Treatment of recurrent tonsillopharyngitis. Stig E. Holm* Department of Clinical Bacteriology, Umeå University, S Umeå, Sweden

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1 Journal of Antimicrobial Chemotherapy (2000) 45, Topic T1, Treatment of recurrent tonsillopharyngitis JAC Stig E. Holm* Department of Clinical Bacteriology, Umeå University, S Umeå, Sweden Penicillin V has long been regarded as the treatment of choice in streptococcal tonsillitis. This is based on factors such as its good tolerability, generally mild side effects, sustained high activity against -haemolytic streptococci and low cost. Over the years the oral dosage prescribed has gradually increased and a 10 day treatment regimen has become standard in most countries, in order to decrease the failure rate. 1,2 In patients with recent failure after penicillin V therapy, recurrence rates as high as 50% have been recorded after a renewed penicillin course. The reasons for this high failure rate have been attributed to several individual factors (Table I), but the multifactorial background should also be considered. It is important from an epidemiological point of view to discriminate between recurrence owing to relapse, where the same streptococcal type is identified, and reinfection, which is caused by another streptococcal type. In the case of relapse the recurrence might be caused by group A streptococci retained in the tonsils, especially if the recurrence occurs within a few days, but it might also be due to ping-pong infection from the patient s surroundings. In most instances it is not possible, despite sophisticated genetic methods, to establish the route of infection as the strains isolated from the recurrence may be identical to the initial strain. In all studies relapses appear to be more common than reinfection, especially if the recurrence occurs within a few weeks after the initial infection. Compliance is an important factor in the treatment of streptococcal tonsillitis. Because most patients will experience a definite improvement during the first 2 3 days of therapy, it is often difficult to persuade the patient to continue therapy for the full course of 10 days. However, all available studies clearly show that a 5 or even 7 day course of penicillin therapy is significantly inferior to a 10 day course, 1 6 including those comparing cefadroxil with penicillin V. 2,7,8 It is not yet known why such a long duration of treatment is necessary. One possible reason is that despite the high sensitivity of the streptococci to -lactams, these organisms are not easily eliminated as they are able to hide within the tonsillar crypts which are not easily accessible to antibiotics. Another possibility is that streptococci are being continuously recruited from the external environment. In this case, time may be of significant importance because it has long been known that -haemolytic streptococci are hardy survivors and only gradually decline in the surrounding of a streptococcus-infected patient. Inadequate concentrations of penicillin in tonsillar tissue have been suggested to explain the sustained recovery of group A streptococci in patients treated with penicillin. 9,10 More recently, other workers 11,12 have shown that salivary and tissue concentrations of penicillin V were well above the MIC (0.002 mg/l) for group A streptococci after an oral intake of 12.5 mg/kg bodyweight and remained high ( 0.05 mg/l) for 4 h. Although considerable individual differences were observed, no correlations were found between patients with the lower concentrations and those with the higher failure rate. Kaplan e ta l. 10 s h o w e d that streptococcal count was reduced by 99% after 4 h of exposure to mg/l of penicillin. It appears unlikely, therefore, that conventional penicillin therapy should result in such low drug concentrations in the tonsillar tissue as to influence the recurrence rate. The localization of group A streptococci in tonsillar intraepithelium 13 may be one reason for the failure of antibiotic treatment of streptococcal pharyngotonsillitis. La Penta et al. 14 showed that stationary-phase, but not logarithmic-phase, streptococcal cultures effectively internalized and persisted in cultured human epithelial cells within vacuoles. Antibiotics like penicillin and gentamicin did not kill these intracellular group A streptococci. Similar findings have been reported by Österlund & Engstrand. 