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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 Azithromycin for Acute Otitis Media Rationale 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
Azithromycin for Acute Otitis Media Rationale 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 Azithromycin for Acute Otitis Media Rationale 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 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 Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics
Microbiology
Clinical Data
Conclusion Azithromycin: The First Azalide Antibiotic H3C H3
C H3
C H3C H3
C N HO HO HO O O O O O O N O CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 CH3 OH OH Azithromycin Azithromycin Uptake by White Blood Cells Acute Otitis Media Histopathology S. Giebink, M.D., FDA AC presentation, November 1997 Azithromycin Serum and Middle Ear Fluid Levels in Children *Cells / middle ear fluid Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics
Microbiology
Clinical Data
Conclusion Azithromycin: In Vitro Activity Hoban. CID 2001 Azithromycin: In Vitro Activity aHoban, CID 2001; bShortridge, CID 1999; cMontanari, J Clin Microbiol 2001; dJones, Diagn Microbiol Infec Dis 2000 Antimicrobial Resistance to S. pneumoniae According to Penicillin Susceptibility, 1998 Whitney. NEJM 2000 Antimicrobial Susceptibility of S. pneumoniae by Age Group Thornsberry AAC 1999 % Susceptible Susceptibility of S. pneumoniae to Macrolides and Penicillin in the U.S. From Surveillance Studies Year % Resistant Azithromycin Bactericidal Activity Against Streptococcus pneumoniae* Time (hours) Log10 CFU/ml *MIC =0.06 g/ml Azithromycin Bactericidal Activity Against Haemophilus influenzae* Time (hours) Log10 CFU/ml *MIC =0.78 g/ml Azithromycin Chinchilla 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 Babl. 40th ICAAC 2000 Azithromycin Chinchilla Middle Ear Fluid Concentrations Azithromycin Therapy Total MEF = frozen/thawed middle ear fluid Azithromycin (mg/ml) Day Azithromycin Chinchilla Model of AOM due to H. influenzae * Sterile ears with <10CFU Azithromycin therapy MEDIAN CFU FOR NTHI BY TREATMENT GROUP Babl. 40th ICAAC 2000 Log scale CFU Day Azithromycin Chinchilla Model of AOM due to H. influenzae Babl. 40th ICAAC 2000 Day Percent Culture Positive 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 Azithromycin 5 Day Program Clinical Outcome at Day 30* 128 176 134 Study 27/35 (77%) 36/45 (80%) Cure -- 75/122 (61%) Cure 168/257 (65%) 181/264 (69%) Cure Amox/Clav Azithromycin Outcome Per Protocol *Medical officers assessment; no ITT analysis done Azithromycin 5 Day Program Clinical Success by Baseline Pathogen at Day 30 Azithromycin 5 Day Program Treatment Related Adverse Events* Amox/Clav Azithromycin (2.3) 19 (1.4) 14 Abdominal Pain (4.1) 34 (1.7) 17 Vomiting (12.6) 104 (1.7) 17 Diarrhea No. with Common Adverse Events (23.0) 190 (7.2) 70 No. Patients with Treatment-Related AEs 827 975 No. Patients (%) N (%) N *Protocols 128,134,178,322,334,337; Amox/Clav comparative studies 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 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
1998 FDA Guidance Acute 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 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 Single Dose Program Phase 2 Study 95-001
Phase 3 Study R-0581 Study 1015 Single Dose Program Inclusion 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) Single Dose Program Inclusion 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 Single Dose Program Key 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 Single Dose Program Statistical Methods Primary Endpoint: Clinical Cure
