JAC Comparison of short-course (5 day) cefuroxime axetil with a standard 10 day oral penicillin V regimen in the treatment of tonsillopharyngitis

Transcription

1 Journal of Antimicrobial Chemotherapy (2000) 45, Topic T1, JAC Comparison of short-course (5 day) cefuroxime axetil with a standard 10 day oral penicillin V regimen in the treatment of tonsillopharyngitis Dieter Adam a *, Horst Scholz b and Manfred Helmerking c a Department of Antimicrobial Therapy, Dr v. Haunersches Children s Hospital, University of Munich, Munich; b Institute for Infectiology, Microbiology and Hygienics, Municipal Hospital Buch, Berlin; c Algora Clinical Research, Munich, Germany Oral penicillin V given three times daily in doses of 50, ,000 IU daily has been the standard treatment for tonsillopharyngitis for the last few decades. These regimens, initially recommended by the American Heart Association, were extrapolated from iv dosing with longacting forms of penicillin which had been shown to prevent post-streptococcal sequelae. More recently, several antibiotics, including cefuroxime axetil, have been shown to be at least as effective as penicillin G in eradicating group A -haemolytic streptococci (GABHS) but their influence on post-streptococcal sequelae has never been assessed in a large-scale trial. The German Society for Pediatric Infectious Diseases (DGPI) undertook a large study of cultureproven tonsillopharyngitis involving several agents and included a 1 year follow-up to establish the effect on sequelae. In one arm of this study, cefuroxime 250 mg bid was compared with 50,000 IU penicillin V given in three divided doses. Cefuroxime axetil was more effective than oral penicillin V in eradicating GABHS at the assessment 2 4 days post-treatment (441/490 (90%) patients versus 1196/1422 (84%) patients; P 0.001). Clinically, the two agents were equivalent in efficacy, and carriage rates were similar (11.1% and 13.8%, respectively) in patients receiving cefuroxime axetil and penicillin V, 7 8 weeks post-treatment. One case of glomerular nephritis occurred in a patient given penicillin V. There were no post-streptococcal sequelae confirmed for patients treated with cefuroxime axetil. The findings confirm the previously reported efficacy of short-course (4 5 day) treatments with cefuroxime axetil and indicate that short-course treatment is comparable to the standard oral penicillin V regimen in preventing post-streptococcal sequelae. Introduction The efficacy of penicillin in the treatment of group A streptococcal disease was first documented early in the 1940s. It was noted by the pioneer workers that streptococci returned if penicillin treatment was terminated early. Goerner et al. also showed in 1947 that the carrier state could be eliminated from most patients if penicillin was given for 10 days. 1 In the early 1950s, Wannamaker, Denny and others provided proof of the preventative effect of long-acting injections of penicillin against rheumatic fever following group A -haemolytic streptococci (GABHS) infection. 2 4 By 1953 the American Heart Association recommended treatment of GABHS with oral penicillin for 10 days. 5 The initial data on prevention of rheumatic heart disease came principally from studies in adults in the US armed forces which were considered not necessarily comparable to the civilian condition. In 1981 Schwarz et al. re-evaluated duration of treatment in a study which compared patients with proven GABHS infection treated for 7 or 10 days with penicillin V in tid regimens. 6 They concluded that the 10 day regimen was more effective than a 7 day regimen in eradicating GABHS but also concluded that persistence of S. pyogenes even after adequate therapy may be common (Figure 1). In this study, compliance was carefully assessed by diary cards, return of unused medication and urinary assay as a marker of penicillin dosage. Penicillinuria was present in 66 81% of patients throughout the study. Six years later, Gerber et al. 7 revisited the question of *Infectious Diseases Unit, Kinderklinik der Universität, Lindwurmstrasse 4, München, Germany. Tel: ; Fax: The British Society for Antimicrobial Chemotherapy 23