13 An explanation for this persistence may come from the study by Neeman et al. 15 who found a significant correlation between continued carriage of Streptococcus pyogenes despite antibiotic therapy and the presence of the prtf1 gene encoding fibronectinbinding proteins, which mediate the intracellular localization of bacteria. In striking contrast to erythromycin, 16,17 no increase in penicillin resistance has been observed in vitro among clinical isolates of group A streptococci. Penicillin tolerance in group A streptococci, defined as an increased MBC:MIC ratio (usually 16), was reported 16,17 at a higher frequency in patients who were clinical treatment failures than in those successfully treated for pharyngotonsillitis (Table II). *Tel: ; Fax: The British Society for Antimicrobial Chemotherapy 31

2 S. E. Holm These penicillin-tolerant strains were fully sensitive to cefadroxil in vitro. It is, therefore, tempting to assume that this type of decreased killing capacity could contribute to the higher recurrence rate observed in penicillin therapy, although the tolerance phenomenon is controversial in that it is technically difficult to standardize, and yet is not established as a biological factor of importance for treatment failures. 18,19 The presence of -lactamase-producing bacteria in the throat has been assumed to be another significant factor for the high failure rate of penicillin V therapy. Although many -lactamase-producing bacteria are not pathogenic to this particular ecological niche, they can act as indirect pathogens through their capacity to inactivate penicillin Table I. Possible causes of recurrent streptococcal pharyngotonsillitis Insufficient penicillin V concentration at focus of infection, owing to: poor patient compliance poor absorption in the intestine poor penetration into tonsillar tissue inactivation by -lactamase-producing bacteria Duration of treatment period insufficient Penicillin tolerance Lowered resistance due to ecological disturbances Lack of bacterial interference Reinfections ( ping-pong infections) Immunological defects Table II. Penicillin tolerance in Group A streptococcal pharyngotonsillitis with and without treatment failure a Patient group MBC/MIC 16 MBC/MIC 16 Clinical treatment failure 11 7 Clinically cured 0 15 a From reference 17. V administered to eliminate -haemolytic streptococci. Several microorganisms that are normally present in the throat have been incriminated, e.g. Staphylococcus aureus, 2 0 Bacteroides fragilis, Bacteroides melaninogenicus and Bacteroides oralis, and their presence in vitro as well as in animal experiments has been shown to protect - h a e m o l y t i c streptococci from the killing action of penicillin. 21,22 The emergence of -lactamase-producing bacteria in the throat during penicillin treatment has also been shown repeatedly, and for different organisms, for example anaerobes 22,23 and S. aureus. 20 Roos et al. 24 demonstrated higher -lactamase activity in saliva sediments from patients with recurrent tonsillitis than in cured patients (Table III). The increasing frequency of -lactamase-producing Moraxella (Branhamella) catarrhalis in throat cultures during recent years 25 should be taken into consideration as these - lactamases are potent inactivators of pencillin as well as cephalosporins. The presence of a normal throat flora has been suggested by Sanders et al. 26 to be of paramount importance as a protective mechanism against invading group A streptococci. In further evaluations of the protective capacity of the microorganisms in the throat, focusing on -haemolytic streptococci 24,27 it was found that the lack of -haemolytic streptococci with growth-inhibiting capacity on the invading group A streptococci correlated well with an increased Table III. -Lactamase activity of saliva pellets from pharyngotonsillitis patients with and without recurrences and in healthy controls a No. with Patient group No. -lactamase Bacteriological treatment failures 23 9 (39%) Clinical treatment failures 11 7 (64%) b Clinically cured 17 5 (29%) Healthy controls 17 4 (22%) a From reference 21. b P Table IV. Interference among - and -haemolytic streptococci in pharyngotonsillitis patients with clinical treatment failure and healthy controls (contacts) a No. of patients -inhibiting -inhibiting Patient group total -streptococci -streptococci Clinical treatment failures 12 b 2 (17%) 11 (97%) Healthy contacts (92%) 6 (50%) a From reference 21. b One patient completely lacked -streptococci. 32

