1 Pfizer Global Research & Development, 50 Pequot Ave. MS 6025-C2173, New London, CT 06320; 2 Ark-La-Tex Childrens Clinic, Bossier City, LA; 3 Central Kentucky Research Associates, Inc. and Pediatric Adolescent Associates, Lexington, KY; 4 Willis Knighton Portico Pediatrics, Shreveport, LA; 5 R/D Clinical Research, Inc. and Brazosport Pediatric Clinic, Lake Jackson, TX; 6 Hill Top Research, Inc. and Pediatric Associates of Dallas, Dallas, TX; 7 Radiant Research, Inc., Scottsdale, AZ; 8 Little Rock Childrens Clinic, Little Rock, AR; 9 Hill Top Research, Inc., Fresno, CA and Peachwood Medical Group, Clovis CA; 10 Hill Top Research, Bridgeton, MO; 11 Advanced Clinical Research, Salt Lake City, UT and Jordan Valley Family Health, West Jordan, UT; 12 Skila, Inc., Mahwah, NJ, USA
Received 7 March 2003; returned 27 April 2003; revised 30 May 2003; accepted 4 June 2003
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Abstract |
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Methods: Children of 6 months12 years were enrolled if they had had symptoms and signs of AOM for <4 weeks and tympanic membrane effusion by acoustic reflectometry. Eligible children were randomized to azithromycin 10 mg/kg/day x 3 days or co-amoxiclav 45 mg/kg/day x 10 days. The primary endpoint was clinical response at day 28.
Results: One hundred and eighty-eight children (mean age 3.5 years) were randomized to azithromycin and 185 to co-amoxiclav. At day 10, the clinical success rate was 153/185 (83%) in children treated with azithromycin and 159/181 (88%) in children treated with co-amoxiclav. At day 28, 134/182 (74%) of the children were cured on azithromycin compared with 124/180 (69%) on co-amoxiclav. Also at day 28, signs of AOM, such as abnormal reflectometry (45% versus 59%; P = 0.017), bulging of the eardrum (10% versus 16%; P = 0.059) and loss of tympanic membrane landmarks (11% versus 22%; P = 0.010) were seen less frequently in azithromycin- than co-amoxiclav-treated children, respectively. Adverse events related to therapy were seen in 11% of azithromycin patients compared with 20% on co-amoxiclav (P = 0.014).
Conclusions: Azithromycin given over 3 days is as effective as co-amoxiclav for treatment of AOM, may result in more complete resolution of tympanic membrane disease, and is better tolerated.
Keywords: tympanic membrane disease, children, AOM
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Introduction |
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Azithromycin has been provided as a 3 day regimen for upper respiratory tract infections in Europe for a number of years, but studies have not been performed with this regimen in the USA. As differences in both the microbiological flora and treatment practice may impact on the potential utility of any therapeutic regimen, we undertook a trial in children with AOM to compare a 3 day regimen of azithromycin with 10 days of co-amoxiclav.
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Methods |
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This trial was a randomized, double-blind study conducted at 28 sites in the USA. Children of 6 months12 years were eligible for enrolment if they demonstrated typical signs and symptoms of AOM. Symptoms necessary for enrolment included ear pain or fullness, discharge from the external auditory canal, decreased hearing or fever. In addition to symptoms of AOM, on physical examination they must have had one or more of the following: bulging or marked erythema of the tympanic membrane, loss of the normal light reflex or tympanic membrane landmarks, or impaired tympanic mobility on biphasic pneumatic otoscopy. The effusion was also to be documented by acoustic reflectometry (Ear Check PRO, Becton Dickinson, Franklin Lakes, NJ, USA) with an acoustic spectral gradient angle of less than 70° (i.e. level 3, 4 or 5).4 The majority of primary investigators (23/28) were general paediatricians experienced in the physical diagnosis of otitis media and the use of the acoustic reflectometer. Patients were excluded if they had a history of hypersensitivity to ß-lactams, macrolides or azithromycin, were phenylketonuric, had been treated with antibiotics in the prior 30 days, had had symptoms of otitis media for >4 weeks or had been receiving antimicrobial prophylaxis.