2 D. Adam et al. duration of therapy for penicillin V using 5 and 10 day treatments. They confirmed the need for 10 days of treatment and that 5 days of therapy was less effective. By 1994, a broader range of antibiotics was being used for treatment of tonsillopharyngitis and shorter therapeutic courses (4 5 days of treatment) were being compared with the standard tid 10 day regimen for penicillin V. In most of these studies, GABHS eradication rates were 80% but no information on prevention of rheumatic fever was available. In six of the studies in which 4 5 days of treatment with an oral cephalosporin (967 patients) was compared with 10 days of treatment with penicillin V (1022 patients) the shorter treatments were equivalent or superior in bacteriological eradication and clinical response In contrast, in the two studies where 5 or 7 days of penicillin V treatment was compared with 10 day penicillin V treatment, the shorter courses resulted in significantly greater bacteriological failure rates. 6,7 These findings support the current recommendations for a full 10 day course of oral penicillin V therapy. When the current study was planned in 1995 it was felt that the incidence of post-streptococcal sequelae was still decreasing but there was general concern that shorter treatment courses might lead to an increased incidence of post-streptococcal sequelae such as rheumatic fever or glomerulonephritis. This concern was heightened by clusters of rheumatic fever which occurred in the USA and elsewhere in the late 1980s The German Society for Pediatric Infectious Diseases was also aware that no studies since the 1950s had attempted to monitor the incidence of post-streptococcal sequelae, including sequelae following the reference treatment 10 day therapy tid with oral penicillin V. Accordingly, the German Society for Pediatric Infectious Diseases undertook a study to address the question of eradication rates of GABHS using a number of antibiotics which had potential for use in 5 day therapy regimens. Each antibiotic was compared with the standard tid 10 day penicillin V treatment. The number of patients recruited to the full study was sufficient to detect a difference in incidence of post-streptococcal sequelae in the 5 day and 10 day treatments. 17 The study was designed to include a 1 year follow-up period to capture any late sequelae 6 months or 1 year after the GABHS infection. Specific data are presented here for one arm of the study in which cefuroxime axetil 250 mg bid was compared with the reference regimen, penicillin V 50,000 IU per day given in three divided doses. Materials and methods Study design and inclusion criteria This phase IV, randomized, open-label, comparative, multicentre study was performed at 137 paediatric centres in Germany between December 1995 and May Microbiological investigations were done by two central laboratories. The Institute for Medical Microbiology, Friedrich Schiller University Hospital, Jena, was responsible for all serotyping of GABHS. The study protocol was approved by the Local Ethics Committee, and signed patient consent was obtained in accordance with the Declaration of Helsinki and with national guidelines. Patients eligible for inclusion were aged 1 18 years, with an established diagnosis of group A streptococcal tonsillopharyngitis. Evidence of acute bacterial infection was characterized by fever 38 C (oral or rectal) and at least one of the following symptoms: exudate of the pharynx or tonsils; erythema and swelling of the pharynx or tonsils; sore throat, especially on swallowing; and a positive rapid screening test for GABHS confirmed by throat culture. Further inclusion criteria were patient/parent (or legal guardian) information and informed consent. Exclusion criteria Patients were excluded from the study if they met any of the following criteria: missing informed consent; known allergy to study antibiotics ( -lactams, e.g. penicillins, cephalosporins, carbacephems or macrolides); antimicrobial therapy within 48 h immediately before study entry or in the preceding 2 weeks for long-acting antibacterials; patients previously included in the study (e.g. patients with recurrent disease during follow-up in this study); intercurrent infections or additional disorders likely to interfere with the clinical course of the disease in this study; pregnancy or lactation; evidence of significant hepatic and/or renal