HA, Vos MC, van den Anker JN. An antibiotic policy to prevent emergence of resistant bacilli.Lancet.
2000;355:973–978
3. Quinn JP, Rodvold KA. Antibiotic policies in neonatal intensive care units.Lancet.2000;355:946 –947
4. De Man P, van der Veeke D, Leemreijze M, et al.Enterobacterspecies in a pediatric hospital: horizontal transfer or selection in individual pa-tients?
In Reply.—
The study by Dr van den Anker and colleagues1used a cross-over design to examine the influence of 2 empiric antibiotic regi-mens, namely penicillin/tobramycin versus amoxicillin/cefo-taxime, on resistant bacillary colonization in 2 separate but otherwise identical neonatal intensive care units (NICUs) in the Netherlands. As we reported,2these authors demonstrated a sig-nificant benefit associated with the use of the former regimen. We cited this study, along with several others, in our “Discussion” section to evaluate the influence of antecedent antibiotic adminis-tration in promoting resistant bacillary colonization in the NICU. We speculated that the strength of this association in the article by de Man et al1could have been partially influenced by the in-creased length of stay (LOS) in infants assigned to their amoxicil-lin/cefotaxime group. This speculation was borne from the obser-vation, made in both their article and ours, that resistant colonization is associated with LOS. A small number of outliers with prolonged LOS in their amoxicillin/cefotaxime group, there-fore, may have contributed disproportionately to the outcome while not raising the mean LOS all that much (which was never-theless significantly higher than in those in the penicillin/tobra-mycin group). But this is to quibble: a reading of both articles suggests that an association between antecedent antibiotic expo-sure and resistant colonization likely exists in the NICU. Indeed, the particularly strong association established by de Man and colleagues between antibiotic exposure and resistant colonization may be further attributable to findings not apparent in the Lancet article1but established by a second report3(published after our manuscript was submitted)—namely, that their hospital was ex-periencing an outbreak ofEnterobacterduring the course of their study. The benefits of antibiotic control policies during a unit-wide or hospital-unit-wide outbreak of Gram-negative bacilli have been demonstrated convincingly in a number of reports.4 – 6On the other hand, the effectiveness of control measures during nonout-break periods in ICU settings is less well-defined; hence, why we felt it important to describe the characteristics of the NICU reser-voir of resistant bacilli during a period of endemnicity.
We embrace Dr van den Anker’s statements emphasizing the importance of prudent antibiotic use, surveillance, and strict at-tention to hygiene to control in-hospital antibiotic resistance. We would suggest, however, that many details regarding the optimal versions of these policies to control endemic resistance are miss-ing. Additionally, it is important to note that some factors contrib-uting to antibiotic resistance within the hospital during nonout-break periods may be relatively immune to these measures. These include the recirculation of resistant organisms by readmitted patients,7colonization outside the hospital by organisms resistant to parenteral antibiotics,8,9and the maintenance of antibiotic re-sistance in hospital bacteria through their co-expression of nonan-tibiotic-related survival determinants,10among others. Clearly, we must keep our eyes open to new or expanded paradigms explain-ing the nonoutbreak acquisition of resistant bacilli in the hospital to accurately predict the success of potential interventions to contain or eradicate their presence.
Philip Toltzis, MD
Division of Pharmacology and Critical Care Rainbow Babies and Children’s Hospital Cleveland, OH 44106
REFERENCES
1. de Man P, Verhoeven BA, Verbrugh HA, Vos MC, van den Anker JN. An antibiotic policy to prevent emergence of resistant bacilli.Lancet.
