One of the most vexing problems faced by pediatricians is that of the patient whose throat is rarely if ever free of group A streptococci (GABHS) over a period of months or even a few years. Some such patients have repeated episodes of bona fide acute streptococcal pharyngitis, but most are chronic streptococcal pharyngeal carriers. The following case history is an example:
An 11 year old boy, on Visit 1, complains of sore throat, fever, and abdominal pain for 1 day. Two classmates recently missed school because of sore throats. On physical examination you find a temperature of 38.50C, discrete, large, tender anterior cervical nodes bilaterally, pharyngeal erythema, fine petechiae on the soft palate, and tonsillar enlargement with white tonsillar exudates. There is no rash, conjunctivitis, coryza, or cough. A throat swab is positive for group A streptococci by a rapid antigen detection test, and you prescribe a 10-day course of oral penicillin. He improves within 48 hours. Two months later, on Visit 2, he presents with sore throat for 2 days, temperature up to 38°C, and nasal congestion. No one is sick at home. On examination he has mild pharyngeal erythema, his tonsils are not enlarged, and exúdate is not present. There is no rash, no cervical lymph node enlargement or tenderness, and no hepatosplenomegaly. A rapid strep antigen detection test is negative, but the throat culture subsequently yields group A streptococci. You prescribe another 10 day course of oral penicillin. He improves over 3 to 4 days. One month later, on Visit 3, ne again has sore throat, rhinorrhea, and cough. His sister has a cold. Physical examination is unchanged from the last visit. A rapid strep antigen detection test is positive, and the throat culture is also positive once again. The family insists that virtually all doses of penicillin had been given as prescribed for the previous illnesses. You give an intramuscular injection of benzathine penicillin, and an appointment is made for follow-up throat culture. Three weeks later, at the time of Visit 4, he feels well, and the physical examination is normal. However, a throat swab is again positive for group A streptococci.
Unproven Theories of Chronic Streptococcal Carriage
DEFINING THE CARRIER STATE
A group A Streptococcal pharyngeal carrier is one who harbors GABHS in the pharynx for a prolonged period, even when clinically well. The carrier state can be defined as the presence of GABHS in the pharynx without causing symptoms and without evidence of a subsequent immune response. Of course, throat swabs are generally performed at a time the patient has presented with symptoms or has physical findings of some degree of pharyngitis. As in the case presentation, particularly on Visits 2 and 3, it may not be clear whether the signs and symptoms relate to streptococci or to an intercurrent infection with another agent in someone who carries GABHS in the pharynx for a period of time. Assessment of GABHS antibody titers is rarely helpful, because they are most useful to demonstrate evidence of past, rather than current, infection. In fact, Streptococcal carriers tend to have somewhat elevated anti-streptococcal antibody titers compared with controls, and these titers do not increase significantly over time.1 It makes sense that anti-streptococcal titers are somewhat elevated in these patients, because their carrier state was usually preceded by either a symptomatic (Visit 1 above) or a subclinical Streptococcal pharyngeal infection.
Another somewhat more practical clinical definition of Streptococcal carriage is the persistence of GABHS in die pharynx despite adequate antimicrobial therapy. This clinical definition is based on the universal susceptibility of GABHS to penicillins and cephalosporins and the results of studies of treatment of acute pharyngitis as well as treatment trials of suspected carriers.2"4 To date, there has not been a single GABHS isolate identified that is resistant in vitro to penicillins and cephalosporins.5
It has long been recognized that a significant proportion of patients who appear to have received at least one antibiotic course considered adequate for GABHS pharyngitis continue to harbor the organism in the pharynx during and following treatment, as in Visits 1, 2, and 3 in the case presented above. Treatment with penicillin fails to eradicate GABHS from the pharynx of as many as 25% of patients with apparent Streptococcal pharyngitis.6 Such patients are bacteriologie treatment failures, a term that refers to persistence of GABHS following therapy for acute Streptococcal pharyngitis. Most patients with bacteriologie treatment failure have no symptoms and are identified only when follow-up cultures are obtained, a practice that is generally unnecessary in communities with Jow rates of acute rheumatic fever. Careful analysis leads to the conclusion that many or most such patients had initial signs and symptoms highly suggestive of a viral infection, such as rhinorrhea, cough, and diarrhea.
