Description of the condition
Acute otitis media (AOM) is one of the most common diseases in children. During the first six months of life about 48% of infants have one episode of AOM or otitis media with effusion (OME) and about 20% have two or more episodes (Daly 1999). The peak incidence of AOM occurs between 6 and 12 months of age. It has been found that by the end of the first year of life 62.4% of infants have had one or more episodes of AOM and 17.3% have had three or more episodes (Teele 1989). The risk of developing another episode within one month after the onset of the primary infection is estimated at 35% (Carlin 1987).
The common bacterial pathogens of AOM are Streptococcal pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae) and Moraxella catarrhalis (M. catarrhalis) (Jacobs 1998). These bacteria are becoming increasingly resistant to antibiotics (Barnett 1995; Faden 1994; Henderson 1988; Johnson 1996; Kaplan 1995). Systematic reviews have demonstrated that in uncomplicated AOM, about 20 children must be treated with antibiotics to prevent one child having some pain after two days (Venekamp 2013) and about eight children must receive antibiotics to avoid one clinical failure (Rosenfeld 2001). A study by Rovers 2006 demonstrated that antibiotics seemed to have most benefit in children younger than two years of age with bilateral AOM, and in children with both AOM and otorrhoea. However, the emergence of multiple-drug resistant strains, particularly S. pneumoniae, complicates the management of AOM and increases the risk of treatment failure. Antibiotics are frequently used for AOM in the US (Froom 1997; Venekamp 2013), where it is the most frequent disease that antibiotics are used to treat in outpatient departments (McCaig 1995). In contrast, the national Dutch guidelines recommend that children be treated for symptoms but do not receive antibiotics unless fever or pain persists (Froom 1997).
Description of the intervention
Due to growing bacterial resistance, the Center for Disease Control and Prevention and the American Academy of Pediatrics promotes the judicious use of antibiotics in the treatment of AOM. Antibiotic therapy remains an appropriate treatment option for most children with AOM because spontaneous cure rates are lower in complicated AOM and AOM secondary to S. pneumoniae infection. When amoxicillin, the treatment of choice in AOM, is not effective or not tolerated in children, an alternative antibiotic such as amoxicillin/clavulanate, or second- and third-generation cephalosporins, which can cover beta-lactamase producing bacteria, should be considered (Pichichero 2003).
The effectiveness of antibiotics does not depend solely on their antimicrobial activity against the suspected pathogens, but also on characteristics such as dosage, appropriate dosing intervals, tolerability and palatability, which promote compliance and adherence. A convenient once- or twice-daily dosing schedule increases the likelihood of compliance with a full course of therapy (Leibovitz 2003). The traditional dosing interval for prescribing amoxicillin, with or without clavulanate, is every six to eight hours. These dosing intervals may result in poor compliance especially for children at school or daycare centres, which necessitates the involvement and co-operation of a third person.
How the intervention might work
The length of time that antibiotic serum levels are above the Minimal Inhibitory Concentration (MIC), or time above the MIC, has been demonstrated to be a major determinant in predicting successful clinical outcomes for beta-lactam antimicrobial agents (Cars 1997; Drusano 1997). This finding denotes that the dosing frequency of beta-lactam antimicrobial agents could be reduced by increasing the dose, in order to maximise time above the MIC. An increased dose, instead of three times daily dosing, will enhance compliance (Grob 1992; Urquhart 1992). However, these studies relate to conditions other than otitis media.
Why it is important to do this review
In recent years, an increased dosing interval of amoxicillin, with or without clavulanate, has been more frequently used to treat AOM (AAPS 2004). It is therefore reasonable to assess clinical trials comparing the effectiveness of reduced dosing intervals (one or two daily doses) with traditional dosing intervals (three or four daily doses) of amoxicillin, with or without clavulanate, for the treatment of AOM in children.
