Antibiotik OMSK (Cochrane)

Antibiotics for the prevention of acute and chronic
suppurative otitis media in children (Review)
Leach AJ, Morris PS
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2006, Issue 4
http://www.thecochranelibrary.com
Antibiotics for the prevention of acute and chronic suppurative otitis media in children (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
SUMMARY OF FINDINGS FOR THE MAIN COMPARISON . . . . . . . . . . . . . . . . . . . 3
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
ADDITIONAL SUMMARY OF FINDINGS . . . . . . . . . . . . . . . . . . . . . . . . . . 15
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45
Analysis 1.1. Comparison 1 Antibiotic versus control - primary outcomes, Outcome 1 Prevention - any AOM or CSOM
during intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
Analysis 1.2. Comparison 1 Antibiotic versus control - primary outcomes, Outcome 2 Prevention - episodes of AOM or
CSOM during intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51
Analysis 2.1. Comparison 2 Antibiotic versus control - secondary outcomes, Outcome 1 Prevention - any rAOM or CSOM
Analysis 2.2. Comparison 2 Antibiotic versus control - secondary outcomes, Outcome 2 Prevention - any AOM or CSOM
at end of intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53
Analysis 2.3. Comparison 2 Antibiotic versus control - secondary outcomes, Outcome 3 Prevention - any AOM or CSOM
following cessation of intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . 54
Analysis 2.4. Comparison 2 Antibiotic versus control - secondary outcomes, Outcome 4 Prevention - episodes of illness
Analysis 2.5. Comparison 2 Antibiotic versus control - secondary outcomes, Outcome 5 Side effects - any clinical side
effects during intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Analysis 2.6. Comparison 2 Antibiotic versus control - secondary outcomes, Outcome 6 Side effects - any antibiotic
resistance during intervention. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
Analysis 3.1. Comparison 3 Antibiotic versus control - subgroup analyses, Outcome 1 Prevention - any AOM or CSOM
during intervention: children < 12 months, more than 12 months, or not separated. . . . . . . . . . 58
Analysis 3.2. Comparison 3 Antibiotic versus control - subgroup analyses, Outcome 2 Prevention - episodes of AOM or
CSOM during intervention in children less than 12 months. . . . . . . . . . . . . . . . . . 59
during intervention: otitis prone, non-otitis-prone, or not separated. . . . . . . . . . . . . . . . 60
CSOM during intervention in OP, non-OP or separated. . . . . . . . . . . . . . . . . . . . 61
during intervention in high-risk or not high-risk populations. . . . . . . . . . . . . . . . . . 62
CSOM during intervention in high-risk or not high-risk population. . . . . . . . . . . . . . . . 63
Analysis 4.1. Comparison 4 Antibiotic versus control - sensitivity analyses, Outcome 1 Prevention - any AOM or CSOM
during intervention by study quality. . . . . . . . . . . . . . . . . . . . . . . . . . . 64
Analysis 4.2. Comparison 4 Antibiotic versus control - sensitivity analyses, Outcome 2 Prevention - episodes of AOM or
CSOM during intervention by study quality. . . . . . . . . . . . . . . . . . . . . . . . 66
during intervention by study size. . . . . . . . . . . . . . . . . . . . . . . . . . . . 68
Antibiotics for the prevention of acute and chronic suppurative otitis media in children (Review) i
CSOM during intervention by study size. . . . . . . . . . . . . . . . . . . . . . . . . 69
during intervention by inclusion criteria. . . . . . . . . . . . . . . . . . . . . . . . . 70
CSOM during intervention by inclusion criteria. . . . . . . . . . . . . . . . . . . . . . . 74
during intervention by medication. . . . . . . . . . . . . . . . . . . . . . . . . . . 77
CSOM during intervention by medication. . . . . . . . . . . . . . . . . . . . . . . . 80
during intervention by outcome measure. . . . . . . . . . . . . . . . . . . . . . . . . 83
CSOM during intervention by outcome measure. . . . . . . . . . . . . . . . . . . . . . 84
during intervention by date of study. . . . . . . . . . . . . . . . . . . . . . . . . . . 85
CSOM during intervention by date of study. . . . . . . . . . . . . . . . . . . . . . . . 87
during intervention by compliance. . . . . . . . . . . . . . . . . . . . . . . . . . . 88
CSOM during intervention by compliance. . . . . . . . . . . . . . . . . . . . . . . . 89
ADDITIONAL TABLES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 90
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 91
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 92
Antibiotics for the prevention of acute and chronic suppurative otitis media in children (Review) ii
[Intervention Review]
Antibiotics for the prevention of acute and chronic

suppurative otitis media in children
Amanda J Leach1 , Peter S Morris2

1 Ear and Oral Health Program, Child Health Division, Menzies School of Health Research, Tiwi, Australia. 2 Division of Child Health,
Menzies School of Health Research, Darwin, Australia
Contact address: Amanda J Leach, Ear and Oral Health Program, Child Health Division, Menzies School of Health Research, John
Mathews Building (bldg 58), Royal Darwin Hospital, Tiwi, Northern Territory, 0811, Australia. amanda.leach@menzies.edu.au.
Editorial group: Cochrane Acute Respiratory Infections Group.

Publication status and date: Edited (no change to conclusions), published in Issue 7, 2013.
Review content assessed as up-to-date: 6 August 2010.
Citation: Leach AJ, Morris PS. Antibiotics for the prevention of acute and chronic suppurative otitis media in children. Cochrane
Database of Systematic Reviews 2006, Issue 4. Art. No.: CD004401. DOI: 10.1002/14651858.CD004401.pub2.
ABSTRACT
Background
Acute otitis media (AOM) is a common childhood illness which may be frequent and painful. AOM may be associated with tympanic
membrane perforation and can progress to chronic suppurative otitis media (CSOM).
Objectives
To determine the effectiveness of long-term antibiotics (six weeks or longer) in preventing any AOM, AOM with perforation and
CSOM.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 3) which includes the
Acute Respiratory Infections Group’s Specialised Register, MEDLINE (January 1966 to July Week 4, 2010), OLD MEDLINE (1950
to 1965) and EMBASE (1990 to August 2010).
Selection criteria
Randomised controlled trials of long-term antibiotics versus placebo or no treatment for preventing AOM, AOM with perforation, or
CSOM.
Data collection and analysis
Two authors independently extracted the data for: AOM; episodes of AOM; recurrent AOM; episodes of illness; side effects; antibiotic
resistance; and outcomes at end of intervention (any AOM) and following cessation of intervention (any AOM). For dichotomous
outcomes, we calculated the summary risk ratio (fixed and random-effects models). For rate outcomes, we calculated the summary
incidence rate ratio.
Main results
Seventeen studies (1586 children) were included. All studies enrolled children at increased risk of AOM. In seven studies the children
were prone to otitis media. The majority were high-quality studies and most (16 studies) reported data for our primary outcomes. One
reported AOM with perforation or CSOM. Long-term antibiotics reduced any episode of AOM (14 studies, 1461 children, risk ratio
Antibiotics for the prevention of acute and chronic suppurative otitis media in children (Review) 1
(RR) 0.65, 95% CI 0.53 to 0.79; random-effects model) and number of episodes of AOM (13 studies, 1327 children, incidence rate
ratio (IRR) 0.51, 95% CI 0.39 to 0.66; random-effects model). Approximately five children would need to be treated long-term to
prevent one child experiencing AOM whilst on treatment. Antibiotics prevented 1.5 episodes of AOM for every 12 months of treatment
per child. We explored statistical heterogeneity. Long-term antibiotics were not associated with a significant increase in adverse events
(12 studies, 817 children, RR 1.99, 95% CI 0.25 to 15.89; random-effects model).
Authors’ conclusions
For children at risk, antibiotics given once or twice daily will reduce the probability of AOM while the child is on treatment. In similar
populations, antibiotics will reduce the number of episodes of AOM per year from around three to around 1.5. We believe that larger
absolute benefits are likely in high-risk children. These conclusions were not affected by sensitivity analyses.
PLAIN LANGUAGE SUMMARY

Antibiotics to prevent acute ear infections in children
Acute otitis media (AOM, infection in the middle ear space) is common in children, causing pain and deafness. Most children experience
at least one episode and some children suffer recurrent AOM (more than three episodes in six months or four episodes in 12 months),
and some progress to eardrum perforation. Interventions (antibiotics, vaccines or reduced exposure to bacterial and viral pathogens)
that decrease the frequency and/or the severity of infection are needed. Antibiotics given once or twice daily may reduce episodes of
bacterial AOM and their complications. This review included 17 studies (1586 children). Long-term antibiotics (equal to or more than
six weeks) almost halved the risk of further infections. There was not enough information to know if antibiotics reduced acute otitis
media with perforation or chronic suppurative otitis media (chronic perforation), or improved long-term outcomes. Antibiotics did not
appear to be a frequent cause of significant side effects (for example, allergic reactions or diarrhea). Parents must balance these potential
side effects plus the cost and inconvenience associated with antibiotics against the likely benefits of treatment. Antibiotic resistance
from the long-term use of these drugs is also an issue which should be considered, particularly for children with recurring infections.
Antibiotics for the prevention of acute and chronic suppurative otitis media in children (Review) S U M M A R Y O F F I N D I N G S F O R T H E M A I N C O M P A R I S O N [Explanation]
Antibiotic versus control - primary outcomes for the prevention of acute and chronic suppurative otitis media in children
Patient or population: patients with the prevention of acute and chronic suppurative otitis media in children
Settings:
Intervention: Antibiotic versus control - primary outcomes
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
Control Antibiotic versus control

- primary outcomes
Prevention - any AOM or Low risk population RR 0.65 1461 ⊕⊕⊕

CSOM during interven- (0.53 to 0.79) (14 studies) moderate1
tion 300 per 1000 195 per 1000
(159 to 237)
Medium risk population
550 per 1000 358 per 1000