The term clinical treatment failure refers to the very small number of patients who continue to harbor GABHS and have respiratory tract signs and symptoms. Clinical treatment failure is somewhat puzzling because Streptococcal pharyngitis is a self-limited disease, with symptoms that resolve in substantially less than a week. Patients who remain culture positive with or without symptoms may be reinfected with the same or a different strain of GABHS, or their symptoms may have been (and may still be) related to a viral infection rather than to bona fide infection with GABHS. Some patients may have been noncompliant with therapy, but apparent treatment failure occurs even among patients treated with intramuscular benzathine penicillin. Fortunately, patients who are compliant with therapy are at minimal risk for developing post-streptococcal complications such as acute rheumatic fever (ARF),1 even if they continue to harbor GABHS in the pharynx. This may be because most such individuals represent carriers whose symptoms, in retrospect, were caused by an intercurrent viral infection. Clinical or bacteriologie treatment failure is not related to resistance of GABHS to penicillin; there has never been a clinical isolate of GABHS found to be resistant to the penicillins or cephalosporins.5
Several theories have been advanced to explain bactériologie treatment failures (Table 1). These include "protection" of group A streptococci by ß-lactamases produced by other oral flora,7'8 tolerance of group A streptococci to penicillin, denned as inhibition of bacterial growth without killing of organisms,9 persistent infection hidden within the tonsillar crypts,10 and absence of oral flora (particularly a streptococci) that are inhibitory to group A streptococci.11" 12 None of these theories has been proved. Numerous published reports of the efficacy of ß-lactamase-resistant antibiotics, particularly cephalosporins, for treatment of streptococcal pharyngitis suggest a possible role for ß-lactamase-producing flora in penicillin treatment failures.13'16 The patient populations studied, bactériologie methods used, and modes of followup differ widely among these studies. Few investigators have attempted to correlate isolation of ß-lactamase-producing bacteria from pharyngitis patients with the bactériologie outcome of their treatment. In two such studies we failed to find an association between treatment outcome and the presence of ßlactamase-producing aerobic or anaerobic pharyngeal flora or ß-lactamases in oral secretions.17-18 Tolerance to penicillin or other commonly utilized antibiotics also does not appear to p\ay a role in treatment failure.16,19 Data regarding a possible role for the absence of inhibitory substances produced by normal pharyngeal flora are conflicting.12,13,18
At present the best explanation for asymptomatic persistence of group A streptococci despite appropriate treatment of apparent GABHS pharyngitis is that these patients had pre-existing streptococcal carriage but that theit symptoms were actually related to an intercurrent viral pharyngitis that in retrospect was misdiagnosed as streptococcal pharyngitis (as in Visits 2 and 3).1,6,18 Alternatively, some patients may have had bona fide streptococcal pharyngitis (Visit 1) but evolved to become carriers subsequent to treatment.1,20 The theories advanced to explain bacteriologie treatment failure are also offered to explain chronic streptococcal carriage. The factors that result in carriage of GABHS remain obscure but may relate to the adherence mechanisms and properties of the bacteria and the host oral mucosa,21·22 factors that clinicians have no practical means to evaluate. In summary, we believe that chronic streptococcal carriage and bacteriologie treatment failure are intimately related and that the clinician should approach patients with bactériologie treatment failure as carriers.
MANAGING STREPTOCOCCAL CARRIERS
Pediatricians vary widely in their approach to streptococcal carriers.23 Managing this condition depends on understanding several factors: who is likely to be a carrier; how common asymptomatic carriage is in the population; what the risks of being a carrier are; and what treatment options are available.
The clinician should consider the possibility of chronic carriage of GABHS when a patient or a family member has multiple rapid test or culture-positive episodes of pharyngitis, especially when symptoms are mild or are not typical for acute streptococcal pharyngitis (ie, including rhinorrhea, cough, conjunctivitis, coryza, diarrhea). A history of multiple courses of antibiotic therapy without eradication of GABHS is very common. A rapid test or culture obtained when the suspected carrier is symptom-free or is receiving treatment with penicillin or other appropriate antibiotic (use of intramuscular benzathine penicillin eliminates the possibility of noncompliance) usually is positive for GABHS. There is no need to obtain routine post-treatment cultures in areas with low rates of ARF, including most of the US, Canada, and Westem Europe. We do not recommend obtaining antistreptococcal antibody titers to identify carriers because antibody titers are often elevated from prior infection. They have not proved to be useful to help distinguish between carriage and acute infections.
Streptococcal carriage is fairly common; for example, 8.3% of 5- to 7-year-old children presenting for well-child care had asymptomatic colonization with group A streptococci in one US study.24 In a Danish study of more than 2600 patients followed for 1 year in general medical practices, 10.9% of patients younger than 15 years old had asymptomatic carriage of GABHS.25 Higher rates of carriage have been documented on occasion.6,20 The preponderance of evidence indicates that chronic carriers do not appear to be at increased risk for ARF or for development of suppurative complications.1 Additionally, they are rarely sources of spread of group A streptococci in the community, so there is no reason to exclude carriers from school. However, some recent studies have found that carriers occasionally may be the source of asymptomatic GABHS colonization of other family members.20 Although there is some evidence that the same streptococcal strains that are responsible for clusters of invasive GABHS infections may also be prevalent among asymptomatic carriers and pharyngitis patients in the community, the frequency of transmission of these organisms from the latter groups is unclear at present.20,26
The primary practical problem posed by chronic streptococcal carriage for the primary care provider is that accurate diagnosis of the etiology of acute pharyngitis is confounded (Table 2). That is, a positive throat culture or rapid strep test is unable to distinguish the carrier from the individual with bona fide acute streptococcal pharyngitis. Secondarily, frequent positive throat cultures, even without dramatic symptoms, can stimulate physician and patient anxiety that can develop into "streptophobia." The greatest risk faced by a streptococcal carrier is usually related to the administration of unproved and generally unnecessary therapies in well-intentioned efforts to allay anxiety. These therapies include repeated or prolonged courses of antibiotics, use of expensive β-lactamase-resistant antibiotics, tonsillectomy, and culture and/or treatment of family members and even pets.