To compare the effectiveness of one or two daily doses with three or four daily doses of amoxicillin, with or without clavulanate, for the treatment of AOM in children; and to compare complication rates and adverse reactions.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs) comparing two different dosing intervals of the same intervention, amoxicillin, with or without clavulanate.
Types of participants
Participants aged 12 years or younger, with AOM diagnosed by acute ear pain (otalgia) and an inflamed ear drum (confirmed by positive tympanocentesis or tympanogram of type B or C). A tympanogram is the print-out of an impedance bridge showing the stiffness or the compliance of the middle ear structures as it varies with changes in pressure within the external ear canal. A type B tympanogram suggests fluid in the middle ear; type C suggests that the pressure within the middle ear is below atmospheric pressure.
Types of interventions
Once or twice daily doses compared with three or four daily doses of amoxicillin, with or without clavulanate.
Types of outcome measures
Clinical cure rate at the end of antibiotic therapy (days 7 to 15), in terms of resolution of otalgia, resolution of fever and bacteriological cure rate, if data are provided.
- Clinical cure rate during therapy in terms of resolution of otalgia and resolution of fever.
- Clinical cure rate post-treatment (one to three months), in terms of resolution of middle ear effusion, as determined by tympanometry, assessed only in those who do not have recurrences of AOM after completion of therapy.
- AOM complications: recurrent AOM (after completion of therapy), acute mastoiditis.
- Adverse reactions to medication.
Search methods for identification of studies
For this update we searched the Cochrane Central Register of Controlled Trials (CENTRAL) 2013, Issue 2, part of The Cochrane Library, www.thecochranelibrary.com (accessed 15 March 2013), which contains the Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (January 1950 to March week 1, 2013), EMBASE (July 2010 to August 2012) and the Science Citation Index (2001 to March 2013). See Appendix 1 for details of previous search.
We used the following terms to search MEDLINE and CENTRAL. We combined the MEDLINE search with the Cochrane highly sensitive search strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision): Ovid format (Lefebvre 2011). We adapted the search strategy to search other databases. See Appendix 2 for the EMBASE search strategy and Appendix 3 for the Science Citation Index search strategy.
1 exp Otitis Media/
2 otitis media.tw.
3 (AOM or OME).tw.
4 ((infect* or inflam*) adj2 middle ear*).tw.
6 exp Amoxicillin/
7 (amoxicillin* or amoxycillin*).tw,nm.
8 6 or 7
9 5 and 8
Searching other resources
We checked the reference lists of identified clinical trials and any relevant reviews or meta-analyses. We contacted major pharmaceutical companies that manufacture antibiotics and relevant experts in the field for additional trial information. We contacted the first author of relevant trials if any questions arose.
Data collection and analysis
Selection of studies
Two review authors (ST, PV) retrieved titles and abstracts from the literature search for checking against the inclusion/exclusion criteria and recorded data on a pre-designed screening form. The same review authors independently screened results for each title/abstract. A third review author (ML) resolved any disagreements. We requested the full-text articles if the title or the abstract were unclear.
Data extraction and management
Two review authors (ST, PV) independently reviewed each article and completed data extraction forms. We resolved disagreements through group discussion.
Assessment of risk of bias in included studies
We assessed the methodological quality of the selected trials using the criteria described in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). The methods used for the generation of the randomisation sequence were described for each trial.
1. Random sequence generation
We assessed the possibility of selection bias for random sequence generation, using the following criteria:
- 'Low' risk of bias: description of a random component in the sequence generation process was shown.
- 'High' risk of bias: the investigators describe a non-random component in the sequence generation process such as randomisation based on date of birth, case record number or date of presentation.
- 'Unclear' risk of bias: insufficient information about the sequence generation process to permit a judgement of 'Low' risk or 'High' risk.
2. Allocation sequence concealment
- 'Low' risk of bias: participants and investigators enrolling participants could not foresee assignment due to central allocation, sequentially numbered drug containers of identical appearance, sequentially numbered, opaque, sealed envelopes.