(291 to 435)
High risk population
800 per 1000 520 per 1000

(424 to 632)
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
3
Antibiotics for the prevention of acute and chronic suppurative otitis media in children (Review)
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 Larger effect noted in small studies (see funnel plot). This may be due to publication bias.
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4
BACKGROUND preservation group has stated that populations with children hav-
ing a 4% rate of CSOM have a massive public health problem.
Indigenous children living in Australia, North America, North-
ern Europe and New Zealand appear to be at particularly high
Description of the condition risk of developing CSOM (WHO/CIBA 1996). In a recent cross-
sectional survey of children aged six months to 2.5 years and liv-
Otitis media is a major health problem in young children. Otitis
ing in 29 remote communities in the Northern Territory, rates of
media (OM) is a broad term for any infection or inflammation oc-
perforation varied from less than 10% to 60% (Morris 2005). In
curring in the middle ear space (behind the tympanic membrane).
longitudinal birth cohort studies in this population the onset of
It represents a spectrum of disease: i) otitis media with effusion
disease has been shown to commence within weeks of life, follow-
(OME), fluid behind an intact tympanic membrane without the
ing nasopharyngeal colonisation with Streptococcus pneumoniae (S.
symptoms or signs of acute otitis media; ii) acute otitis media
pneumoniae), non-capsular Haemophilus influenzae (H. influenzae)
(AOM), fluid behind the tympanic membrane with the symptoms
(NCHi) and Moraxella catarrhalis (M. catarrhalis) (Leach 1994).
or signs of an acute infection; and iii) chronic suppurative otitis
This association between bacterial colonisation and early-onset
media (CSOM), persistent discharge of pus through a perforated
OM has led to speculation about the role of long-term antibiotic
tympanic membrane for more than six weeks. The criteria used
therapy.
in definitions of AOM are highly variable. Ear pain (Rosenfeld
2003), bulging of the tympanic membrane (Karma 1989) and re-
cent discharge of pus are regarded as the most diagnostically reli-
able. In populations with high rates of CSOM, it is helpful to dis- Description of the intervention
tinguish between those children with AOM without perforation
Prophylactic antibiotics have been recommended to reduce the
and those children with perforation of the tympanic membrane,
risk of bacterial infection in selected children. For children at high
since AOM with perforation always precedes CSOM. Children
risk of bacterial OM, oral antibiotics active against S. pneumoniae
who have had three episodes of AOM within the last six months
and H. influenzae can be given once or twice daily. The duration
or four episodes within the last 12 months are classified as having
of prophylaxis may vary from weeks to months.
recurrent acute otitis media (rAOM) (Rosenfeld 2003).
A comprehensive search of The Cochrane Library and MED-
LINE identified the following systematic reviews of interventions
for AOM: antibiotics for treatment (Del Mar 1997; Kozyrskyj How the intervention might work
2000; Sanders 2009); decongestants or antihistamines, or both
Prophylactic antibiotics might either reduce nasopharyngeal
for treatment (Coleman 2008); antibiotics for prevention (Bonati
colonisation with pathogens or reduce the risk of colonised chil-
1992; Williams 1993); and pneumococcal vaccines for preven-
dren developing clinically apparent bacterial infections. Antibi-
tion (Jansen 2009). The systematic review of antibiotics to prevent
otics should not affect the incidence of viral upper respiratory tract
AOM by Williams et al (Williams 1993) found that antibiotics
infections.
reduced the rate of AOM by 50%. However, AOM was infrequent
(the AOM recurrence rate in the control groups was 0.062 to 0.488
per patient-month) and each child required around 10 months of
treatment to prevent one episode of infection. Similar overall re- Why it is important to do this review
sults were reported in a more recent evidence summary (Rosenfeld
While antibiotics appear to reduce rates of subsequent AOM in
2003). In this meta-analysis, studies with placebo groups having
high-income countries, important questions remain concerning
higher AOM recurrence rates (more than 0.2 episodes per month)
the relative benefits and costs in populations at high risk of AOM
showed a rate difference of 0.18 episodes per month (95% CI 0.08
or CSOM. The original systematic reviews (Bonati 1992; Williams
to 0.28) compared to a rate difference of 0.06 episodes per month
1993) have not been updated with the publication of new studies.
(95% CI 0.04 to 0.09) for studies where placebo groups that had
In addition, the impact of this intervention in high-risk popula-
lower recurrence rates. The studies included in these reviews were
tions is unclear.
largely conducted in the USA or other industrialised countries. In
these settings the pain or fever associated with an episode of AOM
is the principle concern of the care-giver. However, in disadvan-
taged populations the potential progression to CSOM is more im-
portant. In addition to constant offensive discharge, the hearing OBJECTIVES
loss associated with this severe disease is likely to have a great im-
pact on the language development and behaviour of young chil- To determine the effectiveness of long-term antibiotics (equal to
dren. Not surprisingly, the World Health Organization’s hearing or more than six weeks) in the prevention of acute otitis media
(AOM) and the complications of AOM (this includes AOM with- period of treatment was six weeks or longer. We excluded the use
out perforation and AOM with perforation and chronic suppura- of intermittent antibiotics (for example, at the appearance of signs
tive otitis media (CSOM)) in children at increased risk of future of URTI). We included studies with additional interventions (but
AOM episodes. excluding surgery) if the intervention was equally accessible to
both intervention and control groups.
METHODS Types of outcome measures
Primary outcomes
Criteria for considering studies for this review 1. Prevention, any AOM/CSOM during intervention: the
proportion of participants who developed any AOM, AOM with
perforation, CSOM, complications or withdrawals due to side
Types of studies
effects during the intervention period.
Randomised controlled trials (RCTs) of long-term antibiotics 2. Prevention, episodes of AOM/CSOM during intervention:
(equal to or more than six weeks) versus control (placebo or no the number of episodes per child-year of any AOM, AOM with
treatment) for the prevention of AOM without perforation, AOM perforation or CSOM during therapy.
with perforation and CSOM. Ideally episodes of AOM should be
least two weeks apart. While definitions vary substantially between
Secondary outcomes
studies, AOM should be confirmed by otoscopy. All episodes of
AOM that were associated with perforation were categorised as 1. Prevention, recurring AOM/CSOM during intervention:
AOM with perforation even if the tympanic membrane was intact the proportion of participants experiencing recurrent AOM/
at the time of examination (that is to say, perforations occurred CSOM (rAOM/CSOM) defined as three or more episodes of
within two weeks of the clinical assessment and not secondary to AOM within a six-month period during therapy.
trauma). Similarly we attempted to limit the diagnosis of CSOM 2. Prevention, any AOM/CSOM at the end of intervention:
to episodes of discharge from the middle ear that persisted for the proportion of participants with any AOM, AOM with
longer than six weeks. Ideally, resolution of discharge associated perforation, CSOM, complications or withdrawals due to side
with CSOM was confirmed by a clinician. Cross-over studies were effects at cessation of therapy.
eligible for inclusion but we only used data from the initial treat- 3. Prevention, any AOM/CSOM following cessation of
ment period. There were no language or publication restrictions. intervention: the proportion of participants with any AOM,
AOM with perforation, CSOM, complications or withdrawals
due to side effects following cessation of intervention.
Types of participants 4. Prevention, episodes of illness during intervention: the
Children aged 0 to 18 years at increased risk of future episodes number of episodes per child-year of any illness.
of AOM (as determined by the study investigators). We excluded 5. Side effects, any clinical side effects during intervention: the
studies of children with a diagnosis of AOM, AOM with per- proportion of participants who experienced significant adverse
foration or CSOM at the time of randomisation. We also ex- events such as diarrhea and vomiting or allergic reactions that are
cluded studies of children with diseases associated with immunod- sufficient to recommend cessation of intervention.
eficiency, craniofacial abnormalities, undergoing tympanostomy 6. Side effects, any antibiotic resistance during intervention:
tube insertion or other ear, nose and throat (ENT) surgery at the the proportion of participants colonised (or clinically infected)
time of randomisation. by S. pneumoniae or H. influenzae with resistance or intermediate
resistance to the antibiotic at the first follow-up visit at least six
weeks after starting treatment.
Types of interventions
All randomized comparisons of continuous long-term systemic
antibiotics that are effective against S. pneumoniae or non-capsu- Search methods for identification of studies
lar H. influenzae (NCHi) (intervention group) versus placebo or
no treatment, or treatment considered to be ineffective (control
group). We defined long-term as six weeks or longer. All doses Electronic searches
of antibiotics and all dosing schedules were eligible for inclusion. We searched the Cochrane Central Register of Controlled Tri-
We included antibiotics given continuously during a period of in- als (CENTRAL) (The Cochrane Library 2010, Issue 3) which in-
creased risk (for example, the winter months) and independent cludes the Acute Respiratory Infections Group’s Specialised Reg-
of symptoms of upper respiratory tract infections (URTI) if the ister, MEDLINE (January 1966 to July Week 4, 2010), OLD
MEDLINE (1950 to 1965), EMBASE (1990 to August 2010) Data extraction and management
and the references of relevant studies. We did not exclude any trials that included a treatment and a
We used the following search strategy to search MEDLINE and control group and that met the inclusion criteria. Both review
CENTRAL. The MEDLINE search terms were combined with authors independently reviewed trials that satisfied the inclusion
the Cochrane Highly Sensitive Search Strategy for identifying criteria. We recorded the following information on data collec-
randomized trials in MEDLINE: sensitivity- and precision-max- tion forms: date of study; study setting; source of funding; par-
imising version (2008 revision); Ovid format (Lefebvre 2009). ticipant recruitment details (including number of eligible chil-
The search terms were adapted to search EMBASE (see Appendix dren); inclusion and exclusion criteria; study definitions used; ran-
1). OLD MEDLINE was accessed via the National Library of domisation and allocation concealment methods; numbers of par-
Medicine Gateway using the terms (otitis AND antibiotic). ticipants randomized; baseline characteristics; blinding (masking)
1 exp Otitis Media/ of participants, care providers and outcome assessors; dose and
2 otitis media.tw. type of antibiotic therapy; compliance; frequency of assessments;
3 (aom or ome or csom).tw. other outcome measures used in the study; duration of therapy;
4 or/1-3 duration of follow up post-therapy; co-interventions; numbers of
5 exp Anti-Bacterial Agents/ participants not followed up; reasons for withdrawals from study
6 antibiotic*.tw. protocol (clinical, complications, side effects, refusal and other);
7 (amoxicillin or amoxycillin or ampicillin or azithromycin or details on side effects of therapy; and whether intention-to-treat
azithromicin or cefaclor or penicillin or sulphamethoxazole or sul- (ITT) analyses were possible. We extracted data on primary and
phisoxazole or cotrimoxazole).tw,nm. secondary outcomes as described previously. We requested further
8 or/5-7 information from the trial authors where required. We resolved
9 Chemoprevention/ any disagreements by consensus.
10 (chemoprevent* or chemoprophyla* or prophyla* or pre-
vent*).tw,nm.
11 or/9-10 Assessment of risk of bias in included studies
12 8 and 11
Both review authors independently assessed the quality of the stud-
13 Antibiotic Prophylaxis/
ies included in the review. We assessed six components of quality.
14 12 or 13
1. Method of treatment assignment. Trials were scored as
15 4 and 14
Grade A: randomisation and concealment method correct, or
randomisation and concealment stated and group similarity
documented; Grade B: randomisation and concealment stated
Searching other resources but method not described, or suspect method; Grade C:
We searched reference lists in relevant publications, including randomisation claimed but not described, and outcome assessor
RCTs meeting the inclusion criteria, published systematic re- not blinded; Grade D: randomisation not mentioned (Grade A =
views, Clinical Evidence (Jones 2004), Evidence-Based Otitis Me- high quality).
dia (Rosenfeld 2003) and Evidence-Based Child Health (Moyer 2. Allocation concealment. Trials were scored as Grade A:
2000). We undertook written communication with the authors of adequate concealment, Grade B: unclear, Grade C: clearly
trials included in the review and with major pharmaceutical com- inadequate concealment, Grade D: not used (Grade A = high
panies (with offices in Australia) that manufacture antibiotics. quality).
3. Blinding. Trials were scored as Grade A: participant, care
provider and outcome assessor blinded; Grade B: outcome
assessor blinded; Grade C: unclear; Grade D: no blinding of
outcome assessor (Grade A, B = high quality).
Data collection and analysis 4. Reporting on participants by allocated group. Trials were
scored as Grade A: the progress of all randomized children in each
group described, Grade B: unclear or no mention of withdrawals
or drop-outs, Grade C: the progress of all randomized children
Selection of studies
in each group obviously not described (Grade A = high quality).
One review author (AJL) conducted the electronic search to iden- 5. Follow up. Trials were scored as Grade A: outcomes
tify potentially relevant articles. Both review authors agreed on the measured in more than 90% (where withdrawals due to
final selection of articles that met the inclusion criteria. Both review complications and side effects were categorised as treatment
authors independently reviewed the published systematic reviews, failures), Grade B: outcomes measured in 80% to 90%, Grade
evidence-based guidelines, Clinical Evidence and text books. C: unclear, Grade D: outcomes measured in less than 80%
(Grade A = high quality). Assessment of reporting biases
6. Outcome assessments. Grade A: all patients had We assessed the possibility of reporting bias qualitatively using a
standardized assessment (scheduled for data collection and funnel plot. We did not used statistical tests or imputation.
attempted to use consistent criteria for diagnosis); Grade B: no
standardized assessment, or not mentioned (Grade A = high
quality). Data synthesis
While only the allocation concealment quality assessment was dis- We included the results from studies that met the inclusion cri-
played in the meta-analysis figures, we included all assessments in teria and that reported any of the outcomes of interest in the
the Characteristics of included studies table. We measured inter- subsequent meta-analyses. We calculated the summary weighted
review author reliability for the identification of high-quality stud- risk ratio and 95% CI by the Mantel-Haenszel method using a
ies for each component by the Kappa statistic. fixed-effect model (Cochrane statistical package, Review Manager
(RevMan 2008). We used the number of episodes of AOM and
illness per child-year to calculate the summary weighted incidence
Measures of treatment effect
rate ratio by the generic inverse variance method (Cochrane statis-
For the dichotomous outcome variables of each individual study, tical package, RevMan 2008). We calculated the absolute risk re-
we calculated risk ratio and absolute risk reductions using an ITT duction and the number needed to treat using the summary odds
analysis. For the incidence rate variables of each individual study, ratio and the average control event rate described in the relevant
we estimated the log of the incidence rate ratio and the log of the studies. This was done by multiplying the odds of the event in the
standard error from the raw data using Stata version 7.0 (Stata control arm by the odds ratio to determine the odds of the event
2004). In cases where one of the comparison groups had a rate of in the intervention arm. We then converted the estimated odds to
zero, one case was added to both groups. We carried out an initial probabilities.
qualitative comparison of all the individually analyzed studies to Where individual studies reported outcomes at several different
determine whether pooling of results (meta-analysis) was reason- follow-up times, a summary analysis used data at ’any time greater
able. This took into account differences in study populations, in- than three months’ and at the time ’closest to nine months’ after
clusion and exclusion criteria, interventions, outcome assessment the intervention period. Since we were unsure if there were any
and estimated effect size. long-term effects, and if they remain constant over time, we also
described the primary outcomes at the following time points after
the end of the intervention period:
Unit of analysis issues
a. one to two months;
We only included studies that randomized individual children. For b. three to five months;
cross-over studies, we only included data collected prior to cross- c. six to 11 months;
over. For studies that included non-antibiotic treatment arms, we d. 12 to 23 months; and
only included the antibiotic and control arms in the review. e. greater than 23 months.
Dealing with missing data Subgroup analysis and investigation of heterogeneity