Primary Timepoint (Test of Cure): Day 28
Cure
Failure
Improvement (R-0581 and 95-001)
Single Dose Program Statistical 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 Single Dose Program Definition of Cure Study 95-001
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
Study 95-001 Experimental Design *Baseline tympanocentesis Study 95-001 Patient Disposition Study 95-001 Demographics 0% 2% Black 98% 97% White Race: 48% 56% % Male 2.3 (+ 1.4) 2.5 (+ 1.3) Mean Age (Yrs, ±SD) 31 (47%) 40 (61%) 2 Yrs - 12 Yrs 35 (53%) 26 (39%) < 2 Yrs Age: N = 66
Single Dose
N = 66 Azithromycin 2% 95% 55% 2.7 (+ 1.5) 40 (61%) 26 (39%) Three Day
N = 66 Ceftriaxone 2% 2% Hispanic 3% Study 95-001 Results Study 95-001 Clinical Efficacy Population 4 (6) Failure 5 Improvement [- 5, 25] 56 (86) Cure [-12,6] 61 (94) Success 65 Day 28 2 (3) Failure 36 Improvement 26 Cure [-8,5] 62 (97) Success 64 Day 14 66 Randomized Patients 95% CI1 [%]
1 Day (%) 1 95% CI for (single dose azithromycin – comparator) 5 (8) 10 51 (77) 61 (92) 66 3 (5) 42 18 60 (95) 63 66
3 Day (%) 2 (3) 13 49 (77) 62 (97) 64 1 (2) 40 21 61 (98) 62 66 Ceftriaxone
(%) Azithromycin Study 95-001 Clinical Outcome at Day 28 by Age 5 (16) 6 (15) 3 (8) Failure 26 (84) 33 (85) 37 (93) Cure 31 39 40 > 2 years of age 10 (30) 9 (33) 6 (24) Failure 23 (70) 18 (67) 19 (76) Cure 33 27 25 < 2 years of age Ceftriaxone (%)
3 Day (%)
1 Day (%) Azithromycin 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 Study 95-001 Clinical Cure Per Baseline Pathogen at Day 28 Study 95-001 Treatment Related Adverse Events* 0 (0) 0 (0) 3 (5) Vomiting 4 (6) 0 (0) 1 (2) Rash 4 (6) 3 (5) 2 (3) Diarrhea 6 (9) 6 (9) 7 (11) Patients w/ AE 66 66 66 Patients Treated Ceftriaxone 3 Day 1 Day 0 (0) 0 (0) 0 (0) Discontinued *2 or more events on any treatment regimen Azithromycin Study R-0581 Single Dose Therapy
Study R-0581 Objective
Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM
Design
Multicenter, randomized
All sites in the United States
Double blind, double dummy
Azithromycin: 30 mg/kg single oral dose
Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days
Matching placebo for each active study drug Study R-0581 Visits and Assessments *Patients who vomited within 30 minutes were redosed
1 Including parental questionnaire Study R-0581 Patient Disposition Study R-0581 Demographics Study R-0581 Results Study R-0581 Clinical Outcome 38 (25) 37 (25) Failure 8 2 Improvement [-7, 15] 108 (70) 112 (74) Cure [-10, 11] 116 (75) 114 (75) Success 154 151 Day 28 19 (12) 21 (13) Failure 21 34 Improvement 121 105 Cure [-9, 7] 142 (88) 139 (87) Success 161 160 Day 14 173 173 Number of Patients 95% CI1[%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study R-0581 Clinical Outcome at Day 28 by Age Cure 26 (49) 24 (38) Failure [-8, 31] 95% CI1[%] Failure < 2 years of age 27 (51) 40 (63) Cure 53 64 > 2 years of age Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) N (%) N (%) 72 (83) 15 (17) 87 81 (80) 20 (20) 101 [-10, 15] Study R-0581 Compliance
Based on patients randomized to their study drug regimen Study R-0581 Treatment Related Adverse Events* 7 (4%) 7 (4%) Vomiting 9 (5%) 3 (2%) 22 (13%) 11 (6%) Diarrhea 39 (23%) 29 (17%) Patients w/ AEs Rash Azithromycin N = 173 Amox/Clav N = 173 7(4%) 4 (2%) Discontinued due to AE * Adverse Events greater than 2 percent in either regimen Study 1015 Single Dose Therapy Study 1015 Objectives
To assess per-pathogen clinical response rates
To provide additional data on the safety and toleration of the single dose regimen
Design
Prospective
Open-label
Non-comparative
Multi-center