3 Recurrent tonsillopharyngitis Table V. Time to recurrence after penicillin V treatment in patients with recurrent group A streptococcal pharyngotonsillitis given -streptococci or placebo a No. of clinical recurrences within 1 month 2 months 3 months Placebo (n 19) Alpha-streptococci (n 17) b a From reference 28. b A new streptococcal type. incidence of recurrences (Table IV). Suspensions of -haemolytic streptococci with high interference capacity given orally as a spray for 10 days was recently shown to have protective effect in patients with recurrent streptococcal tonsillitis 27,28 (Table V). Furthermore, Sprunt et al. 29 demonstrated that implantation of -haemolytic streptococci in the throat of newborns could hinder colonization by Gram-negative bacteria. A preventive effect of the normal flora against group A streptococcal colonization has also been reported by Crowe et al. 30 In this context it should be noted that considerable amounts of penicillin V, well in excess of the MIC of -haemolytic streptococci, are released in saliva during the process of swallowing. 31 This could be a contributing factor to the disturbances in the normal baterial flora noted in the throat after penicillin V treatment. It is assumed that administration of penicillin as a suspension or syrup will deliver excessively high concentrations with a potential to eliminate the normal flora although, because the exposure time in the throat is usually short, the ecological effect is limited. It appears logical, however, to seek antimicrobial treatment regimens that result in salivary drug levels that kill -haemolytic streptococci but have no effect on - haemolytic streptococci. Because there is a 10-log difference in sensitivity to penicillin (and to cephalosporins) between the - and -haemolytic streptococci, such an antibiotic policy could be possible, Penicillin tablets that do not release drug into saliva, but only into serum, are already available. It will be of interest to follow their ecological effects and cure rates. It has been repeatedly shown that the recurrence rate after penicillin treatment of streptococcal tonsillitis is significantly higher than after treatment with cephalosporins, clindamycin or erythromycin. 10,32 35 Higher cure rates have been demonstrated for both children and adults (Table VI) after cefadroxil treatment. 7 This occurrence probably results from a multitude of factors which may interact simultaneously and are probably not independent of each other. The ideal anti-microbiological agent would have a good penetration to the focus of infection while causing the least possible ecological disturbance to the normal flora, -lactamase resistance, minor side effects and good patient compliance. On this basis, a trial of cefuroxime axetil was carried out in children aged 3 12 years with recurrent streptococcal pharyngotonsillitis. 36 The results (Table VII) clearly indicate that a significantly better result was obtained with cefuroxime axetil than with penicillin V. In a survey of reports dealing with recurrent streptococcal tonsillopharyngitis, Pichichero et al. 37 demonstrated that this recurrence is more frequent in the 1990s than it was in the 1970s. Recurrence occurred more frequently in children below the age of 8 years than in adults. The recurrence rate was higher after penicillin treatment than after alternative antibiotic therapy. A detailed comparative analysis of the various drugs, taking into consideration their specific activities and profiles in relation to the patients treated, would probably provide further insight into the factors that contribute to recurrence in streptococcal pharyngotonsillitis. Together with the new knowledge gained over the last decade on the background to recurrent streptococcal tonsillitis, a re-evaluation of the first drug of choice for the treatment of streptococcal tonsillopharyngitis may be considered. Table VI. Randomized trial of cefadroxil and penicillin V in patients with streptococcal pharyngotonsillitis a Therapy Clinical failure Bacteriological failure Total Recurrences in children penicillin V (n 81) 7 (8.9%) 11 (13.9%) 18 (22.5%) P P cefadroxil (n 95) 2 (2.1%) 2 (2.1%) 4 (4.2%) Recurrences in adults penicillin V (n 243) 30 (12.3%) 16 (6.6%) 46 (18.9%) P P cefadroxil (n 246) 14 (5.7%) 7 (2.8%) 21 (8.5%) a From reference 7. 33