We applied the principle of an ITT analysis to available outcome We planned a priori subgroup analyses of the primary outcomes
data. We did not use imputation. For estimates of rates of infection for: 1) children aged less than 12 months, greater than 12 months
where the standard deviation was not described, we assumed that or not separated at time of randomisation; 2) otitis-prone chil-
events occurred with a Poisson distribution and that the variance dren (defined as children having four episodes of AOM within 12
was equal to the rate. months or three episodes within a six-month period), not otitis-
prone, or not separated; 3) high-risk children (defined as children
who have experienced an episode of AOM with perforation) at
Assessment of heterogeneity
time of randomisation; and 4) children living in high-risk pop-
Both review authors considered the following sources of clinical ulations (defined as children from study populations where the
heterogeneity: differences in participants, differences in interven- CSOM prevalence rate is 4% or more).
tion (type, dose and duration of antibiotic treatment) and dif-
ferences in outcome measurement. We described any statistical
heterogeneity between the study results using the I2 statistic. We Sensitivity analysis
tested statistical significance using a Chi2 test (P < 0.1 regarded as We planned sensitivity analyses of the primary outcomes to assess
significant). We calculated the effect estimate and 95% confidence the impact of potentially important factors on the overall out-
interval (CI) using a random-effects model whenever there were comes.
concerns about statistical heterogeneity. 1. Study quality.
2. Study size. the illness. Relatively few studies provided data on the long-term
3. Variation in the inclusion criteria. outcomes following cessation of intervention.
4. Differences in the medications used in the intervention and The age eligibility criteria for the 16 studies that contributed data
comparison groups. to the meta-analyses varied. Three studies specifically targeted chil-
5. Differences in outcome measurement. dren less than 18 months of age (Gray 1981; Leach 2008; Teele
6. Analysis by ’treatment received’ rather than ITT. 2000a). Two additional studies did not enrol children older then
30 to 35 months of age (Casselbrant 1992a; Persico 1985a). The
other 11 studies did not exclude older children. Most children in
the studies were younger than five years of age.
RESULTS All the studies randomized children at increased risk of AOM.
This was consistent with the criteria for recurrent AOM (three
episodes in six months or four episodes in 12 months) in seven
studies (Casselbrant 1992a; Liston 1983a; Persico 1985a; Principi
Description of studies 1989a; Roark 1997a; Schuller 1983a; Varsano 1985a). In five stud-
ies children had two episodes of AOM within six months or three
episodes within 18 months (Gaskins 1982a; Gonzalez 1986a; Gray
Results of the search
1981; Perrin 1974a; Sih 1993a). One study enrolled children who
We identified 17 studies that met our inclusion criteria. However had experienced an episode of AOM in the first six months of
one study reported acute otitis media (AOM) combined with oti- life or two episodes in the first 12 months (Teele 2000a). One
tis media with effusion (OME) as their outcome measure and was study enrolled children with frequent middle ear effusion (MEE)
not able to contribute any data to the meta-analyses (Schwartz but infrequent AOM (Mandel 1996a). Two studies enrolled chil-
1982a). Sixteen studies are included in the meta-analysis. Fifteen dren living in populations known to have high rates of severe OM
of the studies were identified through searching the databases de- (Leach 2008; Maynard 1972a).
scribed above. All of these were listed on MEDLINE. We were None of the 11 studies that described ear status at entry to the study
notified about one additional study that had been published as an included children with AOM at the start of treatment (Casselbrant
extended abstract (Gray 1981). Four of the studies used a cross- 1992a; Gaskins 1982a; Gonzalez 1986a; Gray 1981; Leach 2008;
over design (Liston 1983a; Perrin 1974a; Schwartz 1982a; Varsano Liston 1983a; Mandel 1996a; Principi 1989a; Schuller 1983a;
1985a). For these studies we only used data from the first treat- Sih 1993a; Varsano 1985a). Four of these studies only included
ment phase. Three studies also randomized children to non-an- children who were free of middle ear infection (MEE) at the start
tibiotic treatment arms: tympanostomy tubes (Casselbrant 1992a; of treatment (Casselbrant 1992a; Mandel 1996a; Schuller 1983a;
Gonzalez 1986a) and pneumococcal vaccine (Schuller 1983a). For Sih 1993a).
these studies we have only used data from the antibiotic treatment Of the 11 studies that described exclusion criteria, nine ex-
or control treatment arms. cluded children with congenital abnormalities associated with OM
(Casselbrant 1992a; Gaskins 1982a; Gonzalez 1986a; Leach 2008;
Included studies Liston 1983a; Mandel 1996a; Perrin 1974a; Principi 1989a; Roark
1997a). Seven studies did not describe exclusion criteria.
All the 16 studies that contributed data to the meta-analyses ran-
Most studies addressing our research question were small. Ten
domized young children who were regarded as being at increased
studies randomized fewer than 100 children (Gaskins 1982a;
risk of AOM. In seven studies the children met the accepted cri-
Gonzalez 1986a; Gray 1981; Liston 1983a; Perrin 1974a; Principi
teria for being prone to otitis (three episodes in the previous six
1989a; Schuller 1983a; Schwartz 1982a; Sih 1993a; Varsano
months or four episodes in the previous 12 months). At least half
1985a). Six studies randomized from 100 to 200 children
the studies excluded children who had congenital abnormalities
(Casselbrant 1992a; Leach 2008; Mandel 1996a; Persico 1985a;
associated with increased rates of OM (for example, cleft palate
Roark 1997a; Teele 2000a), and one study randomized more than
and immunodeficiency). Most studies were conducted in the USA
200 children (Maynard 1972a).
and were completed prior to 1990. The most commonly used
Eleven of the studies were conducted in the USA (Casselbrant
long-term antibiotic treatments were sulphisoxazole and amoxi-
1992a; Gaskins 1982a; Gonzalez 1986a; Gray 1981; Liston 1983a;
cillin. Nearly all of the studies were placebo-controlled. The long-
Mandel 1996a; Maynard 1972a; Perrin 1974a; Roark 1997a;
term antibiotics were generally given for three to six months. An-
Schuller 1983a; Teele 2000a). The other studies were conducted
tibiotics were given once or twice daily. Most studies used a com-
in Israel (Persico 1985a; Varsano 1985a), Italy (Principi 1989a),
bination of active surveillance (with monthly reviews) and visits
Brazil (Sih 1993a) and Australia (Leach 2008).
to a healthcare provider because of illness to document episodes
All the studies were completed before 1995 with the possible ex-
of AOM. The diagnostic criteria used for AOM were variable but
ception of one in which the date of the study was not reported
generally children had to have symptoms and signs consistent with
(Teele 2000a) and one completed in 2001 (Leach 2008). Upper respiratory tract cultures were collected in seven stud-
A large proportion of the 16 studies that contributed data to the ies (Casselbrant 1992a; Gray 1981; Leach 2008; Mandel 1996a;
meta-analyses had more than two treatment arms. Three studies Perrin 1974a; Persico 1985a; Teele 2000a) and middle ear fluid
randomized children to either one of two antibiotic groups (amox- specimens were collected in five studies (Casselbrant 1992a;
icillin or trimethoprim sulphamethoxazole (or sulfisoxazole)) or Gaskins 1982a; Liston 1983a; Mandel 1996a; Persico 1985a). One
a control group (Principi 1989a; Sih 1993a; Teele 2000a). One study reported the proportion of swabs (but not children) with
study randomized children to once-daily or twice-daily amoxi- carriage and resistance of both H. influenzae and S. pneumoniae by
cillin (Roark 1997a). Ten studies included sulphur drugs as their group (Leach 2008). Two studies reported the proportion of throat
long-term antibiotic intervention: sulfisoxazole (Gonzalez 1986a; or nasopharyngeal cultures positive for beta-lactamase producing
Liston 1983a; Perrin 1974a; Schuller 1983a; Teele 2000a; Varsano H. influenzae or M. catarrhalis, or both, by group (Casselbrant
1985a); or trimethoprim sulphamethoxazole (Gaskins 1982a; 1992a; Mandel 1996a). One study reported proportion of throat
Gray 1981; Principi 1989a; Sih 1993a). Nine studies included cultures positive for pneumococci (but not resistant strains) by
penicillins as their long-term antibiotic intervention: amoxicillin group (Mandel 1996a). One study reported middle ear fluid cul-
(Casselbrant 1992a; Leach 2008; Mandel 1996a; Principi 1989a; ture results for S. pneumoniae (but not resistant strains) and H.
Roark 1997a; Sih 1993a; Teele 2000a); ampicillin (Maynard influenzae (including beta-lactamase producing strains) by group
1972a); or penicillin V (Persico 1985a). Only three studies did not (Casselbrant 1992a). Others failed to report microbiological find-
use a placebo treatment in their control group (Gaskins 1982a; ings by group (Gray 1981; Perrin 1974a; Persico 1985a), com-
Persico 1985a; Schuller 1983a). Two studies used a no-treatment bined pre- and post cross-over data (Liston 1983a), or performed
control group (Gaskins 1982a; Persico 1985a). One study had microbiological studies on immunocompromised patients alone
both a no-treatment control group and another control group (Gaskins 1982a).
where symptomatic use of antihistamines for a blocked nose was
recommended (Schuller 1983a). Excluded studies
In nine studies the antibiotics were given once daily (Casselbrant
One study was excluded because children also received tympanos-
1992a; Gray 1981; Mandel 1996a; Maynard 1972a; Persico
tomy tubes at the time of randomisation (Koivunen 2004). None
1985a; Principi 1989a; Roark 1997a; Sih 1993a; Teele 2000a).
of the other excluded studies assessed the impact of antibiotics on
Eight studies used a twice-daily dose (Gaskins 1982a; Gonzalez
AOM with a valid control group (see Characteristics of excluded
1986a; Leach 2008; Liston 1983a; Perrin 1974a; Roark 1997a;
studies table).
Schuller 1983a; Varsano 1985a). One study included a once-daily
treatment arm and a twice-daily treatment arm (Roark 1997a).
Three studies continued treatment for less than three months
(Roark 1997a; Schwartz 1982a; Varsano 1985a). Three stud- Risk of bias in included studies
ies continued treatment for three months (Liston 1983a; Perrin The overall quality was high with nine studies providing a descrip-
1974a; Sih 1993a). Six studies continued treatment for three to tion of the random assignment or stating random assignment and
six months (Gaskins 1982a; Gonzalez 1986a; Leach 2008; Persico providing group similarity details, and nine studies providing ad-
1985a; Principi 1989a; Teele 2000a). Four studies continued treat- equate information on allocation concealment. Fourteen studies
ment for more than six to 12 months (Gray 1981; Mandel 1996a; had at least the outcome assessor blinded. Nine studies reported
Maynard 1972a; Schuller 1983a), and one had a two-year inter- outcomes for all randomized children in each group; 10 studies
vention period (Casselbrant 1992a). measured outcomes in over 90% of participants and evaluated
All studies used active surveillance and the interval between clin- withdrawals as treatment failures. Standardised assessments were
ical reviews ranged from: monthly (Casselbrant 1992a; Gonzalez used in 14 studies. Agreement was highest for blinding (agree-
1986a; Leach 2008; Liston 1983a; Mandel 1996a; Maynard ment 94%, kappa 0.76) and reporting by allocated group (agree-
1972a; Roark 1997a; Sih 1993a; Teele 2000a); greater than one, ment 88%, kappa 0.75); and lowest for allocation concealment
to three-monthly (Gaskins 1982a; Perrin 1974a; Principi 1989a; (agreement 69%, kappa 0.35) and outcome assessment (agree-
Varsano 1985a); three monthly (Persico 1985a; Schuller 1983a; ment 81%, kappa -0.1). Consensus was readily achieved by re-
Schwartz 1982a); or was unclear (one to three-monthly) (Gray reviewing original publications. A third author was not required
1981). No studies relied only on presentation to a health provider to achieve consensus (Table 1).
to document episodes of illness. All but two studies, in which it
was unclear (Gray 1981; Perrin 1974a), also included episodes de- Summary number of studies meeting high quality for
tected during presentation. each quality measure
Compliance with antibiotics was reported by most studies. Only
1. Randomisation: nine studies (Casselbrant 1992a; Gonzalez
two studies (Gray 1981; Maynard 1972a) compared outcomes for
1986a; Leach 2008; Liston 1983a; Mandel 1996a; Principi
high or not-high compliance by group.
1989a; Roark 1997a; Schwartz 1982a; Teele 2000a).
2. Allocation concealment: 10 studies (Casselbrant 1992a; Allocation
Gonzalez 1986a; Gray 1981; Leach 2008; Liston 1983a; Mandel Overall, allocation generation and concealment was recorded and
1996a; Perrin 1974a; Roark 1997a; Schwartz 1982a; Teele was appropriate in 9/17 studies (53%) - see additional Table 1. Any
2000a). associated bias may exaggerate the pooled estimate of beneficial
3. Blinding: 14 studies (Casselbrant 1992a; Gonzalez 1986a; effect of the intervention.
Gray 1981; Leach 2008; Liston 1983a; Mandel 1996a; Maynard
1972a; Perrin 1974a; Persico 1985a; Principi 1989a; Roark
1997a; Schwartz 1982a;Teele 2000a; Varsano 1985a). Blinding
4. Reporting by allocated group: eight studies (Casselbrant Overall blinding was reported and appropriate in 14/17 studies
1992a; Gaskins 1982a; Leach 2008; Mandel 1996a; Maynard (82%). This was achieved through the use of placebo medications.
1972a; Principi 1989a; Roark 1997a; Teele 2000a). Any associated bias is unlikely to have much impact on the pooled
5. Follow up: 10 studies (Casselbrant 1992a; Gaskins 1982a; estimate of beneficial effect of the intervention.
Gray 1981; Leach 2008; Mandel 1996a; Maynard 1972a; Perrin
1974a; Persico 1985a; Principi 1989a; Teele 2000a).
Incomplete outcome data
6. Outcome assessment: 14 studies (Casselbrant 1992a;
Gaskins 1982a; Gonzalez 1986a; Leach 2008; Liston 1983a; Overall, outcome data were reported and complete for more than
Mandel 1996a; Persico 1985a; Principi 1989a; Roark 1997a; 90% of participants in 10/17 studies (59%). Any associated bias
Schuller 1983a; Schwartz 1982a; Sih 1993a; Teele 2000a; may alter the pooled estimate of effect of the intervention. The
Varsano 1985a). direction of any associated bias is not clear.
We categorised four studies as high quality for all six components of
quality that we assessed (Casselbrant 1992a; Leach 2008; Mandel Selective reporting
1996a; Teele 2000a). We categorised eight studies as high qual- Most of the trials were conducted prior to requirement for trial
ity for randomisation and allocation concealment (Casselbrant registration. However, most studies reported the same primary
1992a; Gonzalez 1986a; Leach 2008; Liston 1983a; Mandel outcome (making selective reporting unlikely). Selective reporting
1996a; Perrin 1974a; Roark 1997a; Teele 2000a). We categorised of secondary outcomes is possible.
12 studies as high quality for blinding of outcome assessment
(Casselbrant 1992a; Gonzalez 1986a; Leach 2008; Liston 1983a;
Mandel 1996a; Maynard 1972a; Perrin 1974a; Persico 1985a; Other potential sources of bias
Principi 1989a; Roark 1997a; Teele 2000a; Varsano 1985a). We There were no other important sources of bias related to the con-
decided that the studies were sufficiently clinically homogeneous duct of the included studies identified. Publication or small study
for meta-analysis. bias is possible (see Figure 1).
Figure 1. Funnel plot of comparison: 1 Antibiotic versus control - primary outcomes, outcome: 1.1
Prevention - any AOM or CSOM during intervention.
proportion of children with recurrent AOM or CSOM at end of