Study 1015 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1015 Endpoints Primary Efficacy Endpoint
Clinical response by baseline pathogen at day 28
Initial local laboratory isolation of pathogen with confirmation by central laboratory
Secondary Efficacy Endpoints
Clinical response at day 28 (test of cure)
Clinical response at day 10
Safety Evaluation
Study 1015 Patient Disposition 242 Clinical at Day 28 127 Bacteriologic Efficacy Azithromycin 248 Safety 248 Enrolled Evaluation Groups Study 1015 Demographics Study 1015 Results Study 1015 Clinical Outcome 36 (15%) Failure [80,90] 206 (85%) Cure 242 Day 28 27 (11%) Failure 74 Improvement 139 Cure [85,93] 213 (89%) Success 240 Day 10 247 Number of Patients 95% CI1 [%] Azithromycin (%) 1 95% CI for azithromycin Study 1015 Clinical Outcome at Day 28 by Age 11 17 Failure [84, 94] 89 142 Cure 159 > 2 years of age 23 19 Failure [67, 87] 77 64 Cure 83 < 2 years of age 95% CI [%] (%) N Azithromycin Study 1015 Clinical Outcome - Per Baseline Pathogen Study 1015 MIC Distribution for S. pneumoniae (N=67) Percent of Patients Azithromycin MIC (mg/ml) Study 1015 Resistant S. Pneumoniae S. pneumoniae MIC = 8 g/ml
7 baseline isolates
All sensitive to clindamycin
All with mef A gene by PCR
S. pneumoniae MIC >256 g/ml
5 baseline isolates
All resistant to clindamycin
All with erm B gene by PCR Study 1015 Day 28 Outcome and MIC Distribution for S. pneumoniae (N=66) # of Patients Azithromycin MIC (mg/ml) Study 1015 Patient 0067 Failed Therapy 1Susceptible to clindamycin; mef A gene identified 2Resistant to clindamycin; erm B gene identified Study 1015 Strains From Patient 0067 Are Clonally Distinct
1 2 3 4 MIC = 8 MIC >256 Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility
*Penicillin MIC > 2 mg/ml
**Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Outcome of S. pneumoniae AOM by Penicillin Susceptibility Penicillin Susceptibility
*Penicillin MIC > 2 mg/ml
**Penicillin MIC > 0.125 - < 2 mg/ml Study 1015 Treatment Related Adverse Events*
(2) 4 Abdominal Pain (6) 14 Vomiting (3) 8 Diarrhea (12) 30 Patients w/ AEs (0) 1 Discontinued due to AEs 248 Patients Treated (%) N * Adverse Events greater than 1% Study 1014 Three Day Dosing Study 1014 Objectives
Provide comparative clinical efficacy data against an established agent commonly used for treatment of AOM
Design
Multicenter, randomized
All sites in the United States
Double blind, double dummy
Azithromycin: 10 mg/kg/day for 3 days
Amoxicillin/clavulanate: 45 mg/kg/day divided BID x 10 days
Matching placebo for each active study drug
Study 1014 Inclusion Criteria: Symptoms Symptoms consistent with AOM (but nonspecific) 2 Symptoms which help confirm the diagnosis of AOM (%) Age 261 X Fever 1 Children had one or more of these signs and symptoms
2 Other (vomiting, diarrhea, inconsolability, anorexia, sleep disturbance) X Irritability 251 X Decreased hearing 601 X Ear fullness 921 X Ear pain (tugging or rubbing) 0.5-11yrs X >6 months 1014 1998 FDA Guidance Either Ear pain or fullness 97 Study 1014 Inclusion Criteria: Signs of Tympanic Membrane Involvement 1 Any one of these findings
2 Associated with discoloration/opacification (edema) of TM and/or ear fluid level Study 1014 Key Exclusion Criteria Other exclusions include: significant GI conditions affecting absorption, on investigational drug, other serious ear conditions, inability to take oral medication, infection at another location, neutropenia, immunosuppressant therapy, cystic fibrosis, retraction pockets, cholesteatoma, phenylketonuria, anticipated use of probenecid or allopurinol Study 1014 Visits and Assessments *Patients who vomited within 30 minutes were redosed Study 1014 Statistical Methods Primary Endpoint: Clinical Cure