2000;355:973–978
2. Toltzis P, Dul MJ, Hoyen C, et al. Molecular epidemiology of antibiotic-resistant gram-negative bacilli in a neonatal intensive care unit during a nonoutbreak period.Pediatrics.2001;108:1143–1148
3. de Man P, van Der Veeke E, Leemreijze M, et al.Enterobacterspecies in a pediatric hospital: horizontal transfer or selection in individual pa-tients?J Infect Dis.2001;184:211–214
4. Meyer KS, Urban C, Eagan JA, Berger BJ, Rahal JJ. Nosocomial outbreak of Klebsiella infection resistant to late-generation cephalosporins.Ann Intern Med.1993;119:353–358
5. Rice LB, Eckstein EC, DeVente J, Shlaes DM. Ceftazidime-resistant
Klebsiella pneumoniaeisolates recovered at the Cleveland Department of Veterans Affairs Medical Center.Clin Infect Dis.1996;23:118 –124 6. Toltzis P, Blumer JL. Antibiotic-resistant gram-negative bacteria in the
critical care setting.Pediatr Clin North Am.1995;42:687–702
7. Toltzis P, Hoyen C, Spinner-Block S, Salvator AE, Rice LB. Factors that predict preexisting colonization with antibiotic-resistant gram-negative bacilli in patients admitted to a pediatric intensive care unit.Pediatrics.
1999;103:719 –723
8. Leistevuo T, Leistevuo J, Osterblad M, et al. Antimicrobial resistance of fecal aerobic gram-negative bacilli in different age groups in a commu-nity.Antimicrob Agents Chemother.1996;40:1931–1934
9. Millar MR, Walsh TR, Linton CJ, Zhang S, Leeming JP, Bennett PM. Carriage of antibiotic-resistant bacteria by healthy children.J Antimicrob Chemother.2001;47:605– 610
10. Timmis KN, Gonzalez-Carrero MI, Sekizaki T, Rojo F. Biological activ-ities specified by antibiotic resistance plasmids.J Antimicrob Chemother.
1986;18(suppl C):1–12
Penicillin Failures?!
To the Editor.—
In their study of penicillin treatment of group A streptococcal pharyngitis, Drs Kaplan and Johnson allude to “the possibility of initial eradication followed by recolonization” to explain the find-ing of positive throat cultures in 37% of patients at 10 to 14 or 29 to 31 days after treatment.1 They dismiss this possibility but provide no good reasons for doing so. Children with streptococcal pharyngitis usually contract the infection from peers, many of whom have mild symptoms that do not lead to medical attention. When treatment is discontinued, it is not surprising that a signif-icant number become reinfected (not just recolonized). For the children in this study who were treated with penicillin V, what is wrong with the simple explanation that they contracted new infections from the same communities that were the sources of their original infections?
suggesting new acute infection after penicillin V was discontin-ued?
D. Stewart Rowe, MD Greenbrae, CA 94904
REFERENCE
1. 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 pharyn-gitis.Pediatrics.2001;108:1180 –1186
To the Editor.—
Kaplan and Johnson, in their article in the November 2001 issue ofPediatrics,claim that oral penicillin V and intramuscular ben-zathine penicillin G (BPG) have an unacceptably high rate of “microbiologic treatment failures.” My problem with their article is that I feel the endpoint, that of “microbiologic treatment fail-ures,” is poorly chosen. The correct endpoint should be “clinical treatment failures,” and the primary measuring standard should be whether or not the patient gets acute rheumatic fever.
Penicillin’s primary purpose, in the treatment of streptococcal pharyngitis, is to prevent rheumatic fever. Penicillin may also help to shorten the duration of streptococcal pharyngitis by as much as 1 day, but this advantage is of much less importance than the prevention of rheumatic fever. The eradication of group A strep-tococci from the pharynx is an issue of no importance, which is one reason repeat throat cultures are not recommended after the treatment of a strep throat. It simply doesn’t matter whether penicillin treatment leads to a “microbiologic treatment failure” or not. What matters is whether the patient gets well, or in this particular case in point, whether a serious illness is prevented.
In an age of increasing antimicrobial resistance by most micro-organisms, the publication of this article has the potential to undermine the goal of using the most narrow spectrum antibiotic for the shortest duration possible. If inexperienced physicians, influenced by an article like this, begin using unnecessarily broad-spectrum antibiotics for a condition quite adequately treated by a very narrow spectrum antibiotic—not to mention a cheap and safe one—then our patients will have been done a disservice. We should not abandon penicillin until it is proven that its effective-ness in the prevention of rheumatic fever has been compromised.