Effects of interventions treatment. Only one study provided data on long-term outcomes.
See: Summary of findings for the main comparison Antibiotic Clinical side effects of treatment were reported in 12 studies. In
versus control - primary outcomes for the prevention of acute these studies, the use of long-term antibiotics was not associated
and chronic suppurative otitis media in children; Summary of with a significant increase in adverse events.
findings 2 Antibiotic versus control - secondary outcomes for For the following prespecified analyses there were no data available
the prevention of acute and chronic suppurative otitis media in and no forest plots produced: i) Prevention - any AOM or CSOM
children following cessation of intervention at one to two months, three
Seventeen studies involving 1586 children met our inclusion cri- to five months, 12 to 23 months, and more than 23 months; ii)
teria. All studies enrolled children at increased risk of AOM and Prevention - any AOM or CSOM during intervention in high-
in seven studies the children met the accepted criteria for being risk children; and iii) Prevention - episodes of AOM or CSOM
prone to otitis (three episodes in the previous six months or four during intervention in high-risk children.
episodes in the previous 12 months). Most eligible studies reported 01 Primary outcomes
data on our two primary outcomes (14 studies reported on any
AOM and 13 studies reported on rates of AOM). One study com-
bined AOM and otitis media with effusion (OME) episodes and 1. Prevention - any AOM/CSOM during intervention
thus contributed no data to this analysis (Schwartz 1982a). Long- Fourteen studies involving 1461 children assessed this outcome
term antibiotics reduced any episode of AOM and the number (Casselbrant 1992a; Gaskins 1982a; Gonzalez 1986a; Leach 2008;
of episodes of AOM. The benefits were modest (absolute risk re- Liston 1983a; Mandel 1996a; Maynard 1972a; Perrin 1974a;
duction of 20%) but highly statistically significant. The results of Persico 1985a; Principi 1989a; Roark 1997a; Sih 1993a; Teele
individual studies were statistically heterogeneous but this was not 2000a; Varsano 1985a). The size of the studies varied from 21 to
sufficient to prevent pooling of studies. No study described the 364 participants. The quality of the included studies was variable.
Overall, 293 of 800 children (37%) in the antibiotic group and One study involving 103 children assessed this outcome (Leach
368 of 661 children (56%) in the control group experienced at least 2008). Eighteen of 52 versus 24 of 51 children had AOM or
one episode of AOM during the intervention period. The pooled CSOM at the end of therapy (RR 0.74, 95% CI 0.46 to 1.18).
risk ratio was 0.65 (95% CI 0.53 to 0.79; random-effects model,
I2 = 68%). We estimated that this is equivalent to an absolute risk
reduction of 21%. In other words, you would need to treat five 3. Prevention - any AOM/CSOM following cessation of
children (95% CI 4 to 6) with long-term antibiotics to prevent intervention
one child experiencing an episode of AOM while on treatment. Only one study reported findings after the intervention period
(Teele 2000a). At six to 11 months, 51 of 76 (67%) children in
the antibiotic group and 32 of 41 (78%) in the control group
2. Prevention - episodes of AOM/CSOM during intervention experienced AOM (RR 0.86, 95% CI 0.69 to 1.08). None of
Thirteen studies involving 1327 children assessed this outcome these children were reported to have CSOM. There were no data
(Casselbrant 1992a; Gaskins 1982a; Gonzalez 1986a; Gray 1981; reported on AOM following cessation of intervention for any of
Leach 2008; Liston 1983a; Mandel 1996a; Maynard 1972a; the other proposed follow-up times.
Principi 1989a; Roark 1997a; Schuller 1983a; Sih 1993a; Varsano
1985a). The number of events in each study varied from 10 to
4. Prevention - episodes of illness during intervention
259 AOM episodes. The rate of AOM per child year varied from
less than one to more than seven (see Table 2). We categorised None of the studies reported directly on rates of illness during
three studies as high quality for all six components of quality that the intervention period. One study reported rates of penicillin
we assessed (Casselbrant 1992a; Leach 2008; Mandel 1996a), and injections for illnesses other than OM (Maynard 1972a). Fewer
seven as high quality for randomisation and allocation conceal- injections were given to children in the amoxicillin group (318
ment (Casselbrant 1992a; Gonzalez 1986a; Leach 2008; Liston injections to 165 children or 1.93 per child-year) than the placebo
1983a; Mandel 1996a; Principi 1989a; Roark 1997a). Overall, group (412 injections to 179 children or 2.30 per child-year) (in-
464 events occurred in the antibiotic group and 863 in the control cidence rate ratio (IRR) 0.84, 95% CI 0.72 to 0.97).
group. The pooled incidence rate ratio was 0.51 (95% CI 0.39
to 0.66; random-effects model). The studies were statistically het-
5. Side effects - any clinical side effects during intervention
erogeneous (P = 0.0001, I2 = 73%). The average rate of AOM in
children in the control group was around three episodes per child- Twelve studies involving 817 children reported side effects (
year. Assuming the effect of antibiotics persists over any treatment Casselbrant 1992a; Gaskins 1982a; Gonzalez 1986a; Gray 1981;
period, a child (typical of those included in these trials) will have Leach 2008; Liston 1983a; Perrin 1974a; Principi 1989a; Schuller
their rate of AOM reduced to 1.5 episodes per year. That is to say, 1983a; Sih 1993a; Teele 2000a; Varsano 1985a). Ten of 457 chil-
on average, antibiotics will prevent 1.5 episodes of AOM for every dren in the antibiotic group and three of 360 in the control group
12 months of treatment per child. experienced side effects (RR 1.99, 95% CI 0.25 to 15.9; random-
effects model, I2 = 53%).
02 Secondary outcomes - first primary outcome (any