- 'High' risk of bias: participants or investigators enrolling participants could possibly foresee assignments and thus introduce selection bias.
- 'Unclear' risk of bias: insufficient information about the allocation concealment to permit a judgement of 'Low' risk or 'High' risk.
3. Blinding (performance bias and detection bias)
- 'Low' risk of bias: any one of the following:
- No blinding or incomplete blinding, but the review authors judge that the outcome is not likely to be influenced by lack of blinding.
- Blinding of participants and key study personnel ensured, and unlikely that the blinding could have been broken.
- 'High' risk of bias: any one of the following:
- No blinding or incomplete blinding, but the review authors judge that the outcome is likely to be influenced by lack of blinding.
- Blinding of participants and key study personnel attempted, and likely that the blinding could have been broken, and the outcome is likely to be influenced by lack of blinding.
- 'Unclear' risk of bias: any of the following:
- Insufficient information to permit a judgement of 'Low' risk or 'High' risk.
- The study did not address this outcome.
4. Incomplete outcome data
- 'Low' risk of bias: any one of the following:
- No missing outcome data.
- Reasons for missing outcome data unlikely to be related to true outcome.
- Missing outcome data balanced in number across intervention groups, with similar reasons for missing data across groups.
- For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk not enough to have a clinically relevant impact on the intervention effect estimate.
- For continuous outcome data, plausible effect size among missing outcomes not enough to have a clinically relevant impact on observed effect size.
- Missing data have been imputed using appropriate methods.
- 'High' risk of bias: any one of the following:
- Reasons for missing outcome data likely to be related to true outcome with either imbalance in numbers or reasons for missing data across intervention groups.
- For dichotomous outcome data, the proportion of missing outcomes compared with observed event risk enough to induce clinically relevant bias in intervention effect estimate.
- For continuous outcome data, plausible effect size among missing outcomes enough to induce clinically relevant bias in observed effect size.
- 'As-treated' analysis done with substantial departure of the intervention received from that assigned at randomisation.
- Potentially inappropriate application of simple imputation.
- 'Unclear' risk of bias: any one of the following:
- Insufficient reporting of attrition/exclusions to permit a judgement of 'Low' risk or 'High' risk (e.g. number randomised not stated, no reasons for missing data provided).
- The study did not address this outcome.
5. Selective outcome reporting
- 'Low' risk of bias: any of the following:
- The study protocol is available and all of the study's pre-specified (primary and secondary) outcomes that are of interest in the review have been reported in the pre-specified way.
- The study protocol is not available but it is clear that the published reports include all expected outcomes, including those that were pre-specified (convincing text of this nature may be uncommon).
- 'High' risk of bias: any of the following:
- Not all of the study's pre-specified primary outcomes have been reported.
- One or more primary outcomes is reported using measurements, analysis methods or subsets of the data (e.g. subscales) that were not pre-specified.
- One or more reported primary outcomes were not pre-specified (unless clear justification for their reporting is provided, such as an unexpected adverse effect).
- One or more outcomes of interest in the review are reported incompletely so that they cannot be entered in a meta-analysis.
- The study report fails to include results for a key outcome that would be expected to have been reported for such a study.
- 'Unclear' risk of bias: insufficient information to permit a judgement of 'Low' risk or 'High' risk. It is likely that the majority of studies will fall into this category.
6. Other bias
- 'Low' risk of bias: the study appears to be free of other sources of bias.
- 'High' risk of bias: there is at least one important risk of bias. For example, the study:
- had a potential source of bias related to the specific study design used; or
- has been claimed to have been fraudulent; or
- had some other problem
- 'Unclear' risk of bias: there may be a risk of bias, but there is either:
- insufficient information to assess whether an important risk of bias exists; or
- insufficient rationale or evidence that an identified problem will introduce bias.
