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Treatment of Acute Otitis Media With Azithromycin

Treatment of Acute Otitis Media With Azithromycin. Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development. Azithromycin for Acute Otitis Media Rationale. Bactericidal against the pathogens responsible for AOM.

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Treatment of Acute Otitis Media With Azithromycin

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  1. Treatment of Acute Otitis Media With Azithromycin Michael Dunne, MD Vice President Clinical Development, Infectious Diseases Pfizer Global Research and Development

  2. Azithromycin for Acute Otitis MediaRationale • Bactericidal against the pathogens responsible for AOM

  3. Azithromycin for Acute Otitis MediaRationale • Bactericidal against the pathogens responsible for AOM • Pharmacokinetic profile suited for treatment of infection • Reaches effective concentrations in middle ear • Sustained concentrations in white blood cells • Complete course of therapy in single dose • Optimizes compliance

  4. Azithromycin for Acute Otitis MediaRationale • Bactericidal against the pathogens responsible for AOM • Pharmacokinetic profile suited for treatment of infection • Reaches effective concentrations in middle ear • Sustained concentrations in white blood cells • Complete course of therapy in single dose • Optimizes compliance • Well tolerated, safe antibiotic • Recommended in penicillin allergic patients • Over 40 million prescriptions for oral suspension

  5. Azithromycin for Acute Otitis MediaRationale • Bactericidal against the pathogens responsible for AOM • Pharmacokinetic profile suited for treatment of infection • Reaches effective concentrations in middle ear • Sustained concentrations in white blood cells • Complete course of therapy in single dose • Optimizes compliance • Well tolerated, safe antibiotic • Recommended in penicillin allergic patients • Over 40 million prescriptions for oral suspension • Clinical efficacy equivalent to approved therapies • Originally established in five day regimen • Extended to shorter regimens of three day and single dosing

  6. Advantages of Single Dose Azithromycin • Provides best drug levels early in course of infection • Takes advantage of important host defenses • Maximal neutrophil recruitment optimizes azithromycin delivery • Febrile response increases azithromycin uptake1 • Maximizes rate of compliance • Minimizes burden on caregiver 1Fietta, et al., J.Chemotherapy 1997

  7. Azithromycin for Acute Otitis Media • Chemistry/Pharmacokinetics • Microbiology • Clinical Data • Conclusion

  8. H3C CH3 CH3 N HO H3C N OH H3 C CH3 HO CH3 O O CH3 HO O H3 C CH3 O O OH CH3 CH3 O CH3 H3 C O Azithromycin Azithromycin: The First Azalide Antibiotic

  9. Acid Vesicle pH 5.0 A A A AH+ AH+ AH+ Extracellular Blood, pH 7.4 Cytoplasm pH 7.2 AzithromycinUptake by White Blood Cells

  10. Acute Otitis MediaHistopathology S. Giebink, M.D., FDA AC presentation, November 1997

  11. AzithromycinSerum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid

  12. Azithromycin for Acute Otitis Media • Chemistry/Pharmacokinetics • Microbiology • Clinical Data • Conclusion

  13. Azithromycin: In Vitro Activity Hoban. CID 2001

  14. Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000

  15. Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000

  16. Antimicrobial Susceptibility of S. pneumoniaeby Age Group % Susceptible Thornsberry AAC 1999

  17. Susceptibility of S. pneumoniae to Macrolidesand Penicillin in the U.S. From Surveillance Studies % Resistant Year

  18. AzithromycinBactericidal Activity Against Streptococcus pneumoniae* Log10 CFU/ml Time (hours) *MIC =0.06 g/ml

  19. AzithromycinBactericidal Activity Against Haemophilus influenzae* Log10 CFU/ml Time (hours) *MIC =0.78 g/ml

  20. AzithromycinChinchilla Model of AOM due to H. influenzae Day -2 to -4: Inoculate 10-100 CFU in 0.1 ml GBBS Day 0: Otomicroscopic exam of TM and tympanometry Culture middle ear fluid (MEF) Initiate therapy via orogastric feeding tube Day 3: Otomicroscopic exam and tympanometry Culture and collect MEF and serum Continue therapy Day 5: Otomicroscopic exam and tympanometry Culture and collect MEF Complete therapy Day 7-10: Repeat exams; Culture and collect MEF Babl. 40th ICAAC 2000