6. Side effects - any antibiotic resistance during intervention
AOM/CSOM during intervention)
Two studies reported carriage of resistant respiratory bacterial
pathogens (Casselbrant 1992a; Mandel 1996a). Overall, 31 of
101 (30.7%) of the antibiotic group and 18 of 80 (22.5%) of the
1. Prevention - any rAOM/CSOM during intervention
control group carried beta-lactamase resistant H. influenzae or M.
Five studies involving 329 children assessed this outcome (Gaskins catarrhalis, or both, at three to four months post-study entry (RR
1982a; Liston 1983a; Principi 1989a; Sih 1993a; Teele 2000a). 1.37, 95% CI 0.83 to 2.26); fixed-effect model, I2 = 0%).
The size of the studies varied from 21 to 117 participants. Overall,
nine of 211 (4.2%) children in the antibiotic group and 12 of 118
(10.2%) in the control group experienced recurrent AOM during 03 Subgroup analyses - first and second primary
the intervention period. The pooled risk ratio was 0.45 (95% CI outcomes (any AOM/CSOM and episodes of
0.20 to 1.01, fixed-effect model; I2 = 5%). No studies reported AOM/CSOM during intervention)
data on CSOM.
1. Children less than 12 months or age, older than 12

2. Prevention - any AOM/CSOM at end of intervention months or not separated
Two studies reported any AOM/CSOM during intervention in 4. High-risk populations or not high-risk populations
children less than 12 months of age (Leach 2008; Teele 2000a). Two studies (Leach 2008; Maynard 1972a) reported outcomes
Seventy-one of 128 (55%) children in the antibiotic group and 65 from a high-risk population (defined as a population with a CSOM
of 92 (71%) in the control group had AOM/CSOM (RR 0.81, prevalence rate of 4% or more). Overall, 82 of 255 children in
95% CI 0.45 to 1.44). Two studies reported episodes of AOM/ the antibiotic group and 113 of 242 children in the control group
CSOM during intervention in children aged less than 12 months experienced any AOM/CSOM (RR 0.81, 95% CI 0.44 to 1.5).
(Leach 2008; Roark 1997a); 127 episodes were reported in the There were 177 episodes of AOM or CSOM in the antibiotic
antibiotic group and 121 in the control group (IRR of 1.00, 95% group and 262 episodes in the control group (IRR 0.67, 95% CI
CI 0.6 to 1.7). Only one study reported any AOM/CSOM in 0.42 to 1.08). Removing these studies from the pooled analysis
children older than 12 months (RR 0.06, 95% CI 0.0 to 0.99) for any AOM/CSOM or episodes of AOM/CSOM did not sub-
(Gaskins 1982a). Two studies reported episodes of AOM/CSOM stantially change the pooled estimates (RR 0.62, 95% CI 0.51 to
in children older than 12 months (IRR 0.56, 95% CI 0.09 to 0.76; random-effects model, I2 = 56%) (IRR 0.51, 95% CI 0.3
3.67) (Gaskins 1982a; Roark 1997a). Studies that did not separate to 0.87; random-effects model, I2 = 90%).
age had a pooled risk ratio for prevention of AOM/CSOM (RR
0.7, 95% CI 0.59 to 0.84; random-effects model, I2 = 45%) that
was consistent with the overall estimate. 04 Sensitivity analyses - first and second primary
outcomes (any AOM/CSOM and episodes of
AOM/CSOM during intervention)
2. Otitis-prone children, non-otitis prone, or not separated

We conducted a range of sensitivity analyses. In all of these meta-
analyses (excluding compliance) the pooled effect size remained
Seven studies involving 636 children reported any AOM/CSOM consistent with the overall pooled effect size for both primary out-
during the intervention for otitis-prone children (Casselbrant comes. The studies included in this meta-analysis were statistically
1992a; Gonzalez 1986a; Liston 1983a; Persico 1985a; Principi heterogeneous (P = 0.02, I2 = 52%). This statistical heterogeneity
1989a; Roark 1997a; Varsano 1985a). There were 156 of 366 was less marked (but still significant) if the odds ratio rather than
(42.6%) children in the antibiotic group and 167 of the 270 risk ratio was used (P = 0.06, I2 = 42%). We used the sensitivity
(61.9%) children in the control group with AOM/CSOM (RR analyses to explore the potential causes of this heterogeneity. All of
0.73, 95% CI 0.61 to 0.88; random-effects model, I2 = 33%). the planned sensitivity analyses provided pooled estimates of effect
Eight studies reported episodes of AOM/CSOM in otitis-prone that were consistent with the overall estimate (see below). Visual
children (Casselbrant 1992a; Gonzalez 1986a; Gray 1981; Liston assessment of the funnel plot asymmetry identified four smaller
1983a; Principi 1989a; Roark 1997a; Schuller 1983a; Varsano studies that described the largest effect of antibiotics (RR 0.33,
1985a). Overall, there were 264 episodes in the antibiotic groups 95% CI 0.2 to 0.54; random-effects model, I2 = 0%). Removal of
and 532 in the control group (IRR 0.52, 95% CI 0.37 to 0.73; these studies from the pooled analysis did not change the pooled
random-effects model, I2 = 73%). One study (Teele 2000a) re- estimate of effect but did reduce the heterogeneity between studies
ported slightly greater benefits in prevention of any AOM/CSOM (RR 0.7, 95% CI 0.6 to 0.82; I2 = 34%).
in non-otitis prone children (RR 0.6, 95% CI 0.42 to 0.84). Stud-
ies that did not separate otitis-prone and non-otitis prone had
a greater benefit of antibiotics in the prevention of any AOM/ 1. Study quality
CSOM (RR 0.51, 95% CI 0.30 to 0.87; random-effects model, I Pooling the results of studies with high-quality randomisation and
2 = 83%). Similarly for prevention of episodes of AOM/CSOM,
allocation concealment resulted in a reduced (but still statistically
benefits were greater in studies that did not separate otitis-prone significant) effect of the intervention (RR 0.75, 95% CI 0.59 to
from non-otitis prone children (RR 0.47, 95% CI 0.29 to 0.76; 0.95; random-effects model, I2 = 67%) (IRR 0.63, 95% CI 0.45
random-effects model, I2 = 73%). to 0.88; random-effects model, I2 = 70%). The studies without
high-quality randomisation and allocation concealment estimated
a larger effect size (RR 0.53, 95% CI 0.40 to 0.69; I2 = 39%) (IRR
0.43, 95% CI 0.31 to 0.59; I2 = 39%). Although most studies had
3. High-risk children or not high-risk children
at least one high-quality feature, only three studies that reported
No studies reported outcomes for high-risk children (defined as any AOM/CSOM (283 children) were categorised as high quality
children who had experienced an episode of AOM with perfora- for all six criteria (Casselbrant 1992a; Mandel 1996a; Teele 2000a).
tion) at time of randomisation. One study (Maynard 1972a) ap- The pooled risk ratio for prevention of any AOM/CSOM from
peared to include a large proportion of children who had previ- these three studies (RR 0.61, 95% CI 0.50 to 0.76; I2 = 2.5%)
ously experienced AOM with perforation. The outcomes for this removed heterogeneity but remained consistent with the overall
subgroup of children were not described. estimate.
2. Study size CSOM (RR 0.71, 95% CI 0.58 to 0.86; random-effects model,
Smaller studies (fewer than 100 participants) tended to describe I2 = 67%) was consistent with the overall estimate. Less frequent
a larger effect size (RR 0.49, 95% CI 0.3 to 0.8; random-effects surveillance (four to six-weekly or three-monthly) in five studies
model, I2 = 74%) than larger studies (more than 100 children) (RR estimated a greater benefit of antibiotics for prevention of any
0.72, 95% CI 0.57 to 0.89; I2 = 70%) (Casselbrant 1992a; Leach AOM/CSOM (RR 0.45, 95% CI 0.28 to 0.72; random-effects
2008; Mandel 1996a; Maynard 1972a; Persico 1985a; Roark model, I2 = 58%) and for prevention of episodes of AOM/CSOM
1997a; Teele 2000a). Similarly for studies that reported prevention (IRR 0.32, 95% CI 0.19 to 0.56; random-effects model, I2 =
of episodes of AOM/CSOM, smaller studies indicated a larger 74%).
benefit (IRR 0.42, 95% CI 0.3 to 0.61; random-effects model, I
2 = 57%) than larger studies (IRR 0.62, 95% CI 0.44 to 0.87;
6. Differences in the date of study
random-effects model, I2 = 78%). This apparent study size effect
may be due to publication bias (see Figure 1). The pooled estimates of effect were consistent between studies
conducted in the 1970s, 1980s and 1990s. The only study con-
ducted since 2000 indicated no benefit of antibiotics over placebo
3. Variation in inclusion criteria for any AOM/CSOM (RR 1.06, 95% CI 0.85, 1.33; random-
Sensitivity analyses examining a range of differences in entry cri- effects model) or episodes of AOM or CSOM (IRR 0.85, 95%
teria did not identify any important effect measure modification. CI 0.65 to 1.12; random-effects model). However, a reduction
Potentially the most important inclusion criterion is the presence in rates of perforation was observed (an outcome not assessed in
or absence of ear disease at the time of randomisation. Three stud- this review). At this point in time, there is a lack of evidence from
ies (332 children) randomized children free of middle ear effu- randomized trials of antibiotics to prevent AOM in populations
sion (MEE) at the start of treatment (Casselbrant 1992a; Mandel conducted in the era of relatively high rates of penicillin-resistant
1996a; Sih 1993a). The pooled risk ratio for prevention of any pneumococcal infection.
AOM/CSOM (RR 0.53, 95% CI 0.35 to 0.80; I2 = 48%) was
consistent with the overall estimate.
7. Analysis by compliance
Where reported, compliance with recommended treatment was
4. Differences in medications used (class or regimen) generally high and there was little difference in compliance be-
A range of antibiotics, doses and regimens were used in the stud- tween antibiotic and control groups. Two studies (Gray 1981;
ies. In eight studies (1131 children) antibiotics were given once Maynard 1972a) formally compared outcomes between ’compli-
daily (Casselbrant 1992a; Mandel 1996a; Maynard 1972a; Persico ers’ and ’non-compliers’. One study (Maynard 1972a) reported
1985a; Principi 1989a; Roark 1997a; Sih 1993a; Teele 2000a). any AOM/CSOM; a greater benefit of antibiotics over placebo
The pooled risk ratio for prevention of any AOM/CSOM was was seen in the high compliance group (RR 0.47, 95% CI 0.29
consistent with the overall estimate (RR 0.61, 95% CI 0.52 to to 0.76) compared to a non-significant benefit in the not high
0.72; I2 = 30%). Similarly, we were not able to identify any im- compliance group (RR 0.77, 95% CI 0.5 to 1.19). A highly sig-
portant differences in outcome according to the major classes of nificant benefit of antibiotics over placebo in preventing episodes
antibiotics used or the duration of the intervention period. of AOM/CSOM was noted for high compliance (IRR 0.36, 95%
CI 0.24 to 0.54; I2 = 0) compared to a non-significant benefit
for not high compliance (IRR 0.87, 95% CI 0.62 to 1.22; I2 =
5. Differences in outcome measurement 0%). The pooled incidence rate ratio for prevention of episodes of
In nine studies (1100 children) monthly active surveillance was AOM/CSOM in these studies (IRR 0.61, 95% CI 0.35 to 1.07;
applied (Casselbrant 1992a; Gonzalez 1986a; Liston 1983a; Leach random-effects model, I2 = 75%) was associated with significant
2008; Mandel 1996a; Maynard 1972a; Roark 1997a; Sih 1993a; heterogeneity and was substantially less than the overall estimate
Teele 2000a). The pooled risk ratio for prevention of any AOM/ (IRR 0.48, 95% CI 0.37 to 0.62; I2 = 65%).
Antibiotics for the prevention of acute and chronic suppurative otitis media in children (Review) A D D I T I O N A L S U M M A R Y O F F I N D I N G S [Explanation]
Antibiotic versus control - secondary outcomes for the prevention of acute and chronic suppurative otitis media in children
Patient or population: patients with the prevention of acute and chronic suppurative otitis media in children
Settings:
Intervention: Antibiotic versus control - secondary outcomes
Outcomes Illustrative comparative risks* (95% CI) Relative effect No of Participants Quality of the evidence Comments
(95% CI) (studies) (GRADE)
Assumed risk Corresponding risk
Control Antibiotic versus control