impairment; malabsorption disorders or other gastrointestinal disease that could affect absorption of the oral study drug; rheumatic diseases or glomerulonephritis in the medical history of the patient or persons living in the same household; haematological disease, immunological or neoplastic disease or immunosuppressive therapy. If the screening test was not confirmed by the bacteriological culture in the reference laboratory, the patient was also excluded. Treatment and examination Patients were screened and baseline physical examination and assessment of clinical symptoms and screening test for GABHS (confirmed by throat culture) were performed. Dose administration began on the same day. Patients were randomized to receive either a 5 day treatment with cefuroxime axetil 250 mg bid or 20 mg/kg/day (maximum 500 mg) or a 10 day treatment with penicillin V 50,000 IU/kg bodyweight daily in three doses. Safety and efficacy were evaluated on days 7 9 (2 4 days after the end of treatment in the 5 day treatment groups), 24

3 Short-course cefuroxime in tonsillopharyngitis days (7 9 days after treatment in the 5 day group and 2 4 days after the end of treatment in the 10 day treatment group) and days (7 9 days after the end of treatment in the 10 day treatment group) Follow-up Patients were examined 7 8 weeks after the end of treatment (follow-up) for culture and post-streptococcal sequelae, after 6 months for streptococcal sequelae and again after 12 months for streptococcal sequelae. Efficacy assessment The primary efficacy outcomes in this study were clinical and microbiological response at the end of treatment (final assessment 7 9 days post-treatment). Further evaluation criteria were: the incidence of rheumatic fever and glomerulonephritis with late follow-up after 6 and 12 months; identification of asymptomatic A-streptococcal carriers 7 8 weeks after the end of treatment; the frequency of clinical relapse and new infections defined after GABHS serotyping; and the frequency of adverse events. Evaluation of symptoms Patients were monitored by the investigator at the end-oftreatment and follow-up visits. A patient was considered a treatment failure for subsequent visits if concomitant antimicrobials were given. Assessments included clinical efficacy (cure, improvement, failure) and microbiological data (eradication, persistence or relapse). A physical examination was done at the pretreatment visit and clinical symptoms were recorded before treatment and after the end of treatment (2 4 days and 7 9 days post-treatment). improvement, reduction in the severity and/or number of signs and symptoms; failure, marginal resolution, persistence or worsening of symptoms, discontinuation of therapy owing to poor efficacy. For final clinical outcome the categories responder (cure and improvement) and non-responder (failure) were used. Microbiological assessment Microbiological response was assessed 2 4 days after the end of treatment and at follow-up after 7 8 weeks. Bacteriological response was defined as follows: eradication, absence of GABHS in the culture 2 4 days post-treatment; persistence, presence of GABHS in the post-treatment evaluation; relapse, GABHS eliminated during therapy but present at a later visit. Asymptomatic carriers of group A streptococci were identified 7 8 weeks post-treatment and the frequency of clinical relapse and new infections was determined from GABHS serotyping. Rheumatic fever and glomerulonephritis A diagnosis of rheumatic fever was recorded if at least two of the primary symptoms (carditis, polyarthritis, chorea, erythema marginatum and subcutaneous nodules) or one primary and two secondary symptoms (fever, arthralgia, increased erythrocyte sedimentation rate (ESR) and C reactive protein, leucocytosis, P R elongation in the ECG) were present. The signs and symptoms for glomerulonephritis were pain in the kidney region, oedema, hypertension, central nervous system symptoms, haematuria, proteinuria and the paediatrician s assessment if glomerulonephritis was confirmed based on additional diagnostics. Bacteriological testing Tonsil swabs were taken from each patient before randomization for rapid screening for GABHS confirmed by throat culture, swabs were also taken 2 4 days post-treatment and at follow-up 7 8 weeks post-treatment. Swabs were sent by mail, in agar storage and transport medium, to the two central laboratories. Susceptibility testing (agar disc diffusion) was performed according to NCCLS methodology. 