10th March 2011
Two recent RCTs showed that, when diagnosed according to stringent criteria, more children with acute otitis media recover more quickly with antibiotics than with placebo. Benefits are more likely in those who are systemically unwell or have more severe disease. However, the condition of many children taking placebo improves without antibiotics and more children taking antibiotics suffer adverse effects.
Healthcare professionals should continue to follow NICE guidance on prescribing of antibiotics for self-limiting respiratory tract infections in adults and children in primary care. The majority of adults and children over 3 months with acute otitis media (AOM), who are otherwise well, generally do not require antibiotics because it is a self-limiting illness and complications are likely to be rare if antibiotics are withheld. NICE advises that two antibiotic management strategies should be considered: delayed antibiotic prescribing, in which an antibiotic prescription is written for use at a later date if symptoms worsen; or no antibiotic prescribing.
NICE recommend that antibiotics are prescribed immediately, and/or further appropriate investigation and/or management should be offered if the patient is systemically very unwell, or is at high risk of serious complications because of pre-existing co-morbidity, or has symptoms and signs suggestive of serious illness and/or complications. In patients with AOM this includes those who have mastoiditis.
NICE also say that, depending on clinical assessment of severity, children can also be considered for immediate antibiotics if they have bilateral AOM and are less than 2 years old, or if they have otorrhoea. However, a no antibiotic or delayed antibiotic strategy should also be considered and the decision should be made on an individual patient basis, depending on the clinical assessment of the severity of the child’s illness.
For all antibiotic prescribing strategies, patients should be given advice about the usual natural history of the illness, including the average total length of the illness (four days for AOM), and advice about managing symptoms, including fever (particularly analgesics and antipyretics).
What is the background to this?
Many guidelines for the management of AOM, including the NICE guideline, recommend a watchful waiting strategy, rather than immediate antibiotics, based on the results of clinical trials that showed relatively high rates of spontaneous improvement in children with AOM. However, it is argued that such trials had limitations, for example, a lack of stringent diagnostic criteria, the inclusion of very few young children, and the use of an antibiotic with limited efficacy or that was administered in suboptimal doses. Two RCTs in Pittsburgh (US) and Turku (Finland) aimed to address these concerns by carrying out studies in the age group at greatest risk and assessing the efficacy of co-amoxiclav vs. placebo in young children diagnosed with AOM according to specified criteria.
What do these studies claim?
The Pittsburgh study found that, among children aged 6 to 23 months with AOM diagnosed according to stringent criteria, treatment with co-amoxiclav for 10 days reduced the time to resolution of symptoms and reduced the overall symptom burden and the rate of persistent signs of acute infection on otoscopic examination, compared with placebo.
Seventeen children needed to be treated with co-amoxiclav, compared with placebo for one to have sustained resolution of symptoms at day 2. This NNT was reduced to 7 for resolution of symptoms with antibiotics at day 7. Five children needed to be treated with co-amoxiclav for one fewer to suffer clinical failure (defined as the persistence of signs of acute infection on otoscopic examination) at or before the visit on day 4 to 5. This NNT was reduced to 3 at day 10 to 12. Mastoiditis developed in one child who received placebo. Diarrhoea (NNH 10) and nappy-area dermatitis (NNH 6) were more common among children who received co-amoxiclav.
The Turku study found that children aged 6 to 35 months diagnosed with AOM according to stringent criteria benefited from co-amoxiclav treatment for 7 days, compared with placebo, although they had more side effects. Four children needed to be treated with co-amoxiclav for one fewer to suffer clinical failure at day 8. However, five children needed to be treated with co-amoxiclav, compared with placebo, for one to suffer diarrhoea.
How does this relate to other studies?
The numbers needed to treat in these studies, which were undertaken in young children with AOM diagnosed according to strict criteria, appear more impressive than those seen in a Cochrane review (10 RCTs, n=2,928), which included a much broader population of children with AOM. (See Table 1) However, it is difficult to compare the results directly because of the different populations and antibiotic regimens, and the different outcomes considered.