- secondary outcomes
Side effects - any clin- 8 per 1000 16 per 1000 RR 1.99 817 ⊕⊕⊕
ical side effects during (2 to 127) (0.25 to 15.89) (12 studies) moderate1
intervention
*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the
assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).
CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence

High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.
1 Small number of adverse events noted.
16
DISCUSSION even in children randomized to placebo or no treatment. The con-
trol event rate for any AOM during the intervention period varied
from 40% to 85%. Overall, 56% of children enrolled in these
trials and randomized to the control group experienced one or
Strength of evidence more episodes of AOM; they experienced around three episodes
of AOM per child-year. This review did provide some evidence
The evidence contained within this review is consistent with an-
that the relative benefit of antibiotics was reasonably consistent
tibiotics preventing any AOM in children at risk of future infec-
across a range of risk groups. Therefore, the potential benefit is
tions. This conclusion is based on the results of 14 RCTs involv-
most readily determined by the baseline risk. Since the risk of dis-
ing 1461 children. The estimated effect size was a 35% reduction
ease also tends to resolve spontaneously over time, children who
in risk of experiencing any episode of AOM (RR 0.65, 95% CI
have either persistently frequent or severe episodes of AOM are
0.53 to 0.79 for any episode of AOM). In the 13 RCTs involving
most likely to benefit. For children living in temperate climates
1215 children, a similar reduction in episodes of AOM/CSOM
the baseline risk is considerably higher during winter (Rosenfeld
during the intervention period was described (IRR 0.51, 95% CI
2003).
0.39 to 0.66 for rates of AOM). These results were not substan-
tially affected by a range of sensitivity analyses. The clinical im-
portance of this beneficial effect was limited by the spontaneous
reduction in rates of AOM over time in children not receiving
treatment. If these studies are valid, and there is no publication Other relevant information
bias, the probability that antibiotics appeared effective by chance The results of this systematic review are consistent with previous
alone is remote. More than half of the studies used appropriate systematic reviews and evidence summaries of the use of antibi-
methods of randomisation and blinding. The effect size tended to otics to prevent AOM. They are also consistent with the size of the
be slightly larger in the studies that were of poorer quality or were beneficial effect described in the systematic review of pneumococ-
small. However, exclusion of these studies had little impact on the cal vaccines. Antibiotics have also been shown to be similarly ef-
pooled effect size. fective in treating AOM and other mucosal respiratory infections
Overall, the observed beneficial effect of antibiotics cannot be ex- such as sore throat, persistent rhinosinusitis and bronchitis.
plained by bias or co-intervention. The pooled effect size was also There is some evidence that the frequency of AOM diagnosed
clinically consistent with the results from individual studies. How- by clinicians has increased but the severity of episodes (as deter-
ever, there was some statistical heterogeneity that could not be mined by tympanic membrane perforation) has decreased. If we
easily explained. There may be other factors not measured in the assume that the total number of respiratory infections experienced
individual studies that influence outcome. The conclusion that by young children has not changed substantially, it may be that
antibiotics are effective in the prevention of AOM is supported clinicians are identifying AOM in children previously thought to
by the knowledge that AOM is often a bacterial infection, which have a non-specific viral upper respiratory infection. Whether the
antibiotics act to resolve (Rosenfeld 2003). While this review pro- reduction in tympanic membrane perforations is due to changes
vides strong evidence that antibiotics are effective in preventing in the severity or aetiology of the infection or earlier treatment
AOM during the intervention period, the long-term effects of is not clear. An appreciation of the size of the beneficial effect of
the intervention remain uncertain. Long-term use of antibiotics antibiotics, the low risk of long-term complications like CSOM,
should take into account the possibility of developing antibiotic and the association between antibiotic use and antibiotic resistance
resistance and side effects, which are discussed in the ’Trade-offs’ has meant that clinicians in high-income countries are encouraged
section. to withhold antibiotics wherever feasible (Dowell 1999). While
this approach is reasonable, clinicians should be aware that this
decision is based on a trade-off between the benefits and risks of
treatment
Applicability For clinicians using antibiotics to prevent AOM in children, local
Nearly all studies were conducted in developed countries and only knowledge of the resistance patterns of the infecting organisms
two studies involved a population of children at high risk of long- may be helpful. Rates of infection with penicillin-resistant and
term complications such as CSOM (Maynard 1972a). Most stud- multi-resistant pneumococci have increased dramatically since the
ies enrolled children with a history of recurrent AOM. While there mid-1990s (Dowell 1999). Since no studies have been conducted
was statistical heterogeneity in the results this could not be ex- since this time, this review was unable to assess the impact of
plained by biologic or cultural variation, variation in compliance, these changes. More recently, the introduction of the conjugate
or variation in baseline risk. pneumococcal vaccine has meant that rates of penicillin-resistant
Although antibiotics will prevent AOM, the overall beneficial ef- infection are likely to decrease again in countries with a universal
fect is not large. This is because rates of AOM generally decreased childhood immunisation programme.
Trade-offs Quality of the evidence
It would appear that the benefit of antibiotics must be weighed Overall, 17 RCTs (1586 children) have addressed this research
up against the cost and inconvenience of therapy and the risk of question. The quality of evidence included in this review is gener-
occasional side effects. Although the increase in side effects was ally high (see Table 1). The results across the studies are consistent.
not statistically significant in this review, it is generally accepted The pooled estimates of effect are likely to be internally valid and
that antibiotics are associated with a small increased risk of gas- qualitatively reliable. However, sensitivity analyses of high-quality
trointestinal side effects and allergic reactions. How often these studies (see Data and analyses), suggest the true effect may be more
effects lead to withdrawal of the intervention is unclear. In the modest than that described.
studies included within this review only 10 of 405 children in the
antibiotic group and three of 309 children in the control group
experienced significant side effects. Not all studies in this review Potential biases in the review process
reported on side effects or antibiotic resistance, hence there are
limitations to the power of this meta-analysis to detect potentially The most important limitation of this review is that publication or
important adverse events or antibiotic resistance. Antibiotics may small study bias cannot be excluded (see Figure 1). The methods
also influence the prevalence of antibiotic resistance within the used in this review are unlikely to have introduced bias. Both
community. This was only reported by two of the studies included review authors were investigators of one included study.
within the review (Casselbrant 1992a; Mandel 1996a). Although
there was an increase in carriage of antibiotic-resistant pneumo-
cocci or haemophilus in both studies, the pooled estimate was not Agreements and disagreements with other
statistically significant. While this remains an important issue, the studies or reviews
hypothesis that antibiotic use leads to increased antibiotic resis- The findings of this systematic review are similar to the findings of
tance has still not been tested in appropriate large randomized other systematic reviews and evidence-based guidelines. Although
controlled trials. Increasing antibiotic resistance may also limit the the evidence for individual studies appears consistent, the expert
potential benefits of this therapy. Local knowledge of epidemiol- opinion about the role of prophylactic antibiotics has changed over
ogy, aetiology and resistance patterns is likely to be helpful. In time. Currently, many experts propose that the risk of antibiotic
addition to these potential side effects, the cost of purchasing the resistance outweighs the benefit of reduced infection.
medication and the inconvenience of giving it to young children
as instructed must also be taken into account.
AUTHORS’ CONCLUSIONS
Summary of main results
Implications for practice
Prophylactic antibiotics reduce the risk of episodic AOM while
Parents should be advised that, for children at risk of future
on treatment by 20% to 50% (see Summary of findings for the
episodes of AOM, the available evidence suggests that antibiotics
main comparison). This is equivalent to a reduction of one to
given once or twice daily will reduce the probability of AOM while
two episodes per year of treatment. In the studies included in
the child is on treatment. The effects of antibiotics beyond the
this review, prophylactic antibiotics were not associated with a
treatment period are unclear. The benefits indicate that around
significant increase in side effects (see Summary of findings 2).
five children must be treated in order for one child to avoid experi-
encing one or more episodes of AOM. A typical otitis-prone child
who has experienced at least three episodes of AOM in the previous
six months (or at least four episodes in the previous 12 months)
Overall completeness and applicability of will have an average rate of AOM of around three episodes in the
evidence next year even if they receive no treatment. Antibiotics will reduce
There is a reasonable amount of evidence about the impact of the rate of AOM to 1.5 episodes per year (that is to say, antibiotics
prophylactic antibiotics on episodic AOM without perforation in will prevent 1.5 episodes of AOM for every 12 months of treat-
children living in high-income countries. There is still uncertainty ment per child). Larger absolute benefits are likely in children who
about the impact of prophylactic antibiotics on episodic AOM have more frequent or more severe AOM. These conclusions are
with perforation and CSOM, and the impact on all forms of AOM based on a large number of randomized controlled trials and are
in children living in low-income countries. The results are consis- not affected by sensitivity analyses. The overall pooled estimate of
tent across the studies. The pooled estimates of effect are likely to effect is unlikely to change dramatically as additional data become
be applicable to similar populations. available.
Antibiotics are not without risk. In these studies around one addi- infections. Outcomes should be assessed at the completion of the
tional child experienced diarrhea or an allergic reaction for every intervention and again at least three to six months later. Addi-
100 treated. This difference was not statistically significant. Un- tional research is needed to examine the impact of antibiotics on
necessary antibiotic prescribing may also contribute to increasing the bacteria infecting the nasopharynx. Any subsequent increases
rates of antibiotic resistance. Parents or children who place great- in antibiotic resistance should be described.
est value on avoidance of any further episodes of AOM during
the treatment period and who are willing to risk the possible side
effects associated with this intervention are most likely to choose
antibiotic therapy. ACKNOWLEDGEMENTS
This review is dedicated to the investigators and participants of
Implications for research the original relevant randomized controlled trials. Thanks to:
Despite increasing concern about inappropriate antibiotic pre- John Mathews (formerly of the Menzies School of Health Re-
scribing for the prevention of AOM, this intervention is associated search, Darwin, Australia) for supervision and advice; Liz Doo-
with some benefits. The challenge is to now identify the children ley and Sarah Thorning at the Cochrane Acute Respiratory Infec-
for whom the absolute benefits outweigh the potential risks of tions Group for ongoing assistance and support; and the National
long-term antibiotic treatment. Consequently, large simple trials Health and Medical Research Council of Australia for funding.
comparing the effects of antibiotics with placebo in children at The authors also wish to thank the following people for comment-
greatest risk of complications of AOM, children at high risk (chil- ing on the first draft review: Marilyn Oates, Michael Pichichero,
dren with previous perforation), and children living in high-risk Maroeska Rovers, Sree Nair and Tom Fahey; and the following
populations would provide useful information. Children should people for commenting on this updated draft: Ann Fonfa, Brian
be stratified according to the frequency and severity of previous Westerberg, Bhavneet Bharti, Teresa Neeman and Tom Fahey.
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CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Casselbrant 1992a
Methods Double-blind
Random assignment (method not stated)
Stratified by seasonal occurrence of previous AOM and by age group
Review monthly plus ENT illnesses
Group similarity reported (T1)
Participants Pittsburgh, USA

