AbstractBackground–Antibiotic resistance is a well-recognisedglobal health problem which is mostly driven by antibiotic use that is not evidence based. Acute otitis media (AOM), an acute middle ear inflammation mostly found in children, has a high antibiotic prescribing rate, although only one third of AOM cases (severe AOM) will benefit from antibiotics. Therefore, an effective non-antibiotic treatment for AOMis needed. To date, studies on these alternatives(e.g.,decongestants, probiotics) for AOM have demonstrated insufficient evidence of efficacy. Due to the inflammatory nature of AOM, an anti-inflammatory agent, such as corticosteroids,could be a potential candidate. Although corticosteroids have been used for inflammatory and autoimmune diseases, their efficacy inAOM remains unknown.
Aim –To assess the effectiveness of syste miccorticosteroids as a monotherapy for mild AOM and as an addition to antibiotics for severe AOM.
Methods–We conducted four studies. The first study was a Cochrane systematic review where we identified, appraised, and synthesised available randomised clinical trials(RCTs) of systemic corticosteroids versus placebo for AOM in children. Our second study was a feasibility study surveying Indonesian physicians to understand their current management of children with AOMand their willingness to participate in our planned RCT. Following the feasibility survey study, we conducted our third study, a pilot pragmatic, randomised, single-blind, controlled study. This pilot study also included a mechanistic sub-study using tympanometry. The study tested the feasibility of all pre-specified procedures and measures of the planned large trial, as well as assessing the effects of oral corticosteroids in improving the middle ear effusion (MEE) in AOM and the correlation between ear pain and other symptom resolution and MEE. Our last study was the finalisation of the protocol for the full-sized RCT based on the results from the pilot study.
Results–Our first study, a Cochrane review,demonstrated insufficient evidence for both efficacy and harm for corticosteroids in AOM thus justifying our decision to design a large,high-quality RCT.
To inform the design of the RCT, we conducted our second study, a feasibility survey study. This confirmed it was feasible to conduct the main RCT in Indonesia by identifying there were sufficient numbers of paediatric AOM cases and physicians who would be willing to: (1) withhold antibiotics and choose observation for mild AOM; (2) prescribe corticosteroids; and (3)participate in our RCT.
Our third study, a pilot study(62 children were recruited, 60 were analysed), demonstrated that it was feasible to successfully implement all pre-specified procedures and measures, and verified we needed fewer children for the main RCT than initially envisaged. We found oral corticosteroids may potentially reduce pain intensity measured using a 100-mm Visual Analogue Scale at Day 3 (mean difference [MD] -7.37, 95% CI -13.36 to -1.39,P = 0.017), but cause more drowsiness than placebo (relative risk [RR] 1.77, 95% CI 1.11 to 2.81, P = 0.016; number needed to harm (NNTH) 3). No excess of other adverse events (e.g., nausea, vomiting, diarrhea) was attributed to oral corticosteroid use and there were no serious adverse events. Oral corticosteroids may also improve tympanometry curves at Day 7 (RR 1.76, 95% CI1.04 to 2.97; P = 0.047; number needed to treat to benefit (NNTB) 3), but with only a small correlation between pain and other AOM-relevant symptoms and MEE.
The findings and feedback from these studies helped us to improve and finalise our fourth study,which is the protocol for a full-scale pragmatic, parallel, randomised double-blind, placebo-controlled study.
Conclusions– Our Cochrane review demonstrated there was insufficient evidence about the effects of systemic corticosteroids for AOM and therefore, the need for a large high-quality RCT. Our feasibility survey and pilot study also confirmed it was feasible and important to conduct a pragmatic, parallel, randomised, double-blind, placebo-controlled study, to be able to provided efinitive conclusions about the effectiveness and harm of oral corticosteroids for children with AOM. If this study demonstrates positive results, physicians would be able to withhold antibiotics and prescribe oral corticosteroids as a monotherapy for mild AOM and prescribe corticosteroids in addition to antibiotics for severe AOM. Long term or second-line antibiotics would not be required. The consequent reduction in antibiotic use would lead to fewer adverse events and reduced antibiotic resistance.
|Date of Award
|11 Jun 2020
|Christopher Del Mar (Supervisor), Elaine Beller (Supervisor) & Amanda McCullough (Supervisor)