Table 1: NNTs and NNHs for selected results
|NNT for resolution of symptoms||NNT to prevent clinical failure||NNH for adverse effects|
|Pittsburgh6 to 23 months||17 at day 2||7 at day 7||5 at day 4 to 5||3 at day 10 to 12||10 for diarrhoea 6 for dermatitis|
|Turku6 to 35 months||4 for condition improved at day 8||4 at day 8||5 for diarrhoea|
|Cochrane1 month to 15 years||16 for pain relief at day 2 to 7||Data unavailable||23 for diarrhoea, vomiting and rash|
The Cochrane Review found that two thirds of children had no pain 24 hours after treatment started, irrespective of whether they received antibiotics or placebo, and 78% of children receiving placebo had spontaneously recovered from pain at two to seven days. Sixteen patients needed to be treated with antibiotics to gain pain relief in one extra patient at day 2 to 7, but antibiotics did not reduce pain at 24 hours, or reduce tympanometry, perforation or recurrence. Few serious complications occurred in either the antibiotic or placebo group, with only one child (who was treated with penicillin) developing mastoiditis. However, for every 23 patients treated with antibiotics, one extra will suffer harms such as diarrhoea vomiting or rash. Putting this in the context of 100 patients taken at random, around 6 extra will gain pain relief, and around 4 extra will suffer adverse effects, as a result of treatment. This is a fine balance.
Figure 1: Pain at 2–7 days in children with AOM
Sometimes it is helpful to look at a pictorial representation of the benefits and risks using visual representations such as the ones shown here produced using Visual Rx, which was developed by Dr Chris Cates and can be found at http://www.nntonline.net/. Figure 1 depicts the likely outcomes for a theoretical group of 100 patients, who are given antibiotics for AOM, and shows that around 78 children (shown by the green faces) will recover whether they take without antibiotics or not, around 6 (the yellow faces) will do better with antibiotics, but the 16 children shown by the red faces still have problems even if they have antibiotics. Of course, when prescribing we have no idea which group an individual person will fall into.
Figure 2: Diarrhoea, vomiting and rash in AOM
In Figure 2, the red faces show the 12 children with AOM who will develop diarrhoea, vomiting or rash anyway, even without antibiotic treatment. The green faces which are crossed out are the extra 4 children who will develop these symptoms because of antibiotics. Again the problem is that we cannot tell in advance which of the patients prescribed antibiotics will be the ones to suffer the treatment-related harms.
NICE concluded that antibiotics for AOM are effective only in reducing duration of pain in children aged between 6 months and 15 years. The NNT in order to prevent one child from having some pain after 2 days was 15, and children who took antibiotics were more at risk of having adverse events. NICE also concluded that antibiotics may be beneficial in children younger than 2 years with bilateral AOM and children with both AOM and otorrhoea. The numbers needed to treat mean that 3 or 4 children, respectively, with those symptoms would need to be treated with antibiotics for 1 additional child to benefit. These results are similar to those seen in the studies considered in this Rapid Review. NICE do point out, however, in those children who still had pain on day 3 it was found to be generally mild. Also, most parents used suboptimal doses of analgesics. NICE stated that “It is debatable whether it is worthwhile to treat children with antibiotics, particularly when analgesic use to relieve pain has not been optimised”
In summary, these two new RCTs support NICE guidance. They show that the benefits of antibiotics may outweigh the risks for young children with AOM diagnosed according to stringent criteria. NICE advises that antibiotics are indicated in patients who are systemically very unwell or at high risk of serious complications because of pre-existing co-morbidity. Other subgroups of children who may benefit include those with symptoms suggestive of mastoiditis, or who have otorrhoea, or who are younger than 2 years with bilateral acute otitis media.
Nevertheless, for many patients with AOM the immediate prescribing of an antibiotic is almost as likely to result in side effects as it is to confer benefit. This, combined with the fact that we know that otitis media is a self limiting condition, and that antibiotics have no benefit on pain at 24 hours and other patient-orientated outcome markers, makes the routine use of antibiotics in the management of many patients with AOM questionable. In addition, antibiotic resistance increases with antibiotic exposure both in the population and in the individual patient, and inappropriate antibiotic prescribing sends out the wrong message to the patient, their family and friends, that antibiotics are necessary for self-limiting infections. The bottom line is that, in each person the benefits of antibiotic prescribing need to be balanced against the risks for that individual and for the population as a whole.
NICE found little evidence on how to identify patients who are most at risk if they don’t receive an antibiotic. They stress the need for safety-netting approaches in case the patients’ illness worsens or becomes prolonged, either by use of delayed antibiotic prescriptions or by offering a prompt clinical review. If a delayed prescription is given, patients should be given advice on using it if symptoms worsen or aren’t resolving as expected. Similarly, if symptoms worsen despite using the delayed prescription, the patient should be advised to re-consult their doctor.