March 1981 to January 1988
Eligibility - children 7 to 35 months (mo) of age with rAOM (more than 2 AOMs in
6 mo or more than 3 in 12 mo if mainly in previous 6 mo). Exclusion - potentially
complicating or confounding conditions
Number eligible not given. 264 enrolled, allocation: 90 amoxicillin; 88 placebo; 86
tympanostomy (not used in this analysis)
Baseline characteristics age, recent OM history, sex, race, site, parent occupation and
season comparable for all 264
Interventions 2 years
Amoxicillin (20 mg/kg/d, daily (OD))
Placebo
Outcomes Measured in more than 90%

Format of reporting - rate (episodes of new AOM per child-year) (95% CI), median
time to first AOM, mean proportion of time with any OM (95% CI)
Diagnostic criteria - otoscopic signs, OR more than 1 symptom in the presence of MEE
of both. Signs - erythema or white opacity, fullness or bulging and decreased mobility.
Symptoms - fever, otalgia and irritability
Subgroups - age, seasonality of OM history, sex, race, season at entry
Microbiology - 3-monthly NP and OP - only report carriage of beta-lactamase positive
Hi or M. cat by allocated group (AOM and OME combined). MEF - Spn, Hi and M.
cat and beta-lactamase positive Hi and M. cat by allocated group and diagnosis
Notes Q: AAAAAA
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection Low risk A - randomisation method correct, or ran-
bias) domisation stated and group similarity
documented
Allocation concealment (selection bias) Low risk A - concealment method correct, or con-
cealment stated and group similarity doc-
umented
Casselbrant 1992a (Continued)
Blinding (performance bias and detection Low risk A - participant, care provider and outcome
bias) assessor blinded
All outcomes
Incomplete outcome data (attrition bias) Low risk A - the progress of all randomized chil-
All outcomes dren in each group described and outcomes
measured in more than 90% (where with-
drawals due to complications and side ef-
fects were categorised as treatment failures)
A - outcomes measured in more than 90%
(where withdrawals due to complications
and side effects were categorised as treat-
ment failures)
Selective reporting (reporting bias) Unclear risk Study conducted prior to clinical trial reg-
istration
Other bias Low risk No other potential source of bias identified
Gaskins 1982a
Methods Not blinded

Random assignment, method of randomisation not clear
Review 6 weekly plus at presentations
Participants San Juan, Puerto Rico

Late fall to early Spring. Prior to May 1982
Eligibility - children 1 year (y) to 14 y of age. ’High risk’ more than 3 AOMs in 18 mo,
or 5 AOMs. Exclusion - cleft palate, drug sensitivity, tubes
Number eligible not given. 21 enrolled. Allocation: 10 TMP/SMX, 11 not treated
Baseline characteristics for all; age, race, risk, recent OM history comparable by group
Interventions 6 months
TMP/SMX/ 5 to 8/25 to 40 mg/kg/d BD. Mean dose 6.8/34
No treatment controls

Format of reporting - episodes of AOM per child during therapy
Diagnostic criteria - general symptoms plus any 2 signs; red TM, bulging TM, no
landmarks, abnormal pneumatic otoscopy, tympanocentesis +ve (only 4 done)
Subgroups - none
Microbiology - none
Notes Q:BBCAAA
Risk of bias
Gaskins 1982a (Continued)
Random sequence generation (selection Unclear risk B - randomisation stated but method not
bias) described, or suspect method
Allocation concealment (selection bias) Unclear risk B - unclear
Blinding (performance bias and detection Unclear risk C - unclear

bias)
All outcomes
ment failures)
istration
Other bias Unclear risk No other potential source of bias identified
Gonzalez 1986a
Random number series. Randomised at Pharmacy Dept.
Review monthly plus when AOM suspected
Participants Aurora CO and Tacoma WA, USA

1982 to 1985
Eligibility - children 6 mo to 10 y of age with rAOM (more than 2 AOMs in 6 mo or
more than 4 AOMs in 18 mo). With or without OME at entry. Exclusion: cleft palate,
Down’s syndrome, tubes, sensitivity
Number eligible, enrolled or allocated unclear. 65 completed 6-month follow up, 63
analysed; 21 sulfisoxazole, 20 placebo, 22 tubes
Baseline characteristics for 63; sex, mean age (CI not provided) comparable by group
Sulfisoxazole (500 mg for less than 5 y; 1 g for more than 5 y)
Placebo
Gonzalez 1986a (Continued)
Outcomes Measured in less than 90%

Format of reporting - % patients with 0, 1, 2, 3 or 4 episodes of AOM. Attack rate
(AOMs per child during therapy), AOM-free, more than 0 AOM, more than 1 AOM
in 3 mo (treatment failure)
Diagnostic criteria - rapid and short onset of signs and symptoms of inflammation
(otalgia (ear tugging in infant), fever, bulging or erythema, decreased mobility, loss of
TM landmarks, otorrhoea)
Subgroups - diagnosis at entry
Microbiology - none
Notes Q: AAACCA
Excluded children more than 4 y (unclear if randomized)
Risk of bias
documented
umented
All outcomes
Incomplete outcome data (attrition bias) Unclear risk C - the progress of all randomized children
All outcomes in each group obviously not described
C - unclear
istration
Gray 1981
Randomly assigned. Dispensed by pharmacy
Review schedule not provided. Possibly presentations with illness only
Group similarity reported by allocated group and compliance category within the SXT
group (text)
Gray 1981 (Continued)
Participants Alabama, USA

Eligibility - infants with more than or equal to 2 OM beginning in the first 12 mo of
life. At least 1 episode documented by culture. No exclusion criteria listed
Number eligible not provided. 48 enrolled; 26 SXT, 24 placebo (2 infants re-enrolled)
Baseline characteristics - OM history and age comparable by group
Sulfamethoxazole-trimethoprim (4 mg TMP per 20 mg SX per kg/d). Daily - possibly
once daily
Placebo

Format of reporting - episodes of OM per group. Mean +/-SD episodes per patient
Diagnostic criteria - tympanocentesis and culture
Subgroup - compliance
Microbiology - periodic cultures. Reported number of types carried and proportion with
resistance by allocated group
Notes Q: CAABAB
Two infants had 1 y placebo, 1 y SXT
Risk of bias
Random sequence generation (selection Unclear risk C - randomisation claimed but not de-
bias) scribed, and outcome assessor not blinded
umented
All outcomes
Incomplete outcome data (attrition bias) Unclear risk B - unclear or no mention of withdrawals
All outcomes or drop-outs
ment failures)
istration
Leach 2008
Methods Double-blind, placebo-controlled

Random sequence computer-generated with allocation concealed. Stratified by age
Review 4 weekly
Participants Australia. 3 remote Aboriginal communities 70 km from Darwin in tropical northern

Australia
1996 to 2001 (prior to conjugate vaccine introduction)
Eligibility - Aboriginal children less than 12 months of age with unilateral or bilateral
OME. Exclusion - less than 34 weeks gestation, chronic infection requiring prophylactic
antibiotic therapy, craniofacial abnormalities or immune deficiency syndromes
Number eligible - 188 births, 126 assessed for eligibility, 103 randomized, allocation:
52 amoxicillin; 51 placebo
Baseline characteristics age, gestation, birth weight, sex, recent OM history comparable
for all 103 except for birth weight (placebo group heavier)
Amoxicillin (50 mg/kg/d, daily (BD))
Placebo
Outcomes Measured and analysed in all children

Format of reporting - ear state (primary outcome) and nasopharyngeal carriage at end
of therapy (T3), ear state and nasopharyngeal carriage during therapy (additional file 3),
rate (95% CI) - episodes of new AOMwoP and AOMwiP per child year, nasopharyngeal
carriage per OM pathogen (additional file 4)
Diagnostic criteria (T1) - type B tympanogram plus otoscopic signs of moderate or
marked bulging of the tympanic membrane. Ear examinations were categorised as AOM
without perforation (AOMwoP) even if the child was asymptomatic
Subgroups - none reported
Microbiology - 4 weekly NP - report carriage of Spn, Hi and M. cat and penicillin non-
susceptible Spn and beta-lactamase positive Hi by allocated group
Notes Q: AAAAAA
Risk of bias
documented
umented
All outcomes
Leach 2008 (Continued)
ment failures)
istration
Other bias Low risk No other potential source of bias identified
Liston 1983a
Random number table. Hospital pharmacist
Review monthly plus illnesses
Group similarity reported by group (T2)
Participants San Antonio, Texas, USA

Jan 1978 to June 1979
Eligibility - children 6 mo to 5 y of age. Available for 6 mo. No current AOM. 3 OMs,
one every 2 mo (2 diagnosed by author). Exclusion - cleft palate, tubes or perforations,
known immunodeficiency
Number eligible not provided, 42 enrolled, 43 allocated; 22 sulfisoxazole (one twice),
21 placebo. 35 analysed
Baseline characteristics age, sex, OM history, allergy, season not reported by group
Sulfisoxazole 75 mg/kg/d BD
Placebo

Format of reporting - no. children with 0, 1, 2, 3, 4 or 5 episodes of AOM, by GP, before
and after cross-over. Rate - episodes per patient month by GP
Diagnostic criteria - bulging, opaque or red plus loss of landmarks plus either ’B’ tymp
or discharge through natural perforation
Subgroups - age, sex, OM and allergy histories, child care, season
Microbiology - MEF cultures only. Spn, Hi. Oxacillin screen, beta-lactamase. Cross-over
periods combined
Notes Q: AAACBA
Risk of bias
Liston 1983a (Continued)
documented
umented
All outcomes
B - outcomes measured in 80% to 90%
istration
Mandel 1996a
Randomly assigned in blocks of 4 within 12 stratified groups
Stratified by criterion for entry (OM history) and age
Review monthly and at ENT illness
Participants Pittsburgh, USA

April 1988 to October 1991
Eligibility - children 7 mo to 12 years of age and effusion-free, 4 months OME or >3
episodes OME in previous 12 months and 1 recent episode, and <= 2 episodes AOM
in previous 12 months. Entry criteria revised to 1) if TT in previous 12 mo, TM intact
and MEE for >= 2 weeks in previous 3 months; 2) if no TT in previous 12 months,
>= 3 episodes or 3 months MEE in previous 12 months, or both. All subjects required
documentation of MEE by ENT or research centre clinic at least once or by tympanogram
in previous 3 months. Exclusion - potentially complicating or confounding conditions
Number enrolled 111, 79 completed (25 had less than 1-year follow up), allocation: 57
amoxicillin, 54 placebo
Baseline characteristics: recent OM history, age, race, sex, allergy, socio-economic status
and hearing comparable by group
Amoxicillin (20 mg/kg/d OD)
Placebo
Mandel 1996a (Continued)

Format of reporting - Rates: no. AOM episodes per person year by allocated GP; no.
children with 0, 1, 2, more than or equal to 3 new episodes of AOM; proportion of
children with rAOM, rOME, rMEE; % time with MEE
Diagnostic criteria - otoscopically more than or equal to 1 sign of MEE AND more
than or equal 1 symptom of acute infection. Signs - erythema, white opacity, fullness or
bulging, fluid level, acute perforation. Symptoms - fever, otalgia, irritability
Subgroups - none
Microbiology - 4-monthly throat swabs - report combined carriage of beta-lactamase
positive Hi or M. cat, and Spn by allocated group
Notes Q: AAAAAA
Results exclude subjects with no follow up (2 amox, 3 placebo)
Risk of bias
documented
umented
All outcomes
ment failures)
istration
Maynard 1972a
Randomisation not described
Longitudinal clinical trial. Matched by family size, age, sex, OM history
Review monthly plus presentation, standard care for AOM episodes
Group similarity (age) reported (T1)
Participants West Alaskan villages, USA

Published Jan 1972. Probably conducted between 1969 and 1971
Eligibility - children 0 to 7 y of age previously studied. If consented. Exclusion criteria
not defined
Number eligible not given. 364 enrolled. 173 ampicillin and 191 placebo. All allocated
Baseline characteristics by group: age 49% and 47% less than 3 y, clinical for 153 and
164 (15% and 12% normal ear drums; 92% and 92% intact tonsils), incidence of OM
in preceding year for 164 and 175 “comparable”
Ampicillin (125/5 ml; age 2.5 years 5 ml/d; age more than 2.5 years 10 ml/d)
Placebo
Single dose