Primary Timepoint: Day 28
Cure
Failure Study 1014 Statistical 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 Study 1014 Definition of Cure Study 1014 Patient Disposition Study 1014 Demographics Study 1014 Results Study 1014 Clinical Outcome 56 (31) 48 (26) Failure [-5, 15] 124 (69) 134 (74) Cure 180 182 Day 28 22 (12) 32 (17) Failure 45 53 Improvement 114 100 Cure [-13,3] 159 (88) 153 (83) Success 181 185 Day 10 185 188 Number of Patients 95% CI1 [%] Amox/Clav (%) Azithromycin (%) 1 95% CI for (azithromycin – comparator) Study 1014 Clinical Outcome at Day 28 by Age [-5, 18] (73) 94 (80) 99 Cure 128 124 > 2 years of age [-18, 23] (58) 30 (60) 35 Cure 52 58 < 2 years of age (%) N (%) N Amox/Clav Azithromycin 1 95% CI for (azithromycin – comparator) Failure Failure (27) 34 (20) 25 (42) 22 (40) 23 95% CI1 [%] Study 1014 Compliance Based on patients randomized to their study drug regimen Study 1014 Treatment Related Adverse Events* (15) (20) Azithromycin Amox/Clav Patients Treated Discontinued due to AE Patients with AE Diarrhea Vomiting Rash 1 20 11 4 0 2 37 27 2 8 N N (1) (11) (6) (2) (0) (4) (1) (1) % % 188 185 * Adverse events greater than 2% in either treatment regimen Summary of Clinical Data Acute Otitis Media Summary Clinical Cure at Day 28 [-5, 25]
[-15, 17] 49/64 (77%)
56/65 (86%) 51/66 (77%) 95-001 AzSD-CTX Az3D-CTX [-5, 15] 124/180 (69%) 134/182 (74%) 1014
Az-Amox/Clav 206/242 (85%) 1015 [-7, 15] 108/154 (70%) 112/151 (74%) R-0581 Az-Amox/Clav 95% CI Comparator Azithromycin Single Dose Azithromycin 3 Day Study Effect of Age on Clinical Outcome < 2 years of age *Clinical success; **Clinical cure; 1Single dose regimen Summary of Clinical Trials Clinical Cure by Baseline Pathogen at Day 28 Treatment Related Adverse Events Azithromycin Regimens for AOM Vs. Comparator* 13 (1%) 1 (<1%) 7 (1%) Abdominal pain 11 (1%) 4 (2%) 24 (5%) Vomiting 31 (3%) 14 (6%) 21 (4%) Diarrhea Patients with common AE’s: 69 (8%) 26 (10%) 66 (14%) Patients with Related Adverse Events 888 254 487 Number of Patients 5 3 1 Azithromycin Duration (Days) Comparator 23 (2%) 41 (4%) 171 (16%) 254 (23%) 1105 *Pivotal studies from 1, 3 and 5 day programs; All AE’s > 2 % 5 (1%) 0 (0%) 6 (1%) Nausea 18 (2%) 6 (1%) 0 (0%) 4 (1%) Rash 27 (2%) 254 (23%) Treatment Related Adverse Events Azithromycin Regimens for AOM Vs. Comparator* 69 (8%) 26 (10%) 66 (14%) Patients with Related Adverse Events 888 254 487 Number of Patients 5 3 1 Azithromycin Duration (Days) Comparator 1105 *Pivotal studies from 1, 3 and 5 day programs 6.7 7.4 9.8 22.7 Related Adverse Events/Patient Year 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 Focus on Selected Topics Vomiting of the single dose therapy
Historical comparison of cure rates at day 28
Timing of the clinical assessment The Influence of Vomiting on Outcome of Single Dose Therapy Patients Who Vomited Single Dose Therapy Clinical Outcome for Children Who Vomited on Day 1 2 2 Missing 79 (19%) 5 (15%) 3 (9%) Fail 345 (81%) 29 (85%) 31 (91%) Cure/Improved No Vomiting Day 28 Day 14 Vomited Vomited No Vomiting 47 (11%) 383 (89%) Azithromycin AUC Values Following 2g and 3g Single Doses Historical Comparison of Cure Rates at Test of Cure Visit (Day 28) Clinical response vs beta-lactams
Empiric treatment
S. pneumoniae at baseline