18 Clinical assessment Clinical response for the primary efficacy analysis 2 4 days after the end of treatment (final assessment 7 9 days posttreatment) was assessed using the following criteria: cure, complete resolution of signs and symptoms that established the acute infection according to the inclusion criteria; Patient population, sample size and statistical methods The principal analytical objectives were to assess equivalence of the 5 day treatment groups with the 10 day penicillin V group with respect to the primary efficacy endpoints. The sample size was calculated to establish equivalence in efficacy for tonsillopharyngitis treatment between the 5 day treatment groups and the 10 day penicillin V group. Sample sizes were calculated as follows (based on a 2 test): in the 5 day therapy group, 600 patients were randomized of whom 530 were evaluable. This assumes 13% of patients would be unevaluable. In the 10 day therapy group 1800 patients were randomized of whom 1590 were evaluable. Bacteriological efficacy. Comparing 10 days of penicillin V (1590 patients) with cefuroxime axetil (530), an elimination 25

4 D. Adam et al. Figure 1. Patients included in the study. rate after therapy of 88% 4.4% would be equivalent ( 2.5% one-sided;, 20%); Clinical efficacy. Comparing 10 days of treatment penicillin V (1590 patients) and cefuroxime axetil (530) cure/ improvement at end of treatment of 94% 3.4% would be equivalent ( 2.5% one-sided;, 20%). Safety All patients who received at least one dose of the study medication were included in the safety analysis. Any adverse event during the study was recorded and the relationship to therapy and severity was assessed by the investigator. An adverse event was classified as serious if it was fatal or life threatening, permanently disabling, required or prolonged hospitalization or was a congenital anomaly, cancer or overdose. A treatment-related adverse event was one which was judged by the investigator to be possibly or probably related to a study drug, or if the study drug relationship was indicated as unknown. The severity was rated as mild, moderate or severe. Results This prospective, randomized, multicentre study was conducted by the German Society for Pediatric Infectious Diseases during the period from December 1995 to May One hundred and thirty-seven centres, located throughout Germany, took part in the study. Children and adolescents aged 1 18 years with acute tonsillopharyngitis, a positive culture for GABHS and no history of rheumatic fever or glomerulonephritis in their household were recruited to the study on the basis of a positive rapid GABHS test which was subsequently confirmed by culture (Table). Incidence of rheumatic fever and glomerulonephritis In the sector of the study that compared cefuroxime axetil 250 mg bid with the standard oral penicillin V regimen, there were no cases of glomerular nephritis in the cefuroxime arm of the study and only one case at the 6 7 week visit in a patient who had received penicillin V. This patient had 26

5 Short-course cefuroxime in tonsillopharyngitis Table. Demographic data of evaluable patients Cefuroxime axetil Penicillin V (5 day) (10 day) Number evaluable Age, years (%) 2 1 (0.2) 11 (0.7) (47.3) 725 (49.2) (48.3) 691 (46.9) (4.2) 46 (3.1) not reported 0 1 mean (range) 6.2 (1 16) 6.0 (1 17) Males/females, % 49.8/ /50.7 Mean weight, kg (range) 24.3 ( ) 24.3 (9.2 80) apparently responded satisfactorily both clinically and bacteriologically in the period immediately post-treatment for tonsillopharyngitis. There were no cases of rheumatic fever in either treatment arm. One patient treated with cefuroxime axetil had a recurrence of an infection that had been treated with antibiotics 5 months before the study began, involving a post-infection vasculitis. This was judged not to be rheumatic fever. Again, this patient had responded both bacteriologically and clinically in the 2 9 day period following treatment for tonsillopharyngitis. The risk of glomerulonephritis or rheumatic fever is a negligible factor in antimicrobial strategies against acute GABHS