4 S. E. Holm Table VII. Bacteriological and clinical failure rates in patients with group A streptococcal pharyngotonsillitis treated with penicillin V or cefuroxime axetil a Follow-up Antibiotic Bacteriological Clinical time (days) (n) failure failure 2 5 cefuroxime axetil (114) 6 (5%) 3 (3%) P P penicillin V (109) 42 (38%) 25 (23%) cefuroxime axetil (114) 22 (19%) 9 P P penicillin V (109) 50 (46%) 37 a From Holm et al. 36 References 1. Gerber, M. A., Randolph, M. F., Chanatry, J., Wright, L. L., de Meo, K. & Kaplan, E. L. (1987). Five vs ten days of penicillin therapy for streptococcal pharyngitis. American Journal of Diseases of Children 141, Strömberg, A., Schwan, A. & Cars, O. (1988). Five versus ten days treatment of group A streptococcal pharyngotonsillitis: a randomised controlled clinical trial with phenoxymethylpenicillin and cefadroxil. Scandinavian Journal of Infectious Diseases 20, Roos, K., Grahn, E., Lind, L. & Holm, S. E. (1989). Treatment of recurrent streptococcal tonsillitis by recolonisation with alphastreptococci. European Journal of Clinical Microbiology and Infectious Diseases 8, Schwartz, R. H., Wientzen, R. L., Pedreira, F., Feroli, E. J., Mella, G. W. & Guandolo, V. L. (1981). Penicillin V for group A streptococcal pharyngotonsillitis. A randomized trial of seven vs ten days therapy. Journal of the American Medical Association 246, Gastanaduy, A. S., Kaplan, E. L., Huwe, B. B., McKay, C. & Wannamaker, L. W. (1980). Failure of penicillin to eradicate Group A streptococci during an outbreak of pharyngitis. Lancet ii, Gerber, M. A., Spadaccini, L. J., Wright, L. L., Deutsch, L. & Kaplan, E. L. (1985). Twice-daily penicillin in the treatment of streptococcal pharyngitis. American Journal of Diseases of Children 139, Holm, S. E., Roos, K. & Strömberg, A. (1991). A randomised study of treatment of streptococcal pharyngotonsillitis with cefadroxil or phenoxymethylpenicillin (penicillin V). Pediatric Infectious Disease Journal 10, S Milatovic, D. (1991). Evaluation of cefadroxil, penicillin and erythromycin in the treatment of streptococcal tonsillopharyngitis. Pediatric Infectious Disease Journal 10, S Pravcev, H., Strancev, Z. & Klein, S. (1978). Antibiotic levels in tonsillar tissue. Pediatiya 17, Kaplan, J. M., McCracken, G. A. & Culbertson, M. C. (1974). Penicillin and erythromycin concentrations in tonsils. American Journal of Diseases of Children 127, Roos, K., Grahn, E., Lind, L. & Holm, S. (1989). Treatment of recurrent streptococcal tonsillitis by recolonisation with alphastreptococci. European Journal of Clinical Microbiology and Infectious Diseases 8, Roos, K., Grahn, E., Ekedahl, C. & Holm, S. E. (1986). Pharmacokinetics of phenoxymethylpenicillin in tonsils. Scandinavian Journal of Infectious Diseases 18, Österlund, A. & Engstrand, L. (1995). Intracellular penetration and survival of Streptococcus pyogenes in respiratory epithelial cells in vitro. Acta Oto-laryngologica 115, LaPenta, D., Rubens, C., Chi, E. & Cleary, P. P. (1994). Group A streptococci invade human respiratory epithelial cells. Proceedings of the National Academy of Sciences, USA 91, Neeman, R., Keller, N. Barzilai, A., Korenman, Z. & Sela, S. (1998). Prevalence of internalisation-associated gene, pvtf1, among persisting group A streptococcus strains isolated from asymptomatic carriers. Lancet 352, Kim, K. S. & Kaplan, E. L. (1985). Association of penicillin tolerance with failure to eradicate group A streptococci from patients with pharyngitis. Journal of Pediatrics 107, Grahn, E., Holm, S. E. & Roos, K. (1987). Penicillin tolerance in beta-streptococci isolated from patients with tonsillitis. Scandinavian Journal of Infectious Diseases 19, Stjernquist-Desatnik, A., Orrling, A., Schalen, D. & Kamme, K. (1992). Penicillin tolerance in acute tonsillitis. In New Perspectives on Streptococci and Streptococcal Infections, (Orefici, G., Ed); pp Gustaf Fischer Verlag, Stuttgart. 