Bryan L. Burke, Jr, MD, FAAP Department of General Pediatrics DeVos Children’s Hospital Grand Rapids, MI 49506
REFERENCE
1. Kaplan EL, Johnson DR. Unexplained microbiological efficacy of intra-muscular benzathine penicillin G and of oral penicillin V in eradication of group A streptococci from children with acute pharyngitis.Pediatrics.
2001;108:1180 –1186
To the Editor.—
How can a “treatment of choice” have a failure rate of 35% to 42% and remain a preferred agent? Members of the American Academy of Pediatrics (AAP), it is time for a change. The paper by Kaplan’s group1on penicillin treatment results for group A strep-tococcal (GAS) tonsillopharyngitis puts an exclamation point to my position for the past decade.2In 1991 our group made the observation that penicillin, whether administered by injection or the oral route, produced inferior microbiologic results when com-pared with past eradication rates and comcom-pared with oral cepha-losporins2; we accumulated more data pointing to the need for change3and controversy followed.4,5 More recently our group was able to show that the drop in penicillin efficacy occurred around 1980,6as hypothesized earlier by Kaplan.7We also found that the major variables associated with penicillin treatment fail-ure include the number of days ill before initiation of treatment and the patient’s age, with adolescents and adults experiencing reasonable cure rates.8Despite the evidence, penicillin remained the recommended antibiotic of choice for treating these infections
according to guidelines published by respected national and in-ternational advisory bodies. Why have these committees over the past 10 years not accepted the mounting body of data challenging the universal recommendation of penicillin as the treatment of choice for all patients with GAS tonsillopharyngitis?
Perhaps the data were slow to be accepted because we don’t know why the microbiologic efficacy of penicillin in eradication of GAS from children with acute tonsillopharyngitis has occurred. In their excellent article, Kaplan and Johnson1discuss the possibili-ties that they considered:
1. Compliance. Many have recognized that the taste of penicillin oral suspension is a significant compliance barrier. So compli-ance was examined, but complicompli-ance could not be an explana-tion with the use of intramuscular benzathine penicillin G. Therefore, compliance had to be discarded as an explanation. 2. Carriers. The notion that the apparent declining efficacy of
penicillin in all of the many studies over the past 2 decades was attributable to the inadvertent enrollment of large numbers of GAS carriers was a hypothesis without direct supportive data; now it is disproven.1Carriers in practice settings where antibi-otic efficacy trials are usually conducted occur in 2.5% to 7% of children,9far too few to account for a 35% to 42% failure rate. Kaplan and Johnson examined the carrier question. In the end they concluded that “the antibody data unfortunately do not allow us to definitively exclude contamination with carriers as at least partially responsible for the microbiologic failures in the present studies of penicillin efficacy.”
3. Manufacturing. Kaplan and Johnson raise a question about manufacturing processes. There may be something about the way that benzathine penicillin G is prepared in Egypt and in other parts of the world, as they point out, but the penicillin preparations used in their study were made by a United States manufacturer (Wyeth Ayerst Laboratories, Philadelphia, PA), a pioneer and long-standing producer of injectable and oral pen-icillin preparations.
4. Dose. They also raise the issue of an inadequate dose of peni-cillin, although their analysis1and ours8shows no influence on outcome with increased dose.
5. Co-pathogens, Microbial Interference, and Tolerance. The pos-sibility of microbiologic influence of beta-lactamase as pro-duced by normal oral pharyngeal flora on penicillin and/or the impact of penicillin on the microbial ecology of the oral phar-ynx through its bactericidal effect on alpha-hemolytic strepto-cocci remain possibilities. GAS tolerance to penicillin also could be occurring. To demonstrate these possibilities in a definitive manner is a challenge that has yet to be met.