Measures of treatment effect
For categorical data (for example, cure or not cure), we used risk ratios (RR) and 95% confidence intervals (CI). We showed continuous differences between groups in the meta-analysis (for example, pain relief on a visual analogue scale) as a mean difference (MD) and 95% CI.
Unit of analysis issues
We did not find any cluster-randomised trials.
Dealing with missing data
We performed data analysis using the intention-to-treat (ITT) principle. Regarding drop-outs, we applied the worst-case scenario to the once or twice daily groups.
Assessment of heterogeneity
When important heterogeneity was suspected from the Chi
Assessment of reporting biases
We planned to examine publication bias by using funnel plots (Light 1984) and when asymmetry was observed, we would use the trim and fill method to assess the effect of this asymmetry on the conclusions (Duval 2000). However, we did not produce the funnel plots because there were only six studies. When meta-analysis was inappropriate, we drew conclusions from the trials' descriptive elements, methodological quality, the number of trials with consistent findings, the plausibility of the results and the strength of the associations in the primary trials, as well as consensus among the authors.
Subgroup analysis and investigation of heterogeneity
We performed subgroup analyses and investigated heterogeneity on the basis of types of interventions (i.e. amoxicillin alone (Murph 1993; Principi 1986), amoxicillin with clavulanate (Behre 1997; Damrikarnlert 2000; Hoberman 1997)).
We carried out sensitivity analyses to explore the effect of trial quality on the review's conclusions. Analysis of trial quality was based on allocation concealment. We excluded trials with clearly inadequate allocation concealment to assess differences in the overall result.
Description of studies
Results of the search
The MEDLINE search retrieved 171 studies. However, there were only six studies relevant to the objectives of this review (Behre 1997; Damrikarnlert 2000; Hoberman 1997; Jacobsson 1993; Murph 1993; Principi 1986). Among the 229 results retrieved by the EMBASE search, six relevant studies were found (Behre 1997; Damrikarnlert 2000; Hoberman 1997; Jacobsson 1993; Murph 1993; Principi 1986). No randomised controlled trial (RCT) was retrieved by searching the Science Citation Index. We found six studies in health services research meeting abstracts but only one was relevant to the review objectives (Damrikarnlert 2000). We retrieved six out of 98 studies from the CENTRAL search (Behre 1997; Damrikarnlert 2000; Hoberman 1997; Jacobsson 1993; Murph 1993; Principi 1986).
Four studies were supported by pharmaceutical funding (Behre 1997; Damrikarnlert 2000; Hoberman 1997; Principi 1986). Two trials compared amoxicillin without clavulanate (Murph 1993; Principi 1986) and used once and two daily versus three times daily dosing, while the other four studies compared the effectiveness of amoxicillin/clavulanate two times versus three times daily (Behre 1997; Damrikarnlert 2000; Hoberman 1997; Jacobsson 1993). Treatment duration was 10 days in four trials (Behre 1997; Hoberman 1997; Murph 1993; Principi 1986) and 7 to 10 days in one trial (Damrikarnlert 2000).
We excluded the study by Jacobsson (Jacobsson 1993) because it included only recurrent AOM cases or cases that were not responsive to amoxicillin/penicillin or cefaclor, which differed from the other studies. In addition, the total daily dosage for amoxicillin was quite low (20 to 33.2 mg/kg/day).
Risk of bias in included studies
The included studies are summarised in the Characteristics of included studies tables and the quality assessment of each study is summarised in 'Risk of bias' tables. The detailed risks of bias and quality of each study is shown in Table 1. We found that all trials had unclear risk of bias for allocation concealment. A graphical representation of risk of bias among the included studies is shown in Figure 1. A funnel plot is shown in Figure 2 which shows that there was no publication bias.
|Figure 1. 'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.|
|Figure 2. Funnel plot of the five trials included.|
All five studies claimed that they were RCTs but only two studies clearly mentioned the method of randomisation (Damrikarnlert 2000; Murph 1993). One used a computer generation method (Damrikarnlert 2000) and the other generated a table of random numbers (Murph 1993). All studies had an unclear risk of bias because there was no information on the method of allocation concealment.