The penicillins are ineffective treatment for carriers despite their universal in vitro activity, but there are two regimens available that have been proven effective in controlled trials. We found that intramuscular benzathine penicillin (alone or in combination with procaine penicillin) plus oral rifampin (10 mg/kg/dose up to 300 mg, twice daily for 4 days beginning on the day of the penicillin injection), 2,3 was more effective than intramuscular benzathine penicillin alone or no treatment for eradication of carriage. Oral clindamycin given for 10 days (20 mg/kg/day up to 450 mg, divided into three equal doses) is also highly effective and easier to use. We found eradication rates as high as 92% with clindamycin.3 There are no published studies of rifampin with oral antibiotics for this purpose, although one study demonstrated prevention of bactériologie treatment failure when rifampin was used with oral penicillin.14
Options for Managing Chronic Streptococcal Carriers
Treating asymptomatic patients with one of the regimens proven effective for terminating chronic group A Streptococcal carriage should be reserved for particularly anxious patients or families; individuals with history of ARF or living with someone who had ARP; those living or working in nursing homes, chronic care facilities, or hospitals; those in communities experiencing an outbreak of particularly serious GABHS infections or ARF; or those in families exhibiting "ping-pong" spread of Streptococcal pharyngitis among family members. Successful eradication of the carrier state certainly will make evaluation of subsequent episodes of pharyngitis easier, but we have seen chronic carriage recur upon re-exposure to group A streptococci.
Because Streptococcal carriage is a condition with few direct medical risks, the clinician must carefully select those patients who will benefit from treatment with antibiotics. Most asymptomatic patients do not need to be treated with antibiotics, but we do not recommend ignoring all episodes of sore throat in those identified as carriers. Such an approach would risk missing a newly acquired bona fide Streptococcal pharyngitis, thus placing the patient at unnecessary risk for ARF. The most reasonable management approach for most suspected or confirmed carriers is to obtain an antigen detection test or throat culture each time the patient has symptoms and signs that are truly suggestive of acute Streptococcal pharyngitis, but to avoid obtaining these tests when symptoms are more typical of a viral illness ( ie cough, coryza, diarrhea, and conjunctivitis). Each such episode that is associated with a positive test should be treated with a penicillin or other appropriate agent to prevent ARF, as if it were a bona fide acute Streptococcal pharyngitis.
Tonsillectomy is commonly suggested for treatment of chronic Streptococcal carriers, but there are no data available to assess the efficacy of that approach. We do not recommend tonsillectomy for chronic carriage, certainly without first attempting therapy with clindamycin or rifampin plus intramuscular benzathine penicillin. The presence of tonsils is not required for bona fide Streptococcal pharyngitis or for development of chronic carriage.
Chronic Streptococcal carriage creates management dilemmas for primary care physicians. These dilemmas can be minimized if physicians perform diagnostic tests like rapid antigen detection tests or throat cultures only in patients who have signs and symptoms suggestive of Streptococcal rather than viral infection and if they avoid performing follow-up posttreatment cultures. The carrier state appears to be benign with respect to threat to the carrier him or herself and with respect to potential danger to others in his or her environment. Once established, Streptococcal carriage is rather resistant to standard antibiotic therapy, even though GABHS remain universally sensitive to penicillins and cephalosporins. Management generally requires reassurance only, but clindamycin or intramuscular penicillin plus rifampin can eradicate carriage.
1. Kaplan EL. The group A streptococcal upper respiratory tract carrier state: An enigma. J Pediatr. 1980;97:337-345.
2. Tanz RR, Shulman ST, Barrhel MJ, et al. Penicillin plus iifampin eradicata pharyngeal carriage of group A streptococci. J Pediatr. 1985; 106: 876-880.
3. Tanz RR, Poncher JR, Corydon KE, et al. Clindamycin treatment of chronic pharyngeal carnage of group A streptococci. J Pediatr. 1991;119:123-128.