tonsillopharyngitis. Cefuroxime 250 mg bid for 5 days versus penicillin V for 10 days In this report, the clinical and bacteriological results of one section of the study are reported in detail. This was the comparison between cefuroxime axetil given 250 mg bid for 5 days compared with 50,000 IU/day penicillin V tid for 10 days. Details of the patients recruited and follow-up through the study are shown in Figure 1. Inevitably in such a long study, some patients were lost to follow-up but overall almost 70% remained in the study throughout. Of the 2364 patients recruited to the two arms of the study on the basis of a positive rapid GABHS test, 2100 (88.8%) were confirmed as culture-positive. Culture of GABHS was used as the inclusion criterion for evaluable patients in the study, because the primary objective was to assess the incidence of late sequelae following cultureproven GABHS infection. moderately severe infection with a further 15% of infections described as severe. Erythema of the pharynx or tonsils and oral or rectal temperature 38ºC was noted for 99% of all patients included in the study. Exudate of pharynx or tonsils was reported in about two-thirds of cases. Approximately 17% of patients reported contact with others with similar symptoms; 6% mentioned contact with relatives, while 35% of patients reported infections in contacts at school or kindergarten. Eradication of GABHS GABHS was eradicated at the first follow-up visit 2 4 days after the end of treatment in 90.0% (441/490) patients receiving cefuroxime axetil and 84.1% (1196/1422) patients given penicillin V. This difference was statistically significant, indicating superiority of the cefuroxime axetil treatment (P using a two-sided 2 test. The one-sided equivalence test as per protocol, which was not designed to show superiority, showed bacteriological equivalence of the two regimens (Figure 2). All of the isolates collected during the study were fully susceptible to penicillin and to cefuroxime. The incidence of macrolide resistance was approximately 4.6% with a further 6.8% showing intermediate susceptibility to this antibiotic class. There was some regional variation in susceptibility to macrolides in the range %. Recurrence of tonsillopharyngitis A high proportion of patients recruited in both arms of the study had a previous history of tonsillopharyngitis: 37.9% (190/501) patients treated with cefuroxime axetil and 39.2% (578/1474) patients given penicillin V. During the 1 year follow-up period, 21% (105/501) of patients given cefuroxime axetil and 24.4% (360/1474) of the penicillintreated patients had one or more occurrences of tonsillopharyngitis. Two patients in each arm of the study had four or more episodes of tonsillopharyngitis but almost 80% Patient demographics Approximately 70% of all patients in the cefuroxime axetil and penicillin V arms of the study were judged to have Figure 2. Eradication of GABHS 2 4 days after the end of treatment with cefuroxime axetil 250 mg bid (CAE) or oral penicillin V 50,000 IU/day in three divided doses (Pen V). Stippling indicates negative culture and hatching indicates positive culture. 27

6 D. Adam et al. had only one further tonsillopharyngitis infection in the 12 months after treatment. Of those who reported a recurrence, 43.8% (46/105) of patients in the cefuroxime axetil group and 48.6% (175/360) of patients given penicillin V had a history of recurrent tonsillopharyngitis on recruitment to the study. Asymptomatic carriage Seven to eight weeks after the end of treatment, patients were re-examined and culture or rapid testing was used to detect persisting GABHS, possibly indicating asymptomatic carriage of Streptococcus pyogenes. Figure 3 shows the results for 1750 patients who were available for followup. No significant difference was seen in the carriage rates for the two regimens, 11.1% for patients receiving cefuroxime axetil versus 13.8% for penicillin. The findings confirm those from many other studies which show asymptomatic carriage rates of 6 38% after treatment. 