Kaplan and Johnson declined to present the clinical outcomes in their patient population. They noted that “many participants” who are categorized by the examining physician as clinical fail-ures were noted to have pharyngeal erythema alone at the time of the convalescent visit. Although the authors are clearly correct in their argument that virtually all patients with GAS tonsillophar-yngitis improve with or without antibiotic therapy in a matter of 3 to 5 days from onset of symptoms, this does not eliminate the need for considering clinical results. In a recent study, our group found that fewer and milder symptoms were the rule in GAS relapses involving the same serotypes and these patients had bona fide infection as documented with GAS serology.10
Truthfully, the resistance and trepidation to suggest change has been attributable to the recognized fact that many physicians in the United States and certainly worldwide do not use laboratory diagnosis as the gold standard for GAS throat infections. Overdi-agnosis is rampant, probably occurring in⬎90% of teenagers and adults with sore throat illness and⬎70% of children. With such a high overdiagnosis rate, continued advocacy of penicillin seemed prudent because unnecessary treatment in the majority of patients clearly occurs. This rationale from a public health policy view-point has definite merit. All authorities recommend that a confir-matory laboratory test, either GAS rapid antigen detection or throat culture, be performed and be positive for an antibiotic prescription to be administered for patients with tonsillopharyn-gitis. Although I view the absence of such a confirmatory test as substandard care, most physicians in the United States and espe-cially worldwide treat nearly all sore throats empirically with antibiotics. This is a major challenge without a clear answer.
injectable benzathine G based on all follow-up visits, and a 35% to 37% rate focusing on the third and fourth follow-up visits after oral or injectable drug. Both are quite high. The time has come, it is not premature, for the AAP members and committees to initiate change. In my view, cephalosporins should become the treatment of choice for documented GAS tonsillopharyngitis in children below age 12 years.2,3,8They clearly have superior efficacy com-pared with penicillin, have been the most widely studied, and produce the most consistent high level of microbiologic and clin-ical cure.11Easing into the acceptability of cephalosporin therapy, several recommending groups have pointed to first-generation cephalosporins as preferred among the class. However, it should be pointed out that very few comparative clinical trials exist among the cephalosporins to reach a conclusion whether one generation is equivalent to the next. Such studies are needed.
Michael E. Pichichero, MD
Microbiology and Immunology, Pediatrics and Medicine
Rochester, NY 14642
REFERENCES
1. 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 pharyn-gitis.Pediatrics.2001;108:1180 –1186
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 co-pathogenicity.Pediatr Infect Dis J.1991;10:275–281
3. 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
4. Markowitz M, Gerber MA, Kaplan EL. Treatment of streptococcal pharyngotonsillitis: reports of penicillin’s demise are premature.J Pe-diatr.1993;123:679 – 685
5. Shulman ST, Gerber MA, Tanz RR, Markowitz M. Streptococcal pharyngitis: the case for penicillin therapy.Pediatr Infect Dis J.1994;13: 1–7
6. Pichichero ME, Green JL, Francis AB, et al. Recurrent group A strepto-coccal tonsillopharyngitis.Pediatr Infect Dis J.1998;17:809 – 815 7. Kaplan EL. Benzathine penicillin G for treatment of group A
strepto-coccal pharyngitis: a reappraisal in 1985. Pediatr Infect Dis. 1985;4: 592–596
8. Pichichero ME, Hoeger W, Marsocci SM, Murphy ML, Francis AB, Dragalin V. Variables influencing penicillin treatment outcome in strep-tococcal tonsillopharyngitis.Arch Pediatr Adolesc Med.1999;153:565–570 9. Pichichero ME, Marsocci SM, Murphy ML, Hoeger W, Green JL, Sor-rento A. Incidence of streptococcal carriers in private pediatric practice.
Arch Pediatr Adolesc Med.1999;153:624 – 628
10. Lee LH, Ayoub E, Pichichero ME. Fewer symptoms occur in same-serotype recurrent streptococcal tonsillopharyngitis.Arch Otolaryngol Head Neck Surg.2000;126:1359 –1362
11. Pichichero ME, Casey JR, Mayes T, et al. Penicillin failure in strepto-coccal tonsillopharyngitis: causes and remedies.Pediatr Infect Dis J.