19. Tuomanen, E., Durack, D. T. & Tomasz, A. (1986). Antibiotic tolerance among clinical isolates of bacteria. Antimicrobial Agents and Chemotherapy 30, Milatovic, D. & Knauer, J. (1989). Cefadroxil versus penicillin in the treatment of streptococcal tonsillopharyngitis. European Journal of Clinical Microbiology and Infectious Diseases 8, Brook, I. (1985). Role of -lactamase-producing bacteria in the failure of penicillin to eradicate Group A streptococci. Pediatric Infectious Disease Journal 5, Brook, I. & Yocum, P. (1984). Quantitative measurement of -lactamase in tonsils of children with recurrent tonsillitis. Acta Oto-laryngologica 98, Tuner, K. & Nord, C. E. (1986). Emergence of -lactamaseproducing anaerobic bacteria in the tonsils during penicillin treatment. European Journal of Clinical Microbiology 5, Roos, K., Grahn, E. & Holm, S. E. (1986). Evaluation of - lactamase activity and microbial interference in treatment failures of 34

5 Recurrent tonsillopharyngitis acute streptococcal tonsillitis. Scandinavian Journal of Infectious Diseases 18, Olsson-Liljequist, B., Burman, L. G. & Kallings, I. (1992). Antibiotic susceptibility of upper respiratory tract pathogens in Sweden: a seven-year follow-up study including loracarbef. Scandinavian Journal of Infectious Diseases 24, Sanders, C., Nelson, G. & Sanders, E. (1977). Bacterial interference: II. Epidemiological determinants of the antagonistic activity of the normal throat flora against Group A streptococci. Infection and Immunity 16, Grahn, E. & Holm, S. E. (1983). Bacterial interference in the throat flora during a streptococcal tonsillitis outbreak in an apartment house area. Zeitblatt für Bakteriologie und Hygiene A 256, Roos, K., Holm, S. E., Grahn, E. & Lind, L. (1993). Alphastreptococci as supplementary treatment of recurrent streptococcal tonsillitis: a randomised placebo-controlled study. Scandinavian Journal of Infectious Diseases 25, Sprunt, K., Leidy, G. & Redman, W. (1980). Abnormal colonisation of neonates in an ICU: conversion to normal colonisation by pharyngeal implantation of alpha-haemolytic Streptococcus strain 215. Pediatric Research 14, Crowe, C. C., Sanders, W. E. & Longley, S. (1973). Bacterial interference: II. The role of the normal throat flora in prevention of colonisation by Group A streptococci. Journal of Infectious Diseases 128, Grahn, E. & Holm, S. E. (1987). Penicillin concentration in saliva and its influence on bacterial interference. Scandinavian Journal of Infectious Diseases 19, Pichichero, M. E., Disney, F. A., Aronovitz, G. H., Talpey, W. B., Green, J. L. & Francis, A. B. (1987). Randomised single-blind evaluation of cefadroxil and phenoxymethylpenicillin in the treatment of streptococcal pharyngitis. Antimicrobial Agents and Chemotherapy 31, Ginsburg, C. M., McCracken, G. H., Crow, S. D., Steinberg, J. B. & Cope, F. (1980). A controlled comparative study of penicillin V and cefadroxil therapy of Group A streptococcal tonsillopharyngitis. Journal of Internal Medicine Research 8, Suppl. 1, Stillerman, M., Isenberg, H. D. & Facklam, R. R. (1973). Streptococcal pharyngitis therapy: comparison of clindamycin palmitate and potassium phenoxymethylpenicillin. Antimicrobial Agents and Chemotherapy 4, Kaplan, E. L. & Johnson, D. R. (1988). Eradication of Group A streptococci from the upper respiratory tract by amoxicillin with clavulanate after oral penicillin V treatment failure. Journal of Pediatrics 113, Holm, S. E., Henning, C., Grahn, E., Lomberg, H. & Staley, H. (1995). Is penicillin the appropriate treatment of recurrent tonsillopharyngitis? Results from a comparative randomised blind study of cefuroxime axetil and phenoxymethylpencillin in children. Scandinavian Journal of Infectious Diseases 27, Pichichero, M. E., Green, J. L., Francis, A. B., Marsocci, S. M., Murphy, A. M. L., Hoeger, W. et al. (1998). Recurrent Group A streptococcal tonsillopharyngitis. Pediatric Infectious Disease Journal 17,

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