19 Clinical efficacy Cefuroxime axetil bid for 5 days was comparable to penicillin V tid for 10 days in clinical efficacy assessed 2 4 days after the end of treatment (Figure 4). The two treatments were statistically equivalent using the one-sided equivalence test as per protocol. In a two-sided test, cefuroxime axetil was shown to be superior to penicillin V clinically (P 0.001). This finding was similar to results obtained by Gehanno & Chiche 19 and Aujard et al. 20 in studies comparing 4 day cefuroxime axetil regimens with standard 10 day penicillin V treatment. In these studies, eradication rates for GABHS were similar to those obtained in the current study. Symptom alleviation was significantly more rapid following cefuroxime axetil treatment for the following symptoms: reduction in fever, sore throat and dysphagia. 19 Safety and tolerance Both penicillin V and cefuroxime axetil were well tolerated: 1543 patients received penicillin V of whom eight (0.5%) reported skin reactions and five (0.32%) had diarrhoea, while of the 525 patients included in the safety evaluation for cefuroxime axetil, six (1.14%) reported diarrhoea and only two (0.38%) reported skin reactions. Four patients in the penicillin group and five in the cefuroxime axetil group reported nausea or vomiting. There were no severe adverse events attributable to either agent. Discussion Figure 3. Asymptomatic carriage of GABHS 7 8 weeks after the end of treatment with either cefuroxime axetil 250 mg bid (CAE) or oral penicillin V 50,000 IU/day in three divided doses (Pen V). Stippling indicates negative culture and hatching indicates positive culture. 97.2* Figure 4. The clinical efficacy 2 4 days post-treatment of 250 mg bid cefuroxime axetil (CAE) compared with 50,000 IU/day oral penicillin V in three divided doses (Pen V) in the treatment of GABHS culture-proven tonsillopharyngitis. Stippling indicates negative culture and hatching indicates positive culture. Cefuroxime axetil has been evaluated in a number of studies in comparison with penicillin V in conventional 10 day regimens and in several 4 5 day treatment studies in both adults and children. 19,20 Eradication rates in all studies have been consistently high, similar to the 90% eradication rate obtained in this study. A direct comparison of 5 day and 10 day treatment with cefuroxime axetil also showed bacteriological and clinical equivalence between the two regimens. 23,24 It therefore appears that a short-course treatment offers the same prospect of GABHS eradication, prevention and clinical efficacy as 10 day penicillin treatment or longer courses of cefuroxime axetil. The issue of GABHS carriage remains a confounding factor in studies of tonsillopharyngitis. Clearly, whatever treatment is used, there is a possibility of carriage which may not always be detected if numbers of organisms are very low or if S. pyogenes is able to survive intracellularly which may be the case. 25 Use of a 5 day course of cefuroxime axetil was at least equivalent to a 10 day course of penicillin V clinically and possibly may be more effective in terms of eradicating GABHS, particularly in recurrent infection. 26 The efficacy of -lactam antibiotics depends on main- 28

7 Short-course cefuroxime in tonsillopharyngitis tenance of serum concentrations of antibiotic in excess of the MIC at the site of infection for periods of 20 40% of the dosage interval to achieve a bacteriostatic effect and for longer to achieve a bactericidal effect. 27 Penicillin V, although exquisitely active against S. pyogenes(mic 0.06 mg/l), is not absorbed particularly well and peak serum levels reach only 1.0 mg/l after administration of 240 mg penicillin V orally, 28 falling to below the detection limit in 8 h. Craig 28 proposed that the important pharmacodynamic criteria for penicillins are that serum concentrations need to be above the MIC for 30 40% of the dosage interval. Penicillin levels in tonsillar tissue may therefore be borderline in terms of antibacterial cover, particularly if -lactamase-producing commensal strains are also present Cefuroxime levels following cefuroxime axetil 250 mg dosage remain above the MIC (0.03 mg/l) for 100% of the dosing interval of 12 h. 33 It is tempting when discussing tonsillopharyngitis to focus solely on the S. pyogenes penicillin interaction but penicillin interacts with the entire nasopharyngeal flora and affects other components of that flora. 