H. influenzae at baseline Azithromycin Vs Beta-lactams Comparative Trials for AOM: Clinical Cure at Day 28 Favors Comparator Favors Azithromycin % Difference (95% CI) Azithromycin vs Amox/Clav (N=1864) Rodriquez, 1996 (Cefaclor) Pestalozza, 1992 (Amox/Clav) Pfizer, 134 (Amox/Clav) Pfizer, 128 (Amox/Clav) Dagan, 2000 (Amox/Clav) Pfizer, 178 (Amox/Clav) All Studies ( N=2127) Pfizer, 1014 (Amox/Clav) Pfizer, R-0581 (Amox/Clav) Azithromycin 5 Day Azithromycin 3 Day Azithromycin 1 Day Overall Pfizer, 95-001 (Ceftriaxone) Pfizer, 95-001 (Ceftriaxone) S. pneumoniae Clinical Outcome Test of Cure Visit (Day 17-35)* % Successful Clinical Outcome, (95% CI) Cefdinir 5 Day Amox/Clav (Augmentin ES) Azithromycin – 5 Day Azithromycin – 1 Day* Azithromycin – 3 Day* Ceftriaxone Cefpodoxime proxetil Cefprozil Clinical Cure Clinical Success Cefdinir 10 Day *Product labels (PDR, 2001);
Summary basis of approval;
Sponsor study report H. influenzae Clinical Outcome Test of Cure Visit (Day 17-35)* % Successful Clinical Outcome (95% CI) Cefixime Amox/Clav (Augmentin ES) Ceftriaxone Cefpodoxime proxetil Azithromycin 3 Day Azithromycin 5 Day Azithromycin Single Dose Cefprozil Cefdinir 5 Day Clinical Success Clinical Cure *Product labels (PDR, 2001);
Summary basis of approval;
Sponsor study report Cefdinir 10 Day Timing of Clinical Assessment Early (on therapy) time points
Additional antibiotic
Analgesics use
Parental questionnaire
Day 10-14
Overall clinical response vs beta-lactams
Clinical outcome with H. influenzae at baseline Time to Additional Antibiotic Use Azithromycin studies R-0581, 95-001, 1014
Comparators combine amoxicillin/clavulanate and ceftriaxone
Time to failure = time to concomitant antibiotic use for failure Proportion without
Additional Antibiotic Day of First Antibiotic Use Percent Patients on Analgesics/Antipyretics By Study Day – R-0581 Days Percentage Percent Patients on Analgesics/Antipyretics By Study Day – 1014 Percentage Days Study R-0581 Parental Questionnaire How Sick Overall Has Child Been? Extremely Not at all Moderately Timing of Clinical Assessment Early time points
Day 10-14
Overall clinical response vs beta-lactams
Clinical outcome with H. influenzae at baseline Azithromycin Vs Beta-lactams Comparative Trials for AOM: Clinical Success at Day 14 Favors Comparator Favors Azithromycin % Difference (95% CI) Azithromycin 5 Day Azithromycin vs Amox/Clav (N=3271) All Studies (N=3956) Rodriguez, 1996 (Cefaclor) Dagan, 2000 (Cefaclor) Mohs, 1993 (Amoxicillin) Arguedas, 1996 (Amox/Clav) Pfizer, 178 (Amox/Clav) Pfizer, 134 (Amox/Clav) Daniel, 1993 (Amox/Clav) Principi, 1995 (Amox/Clav) Schaad 1993 (Amox/Clav) Pfizer, 128 (Amox/Clav) Dagan, 2000 (Amox/Clav) Pestalozza, 1992 (Amox/Clav) Pfizer, 1014 (Amox/Clav) Pfizer, R-0581 (Amox/Clav) Azithromycin 3 Day Azithromycin 1 Day Overall Pfizer, 95-001 (Ceftriaxone) Pfizer, 95-001 (Ceftriaxone) Timing of Clinical Assessment Early time points
Day 10-14
Overall clinical response vs beta-lactams
Clinical outcome with H. influenzae at baseline H. influenzae Clinical Outcome End of Therapy (Day 7-15)* % Clinical Success (95% CI) Azithromycin 1 Day Overall Erythromycin + sulfa Cefaclor Ceftibuten Clarithromycin Erythromycin Cefuroxime axetil Azithromycin 3 Day Clinical Success Cefpodoxime proxetil Ceftriaxone (Per Protocol) Amox/Clav (Per Protocol) Cefixime Amox/Clav (ITT) Azithromycin 5 Day Loracarbef Clinical Cure *Product labels (PDR, 2001);
Summary basis of approval;
Sponsor study report Azithromycin for Acute Otitis Media Chemistry/Pharmacokinetics
Microbiology
Clinical Data
Conclusion Conclusions Azithromycin for Acute Otitis Media Effective, empiric treatment of acute otitis media
As a single dose or over three days
Well tolerated, safe antibiotic
Optimizes compliance
Complete course of therapy in single dose
Eases burden on the caregiver
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