There was only one study that had a placebo control and the investigator, participants and assessors were blinded to this (Murph 1993). Two studies blinded only the observers (Behre 1997; Damrikarnlert 2000). There was no information on blinding process in one study (Principi 1986).
Incomplete outcome data
There was one study with no drop-outs (Principi 1986). Three studies had less than 10% drop-outs (Behre 1997; Hoberman 1997; Murph 1993) and one study had more than 10% drop-outs (Damrikarnlert 2000). There were three studies with high risk of incomplete outcome data (Behre 1997; Damrikarnlert 2000). Two studies with low risk of bias (Hoberman 1997; Principi 1986) and one study with unclear risk of bias (Murph 1993).
Four studies had important clinical outcomes (Behre 1997; Damrikarnlert 2000; Hoberman 1997; Principi 1986), except one study which had high risk of bias for selective reporting (Murph 1993). Four trials assessed the primary outcome at the end of treatment (Behre 1997; Damrikarnlert 2000; Murph 1993; Principi 1986), while Hoberman 1997 assessed the primary outcome at the follow-up visit, days 32 to 38. Thus we used the secondary outcome (clinical response at days 12 to 14) by Hoberman as the primary outcome in this review and vice versa. The study by Murph 1993 did not reported clinical cure rate at follow-up (post-treatment), including AOM complications.
Other potential sources of bias
Four studies reported comparable baseline characteristics and compliance rates for both treatment and control groups (Behre 1997; Damrikarnlert 2000; Hoberman 1997; Murph 1993). However, the study by Principi 1986 did not report compliance rates.
Effects of interventions
We analysed the effectiveness of the interventions based on one or two daily doses of amoxicillin, with or without clavulanate versus three daily doses. Subgroup analyses were performed based on amoxicillin treatment trials only, amoxicillin/clavulanate treatment trials only and exclusion of the studies with many unclear risk of bias characteristics.
1. All included studies
Clinical cure rate at the end of therapy
|Figure 3. Forest plot of comparison: Clinical cure rate at the end of therapy.|
Five trials involving 1601 participants compared one or two daily doses of amoxicillin, with or without clavulanate, with three daily doses. The risk ratio (RR) showed comparable results between groups (RR 1.03, 95% confidence interval (CI) 0.99 to 1.07).
Clinical cure rate during therapy
|Figure 4. Forest plot of comparison: Clinical cure rate during therapy.|
Clinical cure at post-treatment (one to three months)
|Figure 5. Forest plot of comparison: Clinical cure at post-treatment (one to three months).|
Four trials reported clinical cure rate after therapy which showed no difference in either group (Behre 1997; Damrikarnlert 2000; Hoberman 1997; Principi 1986). The results were comparable (RR 1.02, 95% CI 0.95 to 1.09).
AOM complications: Recurrent AOM after completion of therapy
|Figure 6. Forest plot of comparison: AOM complications: Recurrent AOM after completion of therapy.|
Adverse reactions to medication
Compliance rates were also reported in four trials (Behre 1997; Damrikarnlert 2000; Hoberman 1997; Murph 1993). The pooled data showed no difference in compliance rate (RR 1.04, 95% CI 0.98 to 1.10) ( Table 8; Analysis 1.8).
2. Analysis of amoxicillin treatment trials only
3. Analysis of amoxicillin/clavulanate treatment trials only
4. Exclusion of the studies with many unclear risk of bias characteristics
The study by Principi 1986 had unclear risk of bias for random sequence generation, allocation concealment, blinding and 'other' bias. When we excluded this study from the analysis, both treatment groups still had comparable results ( Analysis 4.1; Analysis 4.2; Analysis 4.3; Analysis 4.4; Analysis 4.5; Analysis 4.6).