NICE advises that the patient’s or parent’s concerns and expectations should be addressed when agreeing which strategy should be used. It may be helpful to advise them that AOM lasts four days, on average. This means that many patients will have symptoms lasting much longer than this, whereas in others the illness will resolve quite quickly. Patients should be advised that, for the majority, antibiotics make little difference to symptoms, and they may have side effects. Advice on use of symptomatic treatments, such as analgesics and antipyretics should also be offered when appropriate.
The Pittsburgh study details
Hoberman A, et al. Treatment of acute otitis media in children under 2 years of age. N Engl J Med 2011;364:105–15
Patients: 291 children aged 6 to 23 months with AOM diagnosed on the basis of three criteria: the onset, within the previous 48 hours, of symptoms that parents rated with a score of at least 3 on the AOM Severity of Symptoms scale; the presence of middle-ear effusion; and moderate or marked bulging of the tympanic membrane or slight bulging accompanied by either otalgia or marked erythema of the membrane.
Intervention and comparison: Children were randomised to receive co-amoxiclav or placebo for 10 days. The primary outcome measures were time to resolution of symptoms and symptom burden over time.
Outcomes and results: Among the children who received co-amoxiclav, 35% had initial resolution of symptoms by day 2, 61% by day 4, and 80% by day 7; among children who received placebo, 28% had initial resolution of symptoms by day 2, 54% by day 4, and 74% by day 7 (P=0.14 for the overall comparison). For sustained resolution of symptoms, the corresponding values were 20%, 41%, and 67% with co-amoxiclav, as compared with 14%, 36%, and 53% with placebo (P=0.04 for the overall comparison). Mean symptom scores over the first 7 days were lower for the children treated with co-amoxiclav than for those who received placebo (P=0.02). The rate of clinical failure (defined as the persistence of signs of acute infection on otoscopic examination) was also lower among the children treated with co-amoxiclav than among those who received placebo: 4% versus 23% at or before the visit on day 4 or 5 (P<0.001) and 16% versus 51% at or before the visit on day 10 to 12 (P<0.001). Mastoiditis developed in one child who received placebo. Diarrhoea and nappy-area dermatitis were more common among children who received co-amoxiclav.
Sponsorship: Supported by a grant from the National Institute of Allergy and Infectious Diseases.
Patients: 319 children aged 6 to 35 months with AOM diagnosed according to three specific criteria: middle-ear fluid detected by means of pneumatic otoscopic examination that showed at least two tympanic-membrane findings; at least one acute inflammatory sign in the tympanic membrane; and acute symptoms, such as fever, ear pain, or respiratory symptoms.
Intervention and comparison: Children were randomised to co-amoxiclav or placebo for seven days. The primary outcome was time to treatment failure from the first dose until the end-of-treatment visit on day 8. The definition of treatment failure was based on the overall condition of the child (including adverse events) and otoscopic signs of acute otitis media.
Outcomes and results: Treatment failure occurred in 18.6% of the children who received co-amoxiclav, as compared with 44.9% of the children who received placebo (P<0.001). The difference between the groups was already apparent at the first scheduled visit (day 3), at which time 13.7% of the children who received co-amoxiclav, as compared with 25.3% of those who received placebo, had treatment failure. Overall, co-amoxiclav reduced the progression to treatment failure by 62% (hazard ratio [HR] 0.38, 95% confidence interval [CI] 0.25 to 0.59; P<0.001) and the need for rescue treatment by 81% (6.8% vs. 33.5%; HR 0.19, 95%CI, 0.10 to 0.36; P<0.001). Analgesic or antipyretic agents were given to 84.2% and 85.9% of the children in the co-amoxiclav and placebo groups, respectively. Adverse events were significantly more common in the co-amoxiclav group than in the placebo group. A total of 47.8% of the children in the co-amoxiclav group had diarrhoea, as compared with 26.6% in the placebo group (P<0.001); 8.7% and 3.2% of the children in the respective groups had eczema (P=0.04).
Sponsorship: Funded by the Foundation for Paediatric Research and others.
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Related PJ Online articles: Antibiotics can improve symptom resolution in otitis media and Otitis media symptoms reduced by antibiotics