The institutional review board of each participating centre reviewed and approved the final protocol and the informed consent documentation. After written informed consent was obtained from the parent or guardian, patients underwent a history and physical examination including pneumatic otoscopy and acoustic reflectometry. Patients then received two suspension formulations containing either azithromycin 10 mg/kg once daily for 3 days and a matching co-amoxiclav placebo suspension, or co-amoxiclav 45 mg/kg/day in divided doses twice daily for 10 days and a matching azithromycin placebo suspension. Assignment to drug was performed from a computer-generated randomization list in which the two drugs were allocated randomly in a 1:1 ratio.
On day 5, patients were contacted by phone for an assessment of adverse events, concomitant medications, and compliance with study drug therapy. A clinical assessment was not obtained at that time. At day 10 and at days 2428, assessments made at the baseline visit were repeated, in addition to an assessment of response to therapy. Definitions included: clinical cure (complete resolution of all signs and symptoms of AOM); improvement (partial resolution of signs and symptoms); or failure (no change or worsening of signs and symptoms, or requirement for additional antibiotic therapy for AOM). Based on guidance from the FDA, the primary endpoint was clinical outcome at day 28. Compliance with study treatment was assessed by measuring the amount of unused study drug returned to the investigator.
Statistical analyses
The study was powered to demonstrate equivalence between the cure rates of the two treatment groups, requiring that the two-sided 95% CI of the difference between the success rates be contained within ±15%. Assuming 10%15% of patients are non-evaluable, 320 subjects were required to meet these criteria. The efficacy analysis was carried out based on a modified intent-to-treat population that included all subjects who had at least one dose of study medication and a diagnosis of AOM. An assessment of failure at the end-of-therapy visit (day 10) was carried forward to the test-of-cure visit (days 2428). The primary measure of efficacy was the investigator assessment of the clinical outcome at the visits on days 2428. The normal approximation to the binomial distribution was used in computing the 95% CIs. P values were calculated using Fishers Exact Test. A KaplanMeier plot was constructed to assess time to additional antibiotic use.
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Results |
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Discussion |
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The totality of the data suggests some differentiating characteristics between the two therapies. While the overall assessment of clinical efficacy was equivalent at each observation point, treatment with co-amoxiclav may have led to a quicker resolution of disease of the tympanic membrane, such as bulging and loss of landmarks, although the most objective measurements, the acoustic reflectometry assessments, appear similar at day 10. Between day 10 and days 2428, however, based on both otoscopic and acoustic reflectometry measurements, there appeared to be an improvement in the status of the tympanic membrane in the children treated with azithromycin not seen in the children treated with co-amoxiclav.
Whereas these findings simply may have appeared by chance and were only secondary endpoints, it is worth considering the possibility that the different mechanisms of bacterial killing may have resulted in a different post-treatment inflammatory response. Recent in vitro investigations have concluded that release of inflammatory mediators after killing of Streptococus pneumoniae with a ß-lactam led to a more significant cytokine response than killing with a protein synthesis inhibitor.911 The post-treatment inflammatory sequelae of AOM, specifically the resolution of tympanic membrane effusion, is possibily related to the method of bacterial killing. If so, there may be significant public health benefits in reducing the likelihood of otitis media with effusion observed at follow-up visits, as the inappropriate use of antibiotics for this condition is one of the primary causes of repeat courses of antibiotic treatment and, hence, a driving force for the emergence of antimicrobial resistance.12
There are limitations to these data. In this trial, a tympanocentesis was not required at baseline. As a consequence it is not possible to associate a response to treatment with a bacterial aetiology of infection. The double-blind nature of this trial, however, allowed for a statistically valid comparison of the two treatment groups based on clinical grounds. In addition, while co-amoxiclav 45 mg/kg/day was the preferred dosing regimen at the time this study was performed, infection due to more resistant S. pneumoniae may no longer be clinically responsive to these exposures of amoxicillin. As the susceptibly profile of offending pathogens changes, new studies will be required to establish clinical effectiveness. The data from this study, however, establish a benchmark of clinical parity against which future studies may be compared.
In conclusion, azithromycin given over 3 days is as effective as co-amoxiclav for treatment of AOM, may result in more complete resolution of tympanic membrane disease, and is better tolerated.
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Acknowledgements |
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Footnotes |
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References |
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