31 The very low levels of penicillin which are likely to be achieved in tonsillar tissue may be sub-clinically active against other important commensals or potential pathogens such as Streptococcus pneumoniae. These low levels may have played a role in development of penicillin resistance over time in S. pneumoniae. There may be benefit in considering use of a more diverse range of agents in tonsillopharyngitis which clearly happens in practice. Use of shorter treatment courses is likely to enhance compliance and reduce overall antibiotic usage, both of which are likely to be beneficial. From the study we have evidence that late complications of tonsillopharyngitis remain very rare in Germany indicating negligible circulation of specific rheumatogenic strains. A 5 day antibiotic treatment regimen with cefuroxime axetil did not result in more post-streptococcal sequelae when compared with standard penicillin V treatment. Cefuroxime axetil 250 mg bid for 5 days was superior to oral penicillin V in eradicating GABHS and in terms of overall clinical efficacy. The results show that a 5 day treatment with cefuroxime axetil is effective in treatment of culture-proven tonsillopharyngitis. References 1. Goerner, J. R., Massell, B. F. & Jones, T. D. (1947) (1958). Use of penicillin in the treatment of carriers of -haemolytic streptococci among patients with rheumatic fever. New England Journal of Medicine 259, Denny, F. W., Wannamaker, L. W., Brink, W. R., Rammelkamp, C. H. & Custer, E. A. (1950). Prevention of rheumatic fever (treatment of the preceding streptococcal infection). Journal of the American Medical Association 143, Wannamaker, L. W., Rammelkamp, C. H., Denny, F. W., Brink, W. R., Houser, H. B., Hahn, E. O. et al. (1951). Prophylaxis of acute rheumatic fever (by treatment of the preceding streptococal infection with various amounts of depot penicillin). American Journal of Medicine 10, Wannamaker, L. W., Denny, F. W., Perry, W. D., Rammelkamp, C. H., Eckhardt, G. C., Houser, H. B. et al. (1953). The effect of penicillin prophylaxis on streptococcal disease rates and the carrier state. New England Journal of Medicine249, Breese, B. B., Bellows, M. T., Fischel, E. E., Kuttner, A., Maesell, B. F., Rammelkamp, H. J. et al. (1953). Prevention of rheumatic fever: statements of American Heart Association Council on rheumatic fever and congenital heart disease. Journal of the American Medical Association 151, 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, Gerber, M. A., Randolph, M. F., Chanatry, J., Wright, L. L., De Meo, K. & Kaplan, E. L. (1987). Five vs ten days of penicillin V therapy for streptococcal pharyngitis. American Journal of Diseases of Childhood 141, Peyramond, D., Tigaud, S., Bremard-Oury, C. & Scheimberg, A. (1994). Multicenter comparative trial of cefixime and phenoxymethylpenicillin for group A -hemolytic streptococcal tonsillitis. Current Therapeutic Research 55, Suppl. A, Aujard, Y., Boucot, I., Brahimi, N., Chiche, D. & Bingen, E. (1995). Comparative efficacy and safety of four-day cefuroxime axetil and ten-day penicillin treatment of group A -hemolytic streptococcal pharyngitis in children. Pediatric Infectious Disease Journal 14, Tack, K. J., Henry, D. C., Gooch, W. M., Brink, D. N., Keyserling, C. H. & the Cefdinir Pharyngitis Study Group. (1998). Five day cefdinir treatment for streptococcal pharyngitis. Antimicrobial Agents and Chemotherapy 43, Pichichero, M. E., McLinn, S. E., Gooch, W. M., Rodriguez, W., Goldfarb, J., Reidenberg, B. E. & members of the Ceftibuten Pharyngitis International Study Group. (1993). Ceftibuten vs penicillin V in group A -hemolytic streptococcal pharyngitis. Pediatric Infectious Disease Journal 12, S Portier, H., Chavanet, P., Gouyon, J. B. & Guetat, F. (1990). Five day treatment of pharyngotonsillitis with cefpodoxime proxetil. Journal of Antimicrobial Chemotherapy 26, Suppl. E, Adam, D., Scholz, H. & the Pharyngitis Study Group. (1996). Five days of erythromycin estolate versus ten days of penicillin V in the treatment of group A streptococcal tonsillopharyngitis in children. European Journal of Clinical Microbiology and Infectious Diseases 15, Eckerd, J. M. & McJunkin, J. E. (1989). Recent increase in incidence of acute rheumatic fever in southern West Virginia. West Virginia Medical Journal 85, Gunzenhauser, J. D., Longfield, J. N., Brundage, J. F., Kaplan, E. L., Miller, R. N. & Brandt, C. A. (1995). Epidemic streptococcal disease among Army trainees, July 1989 through June Journal of Infectious Diseases 172, Wong, D., Bortolussi, R. & Lang, B. (1998). An outbreak of acute rheumatic fever in Nova Scotia. Canada Communicable Disease Report 24, Adam, D., Scholz, H. & Helmerking, M. (1998). Incidence of rheumatic fever and glomerulonephritis after antimicrobial treatment of A-streptococcal tonsillopharyngitis: 5 day vs 10 day treatment. In 29