Acute otitis media (AOM) is one of the most common infections for which antibacterial agents are prescribed for children in the United States (Rovers 2004). The diagnosis and management of AOM has a significant impact on the health of children, the cost of providing health care and the use of antibiotics. Although there has been much discussion surrounding the treatment of uncomplicated AOM using antibiotics or observation, antibiotics are still widely used. The first-line antibiotic of choice for AOM is amoxicillin, with or without clavulanate (AAPS 2004). The effectiveness of antibiotics does not depend solely on their antimicrobial activity against the suspected pathogens, but also on factors such as dosage, appropriate dosing intervals, tolerability and palatability. One or two daily doses of oral antibiotics have a higher compliance rate than doses taken three times daily (Kardas 2007; Pechere 2007).
This systematic review demonstrated that when pooling all data from published trials of treatment with amoxicillin or amoxicillin/clavulanate for uncomplicated AOM in children, the results are comparable for all outcomes when comparing a once or twice daily dose with thrice daily doses. These results may show that both dosages have the same effectiveness or that uncomplicated AOM can self resolve.
Summary of main results
This review identified five RCTs reporting clinical outcomes in children treated with one or two daily doses of amoxicillin, with or without clavulanate, compared to three daily doses. No trial used four daily doses. There were no significant statistical differences in the effectiveness of the two different dosages of amoxicillin, with or without clavulanate.
Overall completeness and applicability of evidence
This review demonstrates that both one or two daily doses of amoxicillin or amoxicillin/clavulanate have comparable effectiveness for the treatment of uncomplicated AOM in children. One or two daily doses might increase compliance in daily practice.
Quality of the evidence
All of the included studies had an unclear risk of bias for allocation concealment and three studies had an unclear risk of bias for randomisation as they did not describe the details of randomisation sequence generation or methods to conceal allocation.
Potential biases in the review process
We have not identified any potential biases in the review process.
Agreements and disagreements with other studies or reviews
There have been no other published studies or reviews comparing the two dosages of amoxicillin, with or without clavulanate, for the treatment of AOM.
Implications for practice
In routine practice amoxicillin with/without clavulanate has been used as a twice daily dose for the treatment of AOM and other infectious diseases of the upper respiratory tract. Our findings confirm that using twice daily doses has the same effectiveness as thrice daily doses for uncomplicated AOM.
Implications for research
More than 90% of AOM cases occur in children less than two years of age. However, in all of the included studies the age ranges were between two months and 12 years, with few cases less than two years of age. A good quality equivalence or non-inferiority trial should be performed to see whether the treatments are either equally effective or whether a lower dosage scheme is as effective as a higher dosage scheme. Children less than two years of age should also be included in the study and a microbiological study of middle ear fluid should be performed.
The authors wish to thank Elizabeth Dooley and Professor Pisake Lumbiganon for their support and advice, Sarah Thorning for undertaking the literature searches, and Prof. Bruce Arroll, Maroeska Rovers, Eugene Leibovitz, Rick Shoemaker and Dilip Raghavan for commenting on the draft review.
Data and analyses
- Top of page
- Authors' conclusions
- Data and analyses
- What's new
- Contributions of authors
- Declarations of interest
- Sources of support
- Index terms
Appendix 1. Previous search
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 2) which contains the Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (January 1950 to July 2010), EMBASE (1974 to July 2010), the Science Citation Index (2001 to July 2010) and NLM Gateway (HSRProj) (July 2010).
We used the following terms to search MEDLINE and CENTRAL. We combined the MEDLINE search with the Cochrane highly sensitive search strategy for identifying randomised trials in MEDLINE: sensitivity- and precision-maximising version (2008 revision): Ovid format (Lefebvre 2011). We adapted the search strategy to search other databases. See Appendix 2 for the EMBASE search strategy; Appendix 3 for the Science Citation Index search strategy; and Appendix 4 for the NLM Gateway search strategy. There were no language or publication restrictions.
1 otitis media.mp.