  21. AzithromycinChinchilla Middle Ear Fluid Concentrations Azithromycin (mg/ml) Azithromycin Therapy Day Total MEF = frozen/thawed middle ear fluid Babl. 40th ICAAC 2000

  22. AzithromycinChinchilla Model of AOM due to H. influenzae MEDIAN CFU FOR NTHI BY TREATMENT GROUP Log scale CFU Day * Sterile ears with <10CFU Azithromycin therapy Babl. 40th ICAAC 2000

  23. AzithromycinChinchilla Model of AOM due to H. influenzae Percent Culture Positive Day Babl. 40th ICAAC 2000

  24. Azithromycin for Acute Otitis Media • Chemistry/Pharmacokinetics • Microbiology • Clinical Program • Overview of Five Day Program • Single Dose • Three Day Dosing • Focus on Selected Topics • Conclusion

  25. Azithromycin 5 Day ProgramClinical Outcome at Day 30* Per Protocol Study Outcome Azithromycin Amox/Clav Cure 181/264 (69%) 168/257 (65%) 134 176 Cure 75/122 (61%) -- Cure 36/45 (80%) 27/35 (77%) 128 *Medical officers assessment; no ITT analysis done

  26. Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30

  27. Azithromycin 5 Day Program Treatment Related Adverse Events* Azithromycin Amox/Clav N (%) N (%) No. Patients 975 827 No. Patients with Treatment-Related AEs 70 (7.2) 190 (23.0) No. with Common Adverse Events Diarrhea 17 (1.7) 104 (12.6) Vomiting 17 (1.7) 34 (4.1) Abdominal Pain 14 (1.4) 19 (2.3) *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies

  28. Azithromycin for Acute Otitis Media • Chemistry/Pharmacokinetics • Microbiology • Clinical Program • Overview of Five Day Program • Single Dose • Three Day Dosing • Focus on Selected Topics • Conclusion

  29. Regimens Used in Azithromycin Clinical Program for Treatment of Acute Otitis Media • Five Day Dosing • 30 mg/kg: 10 mg/kg then 5,5,5,5 • Approved in United States in 1995 • Three Day Dosing • 30 mg/kg: 10 mg/kg qd X 3 • Approved in Europe in 1990 • Single Dose Therapy • 30 mg/kg: given as single dose

  30. 1998 FDA GuidanceAcute Otitis Media “Clinical-only” Trial • One “statistically adequate” and well-controlled trial establishing non-inferiority to approved product, double-blind, randomized • Test-of-Cure visit (2 - 4 weeks from initiation of therapy) Clinical/Microbiologic Trial • One open, non-comparative study utilizing tympanocentesis for pathogen identification & susceptibility to test drug • For the 3 pathogens to be “listed” in the clinical section of the label, must have “clinically acceptable”(i.e., comparable efficacy to labeled comparator drug) eradication rates

  31. Azithromycin Overview of Single Dose and Three Day Programs Pivotal Studies • Single dose program R-0581: double-blind, randomized, comparative clinical trial 1015: open, noncomparative, microbiology study • Three day dosing 1014: double-blind, randomized, comparative clinical trial Supportive Study 95-001: randomized comparative single center study • Baseline tympanocentesis performed • Compares three day dosing with single dose therapy with ceftriaxone

  32. Single Dose Program Phase 2 Study 95-001 Phase 3 Study R-0581 Study 1015

  33. Single Dose ProgramInclusion Criteria: Symptoms 1 Children had one or more of these signs and symptoms; in R-0581, 93% had either ear pain or fever 2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance)