2000;19:917–923
To the Editor.—
I share the concern of Kaplan and Johnson1that current formu-lations 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) pharyn-gitis 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 theselected cases of exudative pharyngitis caused by highly encapsulated, M protein-rich rheumatogenic strains.2Subsequent studies of sporadic streptococ-cal 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 convales-cent 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 iso-lated during acute pharyngitis compared with those isoiso-lated dur-ing convalescence have clearly shown the latter’s diminished vir-ulence.5,6
If the rate of “failure of microbiologic cure” of sporadic GAS pharyngitis by treatment with either oral penicillin or intramus-cular injection of benzathine penicillin G is as high as 35% to 37% in the infections reported by Kaplan and Johnson, why has rheu-matic fever completely disappeared in these cohorts? Doesn’t that alone confirm that higher bacteriologic cure rates of these attenu-ated 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.7Rarely, for example, do cur-rent 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 elu-cidated in recent years. Virulent GAS mutants have been found to lack the gene that represses expression of hyaluronate capsules, streptolysin S, and other toxins.8,9The “Control of Virulence” gene (covRS, also called csrRS) is also subject to as yet unexplained environmental factors that may influence its expression at differ-ent stages of infection. F1 and other surface proteins of unencap-sulated GAS internalize such organisms within epithelial cells where they may remain dormant, colonizing the mucosa asymp-tomatically and resisting penicillin therapy.10Mutations that in-activatecovRresult in encapsulation,11and the hyaluronate cap-sule attaches to and disrupts the epithelium, resulting in invasion of deeper tissues.12Actively 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 fashion13that 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 erad-ication of group A streptococci from children with acute pharyngitis.
Pediatrics.2001;108:1180 –1186
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 strep-tococcal 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 iso-lated during acute pharyngitis and during the carrier state.J Clin Invest.
7. Stollerman GH. Rheumatic fever in the 21st century.Clin Infect Dis.
2001;33:806 – 814
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
9. Engelberg NC, Heath A, Miller A, Rivera C, DiRita VJ. Spontaneous mutations in the CsRS two-component regulatory system of Streptococ-cus pyogenesresult in enhanced virulence in a murine model of skin and soft tissue infection.J Infect Dis.2001;183:1043–1054
10. Neeman R, Keller N, Barzalai A, Korenman Z, Sela S. Prevalence of internalization-associated gene, prtF1, among persisting group-A strep-tococcus strains isolated from asymptomatic carriers.Lancet.1998;352: 1974 –1977
11. Jadoun J, Sela S. Mutation incsrR global regulator reducesStreptococcus pyogenesinternalization.Microbial Pathogenesis.2000;29:1–7
12. Cywes C, Wessels MR. Group A streptococcus tissue invasion by CD44-mediated cell signaling.Nature.2001;414:648 – 652
13. Bisno AL, Gerber MA, Gwaltney JM Jr, et al. Diagnosis and manage-ment of group A streptococcal pharyngitis: a practice guideline. Infec-tious Diseases Society of America.Clin Infect Dis.1997;25:574 –583
In Reply.—
We are pleased to reply to the 4 letters received regarding our article published in the November 2001 issue ofPediatrics.1We 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 “un-explained reduced microbiologic efficacy.” In fact, we were suffi-ciently concerned to write a letter to the Director of the Division of Anti-infective Drug Products at the Food and Drug Administra-tion (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 stan-dard analysis, and the very stringent analysis that we later pub-lished inPediatrics.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 sugges-tions. 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 possi-bility in our view.
The question about negative cultures at 5 to 8 days after initi-ation of therapy is moot. Because 10 days of oral penicillin con-stitutes 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 pos-itive. (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 orig-inally 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.2We 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 man-ufacturing 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 Paki-stan, in Mexico, and in at least one other place outside the United States. Data published by Zaher et al3clearly document the po-tential for variability in bioavailability among benzathine penicil-lin 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.”4Therefore, 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 “report-ed 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.” How-ever, 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.”5His 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 “atten-uated” 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 study7concludes that “the majority of strains do not lose their capacity to synthesize the M protein for relatively long periods after the onset of infec-tion and are therefore potentially dangerous pathogens.” The study by Krause and Rammelkamp examined infectivity (in mon-keys) 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 possi-ble significance of the persistent positive cultures described in our report.