3 1 or 2
6 4 or 5
7 (singl* or one or once or two or twice).tw.
8 ("q.d." or "qd" or "o.d." or "od" or "b.d." or "bd").tw.
9 (three or thrice or four).tw.
10 ("t.d.s." or "tds" or "q.i.d." or "qid").tw.
11 7 or 8
12 9 or 10
13 11 and 12
14 3 and 6 and 13
15 randomized controlled trial.pt.
16 controlled clinical trial.pt.
22 15 or 16 or 17 or 18 or 19 or 20 or 21
24 22 and 23
25 14 and 24
EMBASE search strategy
#1. 'otitis media'/exp AND [embase]/lim
#2. 'acute otitis media'/exp AND [embase]/lim
#3. 'acute suppurative otitis media'/exp AND [embase]/lim
#4. 'otitis media':ti,ab AND [embase]/lim
#5. 'aom':ti,ab AND [embase]/lim
#6. 'asom':ab,ti AND [embase]/lim
#7. #1 OR #2 OR #3 OR #4 OR #5 OR #6
#8. 'amoxicillin'/exp AND [embase]/lim
#9. 'amoxicillin plus clavulanic acid'/exp AND [embase]/lim
#10. amoxicillin:ti,ab AND [embase]/lim
#11. amoxycillin:ab,ti AND [embase]/lim
#12. #8 OR #9 OR #10 OR #11
#13. (singl*:ti,ab OR one:ti,ab OR once:ti,ab OR two:ti,ab OR twice:ti,ab) AND [embase]/lim
#14. ('q.d.':ti,ab OR 'qd':ti,ab OR 'o.d.':ti,ab OR 'od.':ti,ab OR 'b.d.':ti,ab OR 'bd':ti,ab) AND [embase]/lim
#15. (three:ti,ab OR thrice:ti,ab OR four:ti,ab) AND [embase]/lim
#16. ('t.d.s.':ti,ab OR 'tds':ti,ab OR 'q.i.d.':ti,ab OR 'qid':ti,ab) AND [embase]/lim
#17. #13 OR #14
#18. #15 OR #16
#19. #17 AND #18
#20. #7 AND #12 AND #19
#21. 'randomized controlled trial'/exp AND [embase]/lim
#22. 'controlled study'/exp AND [embase]/lim
#23. 'single blind procedure'/exp AND [embase]/lim
#24. 'double blind procedure'/exp AND [embase]/lim
#25. 'phase 3 clinical trial'/exp AND [embase]/lim
#26. random*:ab,ti AND [embase]/lim
#27. placebo*:ti,ab AND [embase]/lim
#28. 'clinical trial':it AND [embase]/lim
#29. 'randomized controlled trial':it AND [embase]/lim
#30. (singl*:ti,ab OR doubl*:ti,ab OR tripl*:ti,ab OR trebl*:ti,ab) AND (blind*:ti,ab OR mask*:ti,ab) AND [embase]/lim
#31. 'controlled clinical trial':ti,ab AND [embase]/lim
#32. 'controlled clinical trials':ti,ab AND [embase]/lim
#33. #21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27 OR #28 OR #29 OR #30 OR # 31 OR #32
#34. ('nonhuman'/exp OR 'animals'/exp) NOT 'human'/exp AND [embase]/lim
#35. #33 NOT #34
#36. #20 AND #35
Science Citation Index
Science Citation Index searched by ISI Web of Knowledge (http://apps.isiknowledge.com) using advanced search
#1 TI = (otitis media)
#2 TI = amoxicillin
#4 #2 OR #3
#5 TI = once
#6 TI = one
#7 TI = single
#8 TI = two
#9 TI = twice
#10 #5 OR #6 OR #7 OR #8 OR #9
#11 TI = three
#14 #11 OR #12 OR #13
#15 #10 AND #14
#16 #1 AND #4 AND #15
We used the terms ((otitis media) AND (amoxycillin OR amoxicillin) AND (one OR once OR two OR twice OR single) AND (thrice OR three OR four)) to search NLM Gateway.