  34. Single Dose ProgramInclusion Criteria: Signs of Tympanic Membrane Disease 1 Any one of these findings 2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level

  35. Single Dose ProgramKey Exclusion Criteria Other exclusions variably applied across studies include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, concurrent ergotamine or digitalis, weight > 40kg

  36. Single Dose ProgramStatistical Methods • Primary Endpoint: Clinical Cure • Primary Timepoint (Test of Cure): Day 28 • Cure • Failure • Improvement (R-0581 and 95-001)

  37. Single Dose ProgramStatistical Methods • Clinical Efficacy Population • At least one dose of study medication • Diagnosis of AOM at baseline • Analyzed at Day 28 • Return for visit at Day 28 • Concomitant antibiotic for failure counts as failure • Bacteriological Efficacy Population • Positive baseline culture for at least one relevant pathogen

  38. Single Dose Program Definition of Cure

  39. Study 95-001

  40. Study 95-001 Methods • Objectives • Pilot study to compare the safety and efficacy of single dose azithromycin, azithromycin dosing over 3 days and single dose ceftriaxone in children with acute otitis media • Design • Prospective • Single-center in Costa Rica • Performed in 1995-1997

  41. Study 95-001 Experimental Design *Baseline tympanocentesis

  42. Study 95-001Patient Disposition

  43. Study 95-001Demographics Azithromycin Ceftriaxone Single Dose N = 66 Three Day N = 66 N = 66 Age: < 2 Yrs 26 (39%) 26 (39%) 35 (53%) 2 Yrs - 12 Yrs 40 (61%) 40 (61%) 31 (47%) Mean Age (Yrs, ±SD) 2.5 (+ 1.3) 2.7 (+ 1.5) 2.3 (+ 1.4) % Male 56% 55% 48% Race: White 97% 95% 98% Black 2% 2% 0% Hispanic 2% 3% 2%

  44. Study 95-001Results

  45. Study 95-001 Clinical Efficacy Population 1 Day (%) Azithromycin 3 Day (%) Ceftriaxone (%) 95% CI1 [%] Randomized Patients 66 66 66 Day 14 64 63 62 Success 62 (97) 60 (95) 61 (98) [-8,5] Cure 26 18 21 Improvement 36 42 40 Failure 2 (3) 3 (5) 1 (2) Day 28 65 66 64 Success 61 (94) 61 (92) 62 (97) [-12,6] Cure 56 (86) 51 (77) 49 (77) [- 5, 25] Improvement 5 10 13 Failure 4 (6) 5 (8) 2 (3) 1 95% CI for (single dose azithromycin – comparator)

  46. Study 95-001 Clinical Outcome at Day 28 by Age 1 Day (%) 3 Day (%) Ceftriaxone (%) Azithromycin < 2 years of age 25 27 33 Cure 19 (76) 18 (67) 23 (70) Failure 6 (24) 9 (33) 10 (30) > 2 years of age 40 39 31 Cure 37 (93) 33 (85) 26 (84) Failure 3 (8) 6 (15) 5 (16)

  47. Study 95-001 Susceptibility • S. pneumoniae susceptibility (N=57) • Azithromycin • 46 susceptible • 11 resistant (MIC > 0.5 mg/ml) • Ceftriaxone • All isolates were susceptible to ceftriaxone • All H. influenzae and M. catarrhalis were susceptible to azithromycin and ceftriaxone

  48. Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28

  49. Study 95-001 Treatment Related Adverse Events* Azithromycin 1 Day 3 Day Ceftriaxone Patients Treated 66 66 66 Discontinued 0 (0) 0 (0) 0 (0) Patients w/ AE 7 (11) 6 (9) 6 (9) Diarrhea 2 (3) 3 (5) 4 (6) Rash 1 (2) 0 (0) 4 (6) 0 (0) Vomiting 3 (5) 0 (0) *2 or more events on any treatment regimen

  50. Study R-0581 Single Dose Therapy

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