4. Gerber MA, Randolph MF, Mavo DR. The group A srteptococcal carnei state: A reexammation. Am J Dis Child. 1988:142:562-565.
5. Coonan KM, Kaplan EL. In vitro susceptibility of tecent North American group A streptococcal isolates to eleven oral antibiotics. Pediatr Infect Dis J. 1994;13: 630-635.
6. Gasianaduy AS, Kaplan EL. Huwe BB. et al. Failure of penicillin to eradicate group A streptococci during an outbreak of pharyngitis. Lancet. 1980;Z:498-50Z.
7. Simon HJ, Saltai W. Staphylococcal antagonism to penicillin-G therapy of hemolytic streptococcal pharyngeal infection: Effect of oxacillin. Pediatrics. 1963;31:463-469.
6. Brook I. Role of beta-lactamase-producing bacteria in the failure of penicillin to eradicate group A streptococci. Pediatr Infect DoJ. I985;4:491-495.
9. Kim KS, Kaplan EL. Association of penicillin tolerance with failure to eradicate group A streptococci from patients with pharyngitis. J Pediatr. 1985;107:681-684.
10. Brook I, Yocum P, Shah K. Surrace vs core-tonsillar aerobic and anaerobic flora in recurrent tonsillitis. JAMA. 1980;244:1696-1698.
11. Roos K, Grahn E, Holm SE. Evaluation of beta-lactamase activity and microbial interference in treatment failures of acute streptococcal tonsillitis. Scand J infect Dis. 1986;18:313-319.
12. Grahn E, Holm SE. The effect of penicillin on bacterial interference in vivo. Stand J Infect Dis. 1987;19:353-359.
13. Pichichero ME, Margolis PA. A comparison of cephalosporins and penicillin in the tteatment of group A beta-hemolvtic streptococcal pharyngitis: A meta-analysis supporting the concept of microbial copathogenicity. Pediatr Infect Dis J. 1991;10:275-281.
14. Chaudhary S, Bilinsky SA, Hennessy JL, et al. Penicillin V and rifampin for the treatment of group A streptococcal pharyngitis: A randomized trial of 10 days penicillin vs 10 days penicillin with rifampin during the final 4 days of therapy. J Pediatr. 1985;106:481-486.
15. Kaplan EL, Johnson DR. Eradication of group A streptococci from the upper respiratory tract by amoxicillin with clavulanate after oral penicillin V treatment failure. J Pediatr. 1988:113:400-403.
16. Smith TD, Huskins WC, Kim KS, et al. Efficacy of p-lactamase- resistant penicillin and influence of penicillin tolerance in eradicating streptococci from the pharynx after failure of penicillin therapy for group A streptococcal pharyngitii. J Pediatr 1987;110:778-782.
17. Tanz RR, Shulman ST, Sroka PA, et al. Lack of influence of beta-lacfamase-produc ing flora on recovery of group A streptococci after treatment of acute pharyngitis. J Pediatr. 1990l117:859-863.
18. Gerber MA, Tanz RR, Kabat W, et al. Potential mechanisms for treatment failure in group A streptococcal pharyngitis. Submitted for publication.
19. Srjernquist-Desatnik A. Orrling A, Schalen C, et al. Penicillin tolerance in group A streptococci and treatment failure in streptococcal tonsillitis. Aon Qtotaryngol. 1992(Suppl 492):68-71.
20. Nguyen L, Levy D, Ferroni A, Gehanno P, Berche P. Molecular epidemiology of Streptococcus pyogenes in an area where acute pharyngotonsillirts is endemic. J Clin Microbiology. 1997;35:2111-2114
21. Bisno AL. Molecular aspects of bacterial colonization. Infect Control Hosp Epidemiol. 1995;16:648-657.
22. Stentors LE, Raisanen S. In vivo attachment of beta-haemolytic streptococci to tonsillar epithelial cells in health and disease. Acta Otoloryngol (Stockh). 1991;111:562-568.
23. Hofer C, Binns HJ, Tanz RR, Strategies fot managing Group A streptococcai pharyngitis: A survey of board-certified pediatricians. Arch Pediatr Adolesc Med. 1997;151:824-829.
24. Ginsburg CM, McCracken GH, Crow SD. et al. Seroepidemiology of the group A streptococcal carriage state in a private pediatrie practice. Am J Dis Child. 1985;139:614-617.
25. Hoffman S. The throat carrier rate of group A and other beta hemolytic streptococci among patients in general practice. Acta Path Microbiol Immunol. Scand. 1985;93:347-351 (Sect. B).
26. Cockerill FR III, MacDonald KL, Thompson RL, et al. An outbreak of invasive group A streptococcal disease associated with high carriage rates of the invasive clone among school-aged children. JAMA. 1997;277:38-43.
Unproven Theories of Chronic Streptococcal Carriage
Options for Managing Chronic Streptococcal Carriers