8 D. Adam et al. Program and Abstracts of the Thirty-Eighth Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA. Abstract L92, p American Society for Microbiology, Washington, DC. 18. National Committee for Clinical Laboratory Standards. (1998). Performance Standards for Antimicrobial Susceptibility Testing Eighth Informational Supplement: Approved Standard M100-S8. NCCLS, Wayne, PA. 19. Gehanno, P. & Chiche, D. (1991). Traitement des angines à streptococque hémolytique du groupe A par le cefuroxime axetil pendant 4 jours: étude comparative à la penicilline V pendant 10 jours. Medecine et Maladies Infectieuse 21, Aujard, Y., Boucot, I., Brahimi, N., Chiche, D. & Bingen, E. (1995). Comparative efficacy and safety of four-day cefuroxime axetil and ten-day penicillin treatment of group A -hemolytic streptococcal pharyngitis in children. Pediatric Infectious Disease Journal 14, Pichichero, M. E., Disney, F. A., Aronovitz, G. H., Ginsberg, C. & Stillerman, M. (1987). A multicenter randomized single-blind evaluation of cefuroxime axetil and phenoxymethy penicillin in the treatment of streptococcal pharyngitis. Clinical Pediatrics 26, Gooch, W. M., McLinn, S. E., Aronovitz, G. H., Pichichero, M. E., Kumar, A., Kaplan, E. L. et al. (1993). Efficacy of cefuroxime axetil suspension compared with that of penicillin V suspension in children with Group A streptococcal pharyngitis. Antimicrobial Agents and Chemotherapy 37, Gooch, W. M., Swenson, E., Higbee, M. D., Cocchetto, D. M. & Evans, E. C. (1987). Cefuroxime axetil and penicillin V compared in the treatment of Group A -hemolytic streptococcal pharyngitis. Clinical Therapeutics 9, Mehra, S., Van Moerkerke, M., Welck, J., Sverrisson, G., Sirotiakova, J., Marr, C. et al. (1998). Short course therapy with cefuroxime axetil for group A streptococcal tonsillopharyngitis in children. Pediatric Infectious Disease Journal 17, Belohradsky, B. H., Weiss, M. & Huber, K. (1998). Randomized comparative trial of cefuroxime axetil once daily for 5 or 10 days in patients with streptococcal pharyngitis. Antiinfective Drugs and Chemotherapy 16, Suppl. 1, Neeman, R., Keller, N., Barzilai, A., Korenman, Z. & Sela, S. (1998). Prevalence of internalisation-associated gene, prtf1, among persisting group-a streptococcus strains isolated from asymptomatic carriers. Lancet 352, Holm, S., Henning, C., Grahn, E., Lomberg, H. & Staley, H. (1995). Is penicillin the appropriate treatment for recurrent tonsillopharyngitis? Results from a comparative randomized blind study of cefuroxime axetil and phenoxymethylpenicillin in children. Scandinavian Journal of Infectious Diseases 27, Craig, W. A. (1995). Interrelationship between pharmacokinetics and pharmacodynamics in determining dosage regimens for broad-spectrum cephalosporins. Diagnostic Microbiology and Infectious Disease 22, Quay, J. F. & Bergstrom, R. F. (1986). Pharmacology and pharmacokinetics of penicillins. In -lactam Antibiotics for Clinical Use (Queener, S. F., Webber, J. A. & Queener, S. W., Eds), pp Dekker, New York. 30. Simon, H. J. & Sakai, W. (1968). Staphylococcal antagonism to penicillin G therapy of haemolytic streptococcal pharyngeal infection: effect of oxacillin. Paediatrics 31, Brook, I. & Yocum, P. (1984). Quantitative measurement of -lactamase in tonsils of children with recurrent tonsillitis. Acta Oto-Laryngologica 98, Brook, I. (1984). The role of -lactamase-producing bacteria in the persistence of streptococcal tonsillar infection. Review of Infectious Diseases 6, Grahn, E., Holm, S. E. & Roos, K. (1987). Penicillin tolerance in -streptococci isolated from patients with tonsillitis. Scandinavian Journal of Infectious Diseases 19, Finn, A., Straughn, M., Mayer, M. & Chubb, J. (1987). Effect of dose and food on the bioavailability of cefuroxime axetil. Biopharmaceutics and Drug Disposition 8,