Short Course Antibiotic Therapy of Streptococcal Pharyngitis: Comparison of Clarithromycin with Amoxicillin/ Clavulanate and Cefuroxime Axetil D. Adam, MD PhD, Munich, Germany H. Scholz, MD PhD, Berlin, Germany H.Haverkamp, M. Helmerking, Algora Clinical Research, Munich
Studydesign A phase IV, randomized, open-labeled, comparative multicenter parallel group study A study of the German Society for Pediatric Infectious Diseases (DGPI)
Aims of the Study (I) To compare the clinical and microbiological efficacy of a five day treatment course of clarithromycin (CLA) b.i.d. vs amoxicillin/clavulanate (AC) t.i.d. and vs cefuroxime axetil (CAE) b.i.d. and vs. 10 days penicillin V t.i.d
Aims of the Study (II) Incidence of post streptococcal sequelae (rheumatic fever & glomerulonephritis) after antibiotic short course treatment of A-streptococcal tonsillopharyngitis.
Evaluation Criteria (I) Eradication of GABHS Clinical efficacy Incidence of rheumatic fever and glomerulonephritis after 6 and 12 months
Evaluation Criteria (II) Resistance determination Identification of asymptomatic GABHS carrier 7-8 weeks after end of treatment Frequency of adverse events
Study Medication Clarithromycin 15 mg/kg/day b.i.d. Amoxicillin/clavulanate 37.5 mg/kg/day t.i.d. Cefuroxime axetil 20 mg/kg/day b.i.d. Penicillin V 50,000 I.U./kg B.W. t.i.d.
Study Logistics Patient enrolment 12/95-4/98 Pediatricians nationwide 2 central laboratories for microbiological investigation 1 central laboratory for serotyping of GABHS
Inclusion Criteria (I) Clinical diagnosis of tonsillopharyngitis based on the following criteria: fever 38 C (oral or rectal) at least one of the following symptoms: Exudate of the pharynx or tonsils Erythema and swelling of the pharynx or tonsils Cervical lymphadenopathy
Inclusion Criteria (II) Age: > 1 year < 18 years Positive rapid screening test for GABHS confirmed by throat culture Patient-/parent (or legal guardian) information Informed consent
Exclusion Criteria (I) Known hypersensitivity to study antibiotics Antimicrobial therapy < 48 hours prior to study Intercurrent infections or additional disorders likely to interfere with the clinical course of the disease in this study Rheumatic diseases or glomerulonephritis in the medical history
Exclusion Criteria (II) Malabsorption or other gastrointestinal conditions Hepatic and/or renal disease/impairment Hematologic -, immunologic or neoplastic disease or immunosuppressive therapy
Schedule of the Evaluation of Efficacy and Safety Day of evaluation Day 7-9 Day 12-14 Clinical efficacy 2-4 days after end of treatment 7-9 days after end of treatment Microbiological efficacy 2-4 days after end of treatment Day 47-52 6-7 weeks after end of therapy
Schedule of Follow-up after End of Treatment 7-8 weeks: culture (eradication; asymptomatic carrier) and poststreptococcal sequelae 6 months: poststreptococcal sequelae 12 months: poststreptococcal sequelae
Study Population at Enrollment Patients confirmed by culture CLA AC CAE PEN Total 541 543 532 1423 3039
Demographic data Gender female male 49.8% 50.2% Age 1-18 years (median 6 years) Weight 9-80 kg (median 21.6 kg) Severity of infection: 14.4 % mild 70.9% mod 14.6% severe Episodes of infection: 60% first 40% >1
Microbiological Efficacy Population 2-4 days after end of treatment Patients evaluable for microbiological efficacy CLA AC CAE PEN Total 506 508 487 1370 1501
GABHS Susceptibility to the Corresponding Antibiotic Treatment-Group n total n susceptible (%) Cefuroxime axetil 498 100 Clarithromycin 506 86.5 Amoxicillin/Clavulanate 508 100 Penicillin V 1408 100
Microbiological Efficacy Eradication of GABHS 2-4 days after end of treatment CLA CA 17.4% 7.1% n=506 n=508 82.6% 92.9% *p<0.001 CAE 10.1% n=487 89.9% *p<0.001 0 100% negative culture positive culture *Fisher s exakt test vs CLA (2-sided)
PEN 15% Microbiological Efficacy Eradication of GABHS 2-4 days after end of treatment n=1370 85% CLA CA CAE 17.4% 7.1% 10.1% n=506 n=508 n=487 0 100% negative culture 82.6% 92.9% 89.9% *p<0.001 positive culture *p<0.001 *Fisher s exakt test vs CLA (2-sided)
Asymptomatic GABHS Carrier 7-8 weeks after end of treatment CLA 16.6% n=452 83.4% AC 14.5% n=455 85.5% CAE 11.1% n=432 88.9% 0 100% Culture or rapid test: negative positive
Asymptomatic GABHS Carrier 7-8 weeks after end of treatment PEN 13.7% n=1268 86.3% CLA 16.6% n=452 83.4% AC 14.5% n=455 85.5% CAE 11.1% n=432 88.9% 0 100% Culture or rapid test: negative positive
Clinical Efficacy 2-4 days after end of treatment CAE 2.8% n=493 97.2% *p=0.0206 AC 3.1% n=509 96.9% *p=0.0487 CLA 5.9% n=510 94.1% responder Nonresponder 0 20 40 60 80 100 % *Fisher s exact test vs CLA (2-sided)
Clinical Efficacy 7-9 days after end of treatment CAE 9.2% n=470 *p=0.0077 89.8% AC 8.4% n=488 *p<0.001 91.6% CLA 16.0% n = 492 84.0% responder Nonresponder 0 20 40 60 80 100% *Fisher s exact test vs CLA (2-sided)
Incidence of Poststreptococcal Sequelae no streptococcal sequelae at 7-8 weeks post treatment at 6 month post treatment at 12 month post treatment
Adverse Drug Reactions N=525 CAE n=14 n=11 2.29% *p=0.375 AC N=534 N=534 n=18 n=15 2.81% *p=0.25 ADRs patients CLA n=8 n=8 1.5% 0 5 10 15 20 *Fisher s exact test vs CLA (2-sided)
Conclusions (I) Clinical efficacy was significantly higher for both, amoxicillin/clavulanate and cefuroxime axetil as compared to clarithromycin Eradication rates: AC=92.9%; CAE=89.9%; CLA=82.6%
Conclusions (II) The higher bacteriological failure of CLA could not be attributed to serotype changes Susceptibility to GABHS was 100% for AC and CAE but only 86.5% for CLA Thus CLA is not recommended as first linetreatment of GAHBS tonsillopharyngitis
Microbiological Efficacy Eradication of GABHS 2-4 days after end of treatment CLA CA 17.4% 7.1% n=506 n=508 82.6% 92.9% *p<0.001 CAE 10.1% n=487 89.9% *p<0.001 0 100% negative culture positive culture *Fisher s exakt test vs CLA (2-sided)
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Clinical Efficacy Population Patients CLA AC CAE eligible for treatment 541 543 532 evaluable for clinical efficacy,2-4 days 510 509 493 post therapy evaluable for clinical 492 488 470 efficacy,7-9 days post therapy
Safety Analysis Population Patients CLA AC CAE eligible for treatment 541 543 532 evaluable for safety analysis 534 534 525