Dr Stollerman’s discussion of genetic control of group A strep-tococcal virulence represents some of the numerous studies in this field, but we believe no direct relevance to the major issues dis-cussed in our article.
have a mucoid phenotype.8However, we have previously re-ported that nearly 60% of rheumatic fever–associated isolates col-lected 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. There-fore, 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 erad-ication of group A streptococci from children with acute pharyngitis.
Pediatrics.2001;108:1180 –1186
2. Shulman ST, Gerber MA, Tanz RR, Markowitz M. Streptococcal pharyngitis: the case for penicillin therapy.Pediatr Infect Dis J.1994;13: 1–7
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Coparent or Second-Parent Adoption by
Same-Sex Parents
To the Editor.—
I am responding to the AAP press release regarding the Feb-ruary 2002 issue ofPediatricsand the “Technical Report: Coparent or Second-Parent Adoption by Same-Sex Parents.”
As a long-time member of the AAP, I am angry and terribly disappointed but not surprised by the Academy’s issuing a state-ment advising the world that the “AAP supports adoption by same-sex parents.” I take issue with the “Technical Report” by the Committee on Psychological Aspects of Child and Family Health. This is a report heavily biased by the homosexual community, with nearly half of the references coming directly from homosex-ual books or journals and none from the perspective of the tradi-tional family. I very much doubt that the Family Research Counsel or Focus on the Family were asked to provide an alternative view. For the AAP to issue such a statement that legitimizes same-sex marriage and calls for same-sex adoption, as if the body of pedi-atricians making up the AAP agree, is outrageous. But why am I not surprised? The AAP has too often taken the moral low ground on other issues such as school-based sex education and abortion. I feel that I must maintain my membership in the Academy for professional reasons and I wish to remain involved at the state level through the Florida Pediatric Society, but I do not want to be associated with this type of proclamation! As a physician who has worked with and for children for over 30 years, I am embarrassed that the AAP would allow this committee to publish such a report.
E. G. Guttery, MD Fort Myers, FL 33919
To the Editor.—
The apparent endorsement by the American Academy of Pedi-atrics of a parenting role by homosexual singles or couples either by biological birth or adoption is very disturbing to me. If, on the basis of the report by the Committee on Psychosocial Aspects of Child and Family Health, the Academy is proposing a policy of “acceptance” for this phenomenon, I am concerned as well as saddened that there was no apparent consultation or vote by the membership of the Academy. Clearly there is in homosexual parenting a radical departure from the heterosexual “traditional family” model that has been the accepted practice since time immemorial. How is it that the Academy is prepared to blithely endorse this new model with the acknowledged limited research and evidence reflected in this report?
The Committee does provide some level of evidence to suggest that children nurtured in the context of same-gender parents do not appear to have been damaged by the experience when con-sidering the 4 topic areas that were the focus of the report. How-ever, I wonder whether the Committee considered any of these issues that are concerns I have.
1. Whether constitutionally or socially induced, promiscuity has tended to be a characteristic of at least the male homosexual. Granted the break-up of heterosexual marriages and families in this country is of epidemic proportions, but do we wish in any way to further aggravate an already bad situation, especially when the welfare of the child is at stake?
2. The human immunodeficiency virus (HIV) rate among male homosexuals is still a serious problem, especially when promis-cuity is a factor. At the present state of medical knowledge, HIV-infected persons die on average within 10 years. If these males adopt children, wouldn’t this be similar to allowing adults over the age of 60 or 70 to become adoptive parents? 3. The Committee report does not take into consideration moral or
religious values and perspectives on homosexuality. Should it have done so? I think yes. The moral teachings of most main-stream Christian denominations, of Orthodox Judaism, and of Islam regard homosexual genital acts as morally wrong. The individuals embracing these faith traditions are not a minority population in the United States. Teaching children, at least implicitly, that such actions are morally neutral or an accept-able alternative to heterosexual intercourse within marriage is not acceptable to many in our society. Should the Academy not acknowledge that its new stance runs counter to these religious teachings and values, especially when many in the Academy’s membership espouse them? Closely allied to this concern is that having to do with the report’s going on record as moving away from support for the traditional family module and accepting on equal footing a same-gender parent model.
