Short Course Antibiotic Therapy of Streptococcal Pharyngitis: Comparison of Clarithromycin with Amoxicillin/ Clavulanate and Cefuroxime Axetil

Transcription

1 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

2 Studydesign A phase IV, randomized, open-labeled, comparative multicenter parallel group study A study of the German Society for Pediatric Infectious Diseases (DGPI)

3 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

4 Aims of the Study (II) Incidence of post streptococcal sequelae (rheumatic fever & glomerulonephritis) after antibiotic short course treatment of A-streptococcal tonsillopharyngitis.

5 Evaluation Criteria (I) Eradication of GABHS Clinical efficacy Incidence of rheumatic fever and glomerulonephritis after 6 and 12 months

6 Evaluation Criteria (II) Resistance determination Identification of asymptomatic GABHS carrier 7-8 weeks after end of treatment Frequency of adverse events

7 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.

8 Study Logistics Patient enrolment 12/95-4/98 Pediatricians nationwide 2 central laboratories for microbiological investigation 1 central laboratory for serotyping of GABHS

9 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

10 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

11 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

12 Exclusion Criteria (II) Malabsorption or other gastrointestinal conditions Hepatic and/or renal disease/impairment Hematologic -, immunologic or neoplastic disease or immunosuppressive therapy

13 Schedule of the Evaluation of Efficacy and Safety Day of evaluation Day 7-9 Day 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 weeks after end of therapy

14 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

15 Study Population at Enrollment Patients confirmed by culture CLA AC CAE PEN Total

16 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

17 Microbiological Efficacy Population 2-4 days after end of treatment Patients evaluable for microbiological efficacy CLA AC CAE PEN Total

18 GABHS Susceptibility to the Corresponding Antibiotic Treatment-Group n total n susceptible (%) Cefuroxime axetil Clarithromycin Amoxicillin/Clavulanate Penicillin V

19 Microbiological Efficacy Eradication of GABHS 2-4 days after end of treatment CLA CA 17.4% 7.1% n=506 n= % 92.9% *p<0.001 CAE 10.1% n= % *p< % negative culture positive culture *Fisher s exakt test vs CLA (2-sided)

20 PEN 15% Microbiological Efficacy Eradication of GABHS 2-4 days after end of treatment n= % CLA CA CAE 17.4% 7.1% 10.1% n=506 n=508 n= % negative culture 82.6% 92.9% 89.9% *p<0.001 positive culture *p<0.001 *Fisher s exakt test vs CLA (2-sided)

21 Asymptomatic GABHS Carrier 7-8 weeks after end of treatment CLA 16.6% n= % AC 14.5% n= % CAE 11.1% n= % 0 100% Culture or rapid test: negative positive

22 Asymptomatic GABHS Carrier 7-8 weeks after end of treatment PEN 13.7% n= % CLA 16.6% n= % AC 14.5% n= % CAE 11.1% n= % 0 100% Culture or rapid test: negative positive

23 Clinical Efficacy 2-4 days after end of treatment CAE 2.8% n= % *p= AC 3.1% n= % *p= CLA 5.9% n= % responder Nonresponder % *Fisher s exact test vs CLA (2-sided)

24 Clinical Efficacy 7-9 days after end of treatment CAE 9.2% n=470 *p= % AC 8.4% n=488 *p< % CLA 16.0% n = % responder Nonresponder % *Fisher s exact test vs CLA (2-sided)

25 Incidence of Poststreptococcal Sequelae no streptococcal sequelae at 7-8 weeks post treatment at 6 month post treatment at 12 month post treatment

26 Adverse Drug Reactions N=525 CAE n=14 n= % *p=0.375 AC N=534 N=534 n=18 n= % *p=0.25 ADRs patients CLA n=8 n=8 1.5% *Fisher s exact test vs CLA (2-sided)

27 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%

28 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

29 Microbiological Efficacy Eradication of GABHS 2-4 days after end of treatment CLA CA 17.4% 7.1% n=506 n= % 92.9% *p<0.001 CAE 10.1% n= % *p< % negative culture positive culture *Fisher s exakt test vs CLA (2-sided)

30 Ab hier backup folien werden als Dias nicht benötigt

31 Clinical Efficacy Population Patients CLA AC CAE eligible for treatment evaluable for clinical efficacy,2-4 days post therapy evaluable for clinical efficacy,7-9 days post therapy

32 Safety Analysis Population Patients CLA AC CAE eligible for treatment evaluable for safety analysis