Appendix 2. EMBASE search strategy
#16 #7 AND #15
#15 #10 NOT #14
#14 #11 NOT #13
#13 #11 AND #12
#12 'human'/de 2
#11 'animal'/de OR 'animal experiment'/de OR 'nonhuman'/de 8
#10 #8 OR #9
#9 random*:ab,ti OR placebo*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR allocat*:ab,ti AND trial:ti AND (doubl* NEXT/1 blind*):ab,ti
#8 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp
#7 #3 AND #6
#6 #4 OR #5
#5 amoxycillin*:ab,ti OR amoxicillin*:ab,ti
#3 #1 OR #22
#2 'otitis media':ab,ti OR ome:ab,ti OR aom:ab,ti OR ((infect* OR inflam*) NEAR/2 'middle ear'):ab,ti OR ((infect* OR inflam*) NEAR/2 'middle ears'):ab,ti
#1 'acute otitis media'/exp OR 'suppurative otitis media'/exp OR 'otitis media'/de
Appendix 3. Science Citation Index search strategy
Once or twice daily versus three times daily amoxicillin with or without clavulanate for the treatment of acute otitis media, 8 May 2014
The new version of the systematic review “Once or twice daily versus three times daily amoxicillin with or without clavulanate for the treatment of acute otitis media” (last assessed as up-to-date: 15 March 2013) includes the same 5 randomized controlled trials (1601 children) that were included in the previous one (last assessed as up-to-date: 10 July 2010). In the Publication History it is reported “New search for studies and content updated (no change to conclusions)”.
We believe this is incorrect; in the 2010 version in fact there was not pooling of the data, as it was judged to be not appropriate, and the authors’ conclusions were: “This review showed insufficient evidence to judge whether once or twice daily doses of amoxicillin, with or without clavulanate, were comparable with three or four daily doses for the treatment of AOM. The evidence appears to be biased and therefore no firm conclusions can be drawn”. On the contrary, in the last updated version of the systematic review data were pooled and conclusions reported: “This review showed that the results of using once or twice daily doses of amoxicillin, with or without clavulanate, were comparable with three doses for the treatment of AOM”.
This change is very relevant for clinicians, policy makers and the public; thus, it should be supported by a thorough discussion, explaining the rationale behind the change. Moreover, we suggest to state clearly in the Publication History: “New search for studies and content updated, no new trials identified, conclusions changed”, highlighting the change accordingly using the [CC] dark blue flag (There has been an important change to the conclusions of the review published in the most recent issue).
Simona Di Mario
I agree with the conflict of interest statement below:
I certify that I have no affiliations with or involvement in any organization or entity with a financial interest in the subject matter of my feedback.
Last assessed as up-to-date: 15 March 2013.
Protocol first published: Issue 4, 2004
Review first published: Issue 4, 2008
Contributions of authors
Sanguansak Thanaviratananich (ST) was responsible for conceiving, designing and co-ordinating the protocol, developing the search strategy, assessing the quality of studies, entering text into RevMan and writing the review.
Patravoot Vatanasapt (PV) was responsible for designing and co-ordinating the review, assessing the quality of the studies and providing general advice on the review.
Malinee Laopaiboon (ML) was responsible for entering text into RevMan and providing general advice on the statistical analysis and the review generally.
Declarations of interest
No conflict of interest known.
Sources of support
- Faculty of Medicine, Khon Kaen, Thailand.
- Thai Cochrane Network, Thailand.
Medical Subject Headings (MeSH)
Acute Disease; Amoxicillin [*administration & dosage]; Anti-Bacterial Agents [*administration & dosage]; Clavulanic Acid [*administration & dosage]; Drug Administration Schedule; Drug Therapy, Combination [methods]; Otitis Media [*drug therapy]; Randomized Controlled Trials as Topic
MeSH check words