Format of reporting - episodes of AOM. New episode after 2 weeks without drainage
Diagnostic criteria - AOM = spontaneous occurrence of purulent drainage from 1 or
both ears
Subgroups - none
Microbiology - none
Notes Q: DBAAAB
Risk of bias
Random sequence generation (selection Unclear risk D - randomisation not mentioned

bias)
All outcomes
Maynard 1972a (Continued)

ment failures)
istration
Perrin 1974a
Cross-over
Randomisation and allocation concealment stated but method not described
Review 6 weekly
Group similarity not reported
Participants Rochester, NY, USA

Dec 1972 to May 1973
Eligibility - children aged 11 mo to 8 y with rAOM (more than or equal to 3 AOMs in
18 m or more than or equal to 5 anytime). Two enrolled did not meet clinical criteria.
Exclusion - anatomic defects, tubes
Number eligible 70, 9 refusals. 61 enrolled. 54 completed the study, allocation: 28
sulfonamide, 26 placebo
Baseline characteristics by group not provided
Sulfisoxazole 500 mg/5 ml. One teaspoon twice daily
Placebo

Format of reporting - episodes of AOM. Proportion of children with more than 1 AOM
in 3 mo. Proportion of children with MEE at 1 mo, 3 mo, 12 mo post-therapy
Diagnostic criteria - clinician diagnosed
Subgroups - none
Microbiology - NP swabs during final 3 visits
Notes Q: BAACAB
Definition of post-therapy unclear - after cross-over?
Risk of bias
Allocation concealment (selection bias) Low risk A - Adequate
Perrin 1974a (Continued)
All outcomes
Incomplete outcome data (attrition bias) High risk C - the progress of all randomized children
ment failures)
istration
Persico 1985a
Methods Outcome assessor blinded

Randomly divided
Review 3-monthly and follow up 6 to 15 mo
Group similarity not reported (matched for age ? pre- or post-allocation)
Participants Israel, Haifa

Submitted May 1984
Eligibility - children aged 3 to 30 mo with more than one AOM or AOM with discharge
per mo during a 3 mo period
Exclusion - numbers eligible not provided, 111 enrolled, 108 with data on primary
outcome; 60 active, 48 no treatment
Baseline characteristics: age distribution given by group but the control group adds to
111%
Interventions At least 3 months

Potassium phenoxymethyl penicillin V 25 mg/kg/d
No treatment

Format of reporting - episodes of AOM. Subacute AOM, SOM
Diagnostic criteria - bulging, red, immobile TM +/- URT symptoms
Subgroups - none
Microbiology - table missing from publication
Notes Q: CBBBAA
Risk of bias
Persico 1985a (Continued)
Random sequence generation (selection High risk C - randomisation claimed but not de-
Allocation concealment (selection bias) Unclear risk B - Unclear
Blinding (performance bias and detection Low risk B - outcome assessor blinded
bias)
All outcomes
Incomplete outcome data (attrition bias) Unclear risk B - unclear or no mention of withdrawals
All outcomes or drop-outs
ment failures)
istration
Principi 1989a
Assigned randomly. Stated but method not described
Review 4 to 6 weekly and when AOM or URTI suspected
Group similarity described (T1)
Participants Milan, Italy

Oct 1986 to Sept 1988
Children aged 9 mo to 5 y with more than 2 AOMs in preceding 6 mo. No AOM at
entry. Exclusion - cleft palate, Down’s syndrome, drug allergy, immunodeficiency, tubes
Numbers eligible not provided, 100 enrolled. Allocation: 34 amoxicillin, 33 SXT, 33
placebo. 96 reported
Baseline characteristics; sex, age, diagnosis, time to most recent AOM, season, day care,
atopy by group
Amox : 20 mg/kg/d. Sulfamethoxazole and trimethoprim (SXT) : 12 mg/kg/d. OD
Placebo

Format of reporting - number of children with number of episodes of AOM during
therapy. Mean no. AOMs per patient, mean no AOMs per patient-month
Diagnostic criteria - AOM = any combination of otalgia and irritation and hyperaemia
or opacity plus fullness, bulging or type B
Subgroups - none
Microbiology - none
Principi 1989a (Continued)
Notes Q: ABAAAA
Risk of bias
documented
All outcomes
ment failures)
istration
Roark 1997a
Randomly assigned (method not described)
Review monthly plus during URT plus onset of pain, fever or severe crying
Participants Denver, CO, USA

Dec 1991 to Sept 1994
Eligibility - children 3 mo to 6 y of age with rAOM. Diagnosis at randomisation not
clear. Exclusion - tubes, anatomic defects, immunodeficiency, allergy to penicillin
Numbers eligible not provided. 194 enrolled. Allocation; 70 amoxycillin (OD), 58
amoxycillin (BD), 66 placebo. Analysis; 55, 44 and 59
Baseline characteristics sex, age, smoke, family OM history, child care, snoring, LRI,
feeding position, mouth breathing, RAD, prematurity, age (mean +/- SD of OM onset,
all comparable by group
Roark 1997a (Continued)
Interventions Up to 90 days or until 2 x AOM (failure). An average of 6.5 weeks (7243 days for 158
children) on study medication (excludes days treated for AOM)
Amoxicillin 20 mg/kg/d OD or BD
Placebo

Format of reporting - incidence density of AOM
Diagnostic criteria - decreased mobility plus red or yellow TM
Subgroups - age, season
Microbiology - none
Notes Q: AAAABA
Risk of bias
documented
umented
All outcomes
istration
Schuller 1983a
Methods Not blinded

Randomly divided on basis of age, sex and allergy. Method of randomisation and allo-
cation concealment not stated
Review 3-monthly plus illness
Group similarity not described
Participants Danville, PA, USA

Presented in Oct 1982, published July 1983
Eligibility - children 2 to 6 y of age with asthma within 6 mo and at least 4 AOMs in
12 mo. Exclusion criteria not stated but no child had enlarged adenoids or tonsils, none
had tubes
Numbers eligible not provided. 80 enrolled (2 moved, 6 non-compliant), 72 completed
2 year study. Allocation of 72: 12 control, 12 symptomatic antihistamine, 12 prophylac-
tic sulfisoxazole 2 years, 6 prophylactic sulfisoxazole 1 year, then pneumococcal vaccine,
12 pneumococcal vaccine, 6 pneumococcal vaccine then sulfisoxazole in 2nd year, 12
pneumococcal vaccine plus sulfisoxazole 2 years. Baseline characteristics mean age com-
parable by group
Interventions 2 years (second year combined therapies used)

Sulfisoxazole 500 mg BD (Group 3)
No treatment (1) or antihistamines when nose blocked (2) or Pneumovax (4) or Pneu-
movax and sulfisoxazole (5)
Outcomes Measured in 72/80 (90%) over all intervention groups

Format of reporting - frequency of AOM episodes per y
Diagnostic criteria - fever more than 38 C, bulging immobile TM
Subgroups - none
Microbiology - none
Notes Q: CCDCBA
Included data from first year only (combined therapies used in year 2)
Risk of bias
Random sequence generation (selection Unclear risk C - randomisation claimed but not de-
Allocation concealment (selection bias) High risk C - Inadequate
Blinding (performance bias and detection High risk D - no blinding of outcome assessor
bias)
All outcomes
Schuller 1983a (Continued)
istration
Schwartz 1982a
Methods Double-blind, cross-over

Method of randomisation unclear (pharmacy prepared, assigned at random by blinded
nurse)
Review 2 - 4 weekly after randomisation, then monthly for 3 months (combined cross-
over periods)
Participants Washington and Virginia, USA

Enrolled between Dec 1979 and January 1980. Published 1982
Eligibility - children 4 to 72 mo of age. Mean 31 mo with more than 3 AOMs in
preceding 12 mo and recent AOM. Exclusion - none described
Numbers eligible not provided. 43 enrolled, 43 allocated; 23 SMX, 20 placebo (pre-
cross-over). 33 completed; 17 SMX, 16 placebo. 10 drop-outs; 6 no follow up, 3 refused
SMX, 1 not accounted
Baseline characteristics not reported by group
Sulfisoxazole 25 mg/kg OD
Placebo
Outcomes Measured in 33/43 (77%)

Format of reporting - number of episodes in 2-month period
OM = 1 bulge of opaque TM. 2. Dec mobility (pneumatic otosc + type B tymp. 3.
Yellow or fiery red TM
Subgroups - tympanometry at baseline
Microbiology - none
Notes Q: AAAADA
Risk of bias
documented
umented
Schwartz 1982a (Continued)
All outcomes
ment failures)
istration
Sih 1993a
Methods Randomised, placebo-controlled

Methods not stated, ’blinding’ not mentioned
Review monthly plus during illness
Group similarity reported
Participants Sao Paulo, Brazil

Enrolled between March 1989 and March 1990. Published 1993
Eligibility - children aged 9 to 108 mo with rAOM (3 AOMs in preceding 12 mo)
. Enrolled with AOM, treated then randomized if type A or C tympanogram and no
symptoms of AOM. Exclusion - type B tympanogram on day 11 of AOM Rx
Number enrolled and randomized 80, 60 completed (20 lost to follow up all enrolled
through public hospital), allocation: 20 amoxicillin, 20TMP-SMX, 20 placebo
Baseline characteristics: age, site, recent OM history, atopy comparable by group
TMP-SMX (12 mg/kg/d) AMX (20 mg/kg/d) OD. Placebo
Outcomes Measured in 75%

Method of reporting - proportion of children with any AOM. Number of episodes for
each child. Number of episodes by month of therapy for placebo and combined antibiotic
groups.
Diagnostic criteria - AOM = acute symptom (pain, irritability, fever, respiratory symp-
toms) and pneumo-otoscopic findings (red, bulging or reduce mobility)
Subgroups - none
Microbiology - none
Notes Q: BBCCDA
Sih 1993a (Continued)
Risk of bias
Blinding (performance bias and detection Unclear risk C - unclear

bias)
All outcomes
D - outcomes measured in less than 80%
istration
Teele 2000a
Randomised computer-generated. Stratified by age and sibling history of rAOM
Review at 0, 2, 6, 10, 14, 18, 22 and 26 weeks, plus presentation
Similarity not reported by group
Participants Boston, MA, USA

Dates not provided. Published in 2001
Birth cohort
Eligibility - single AOM prior to 6 months of age or 2 discrete episodes before 12 months.
Exclusion - none described
Numbers eligible not provided. 117 enrolled and followed 1 y. Allocation: 40 amoxicillin,
36 sulfisoxazole, 41 placebo
Baseline characteristics provide, not by group
Sulfisoxazole (50 mg/kg/d)
Amoxicillin (20 mg/kg/d). Frequency not stated. Assumed once daily
Placebo
Outcomes Measured in 100%

Format of reporting - proportion of children with none, more than or equal to 1, more
than or equal to 2, more than or equal to 3 AOM episodes during 6 months therapy
and during therapy and an additional 6 months of post-therapy follow up
Diagnostic criteria - AOM = effusion plus more than 1 sign of acute illness (fever,
Teele 2000a (Continued)
irritability, lethargy, otalgia, anorexia, vomit)

New episode 21 days after previous AOM
Subgroups - none
Microbiology - throat cultures at entry and monthly. Spn, Hi and M. cat tested for
antimicrobial susceptibility. Results not reported
Notes Q: AAAAAA
Risk of bias
documented
umented
All outcomes
ment failures)
istration
Varsano 1985a
Methods Double-blind, cross-over

Randomised (method not described)
Review 5 weekly and when symptoms of URT or OM suspected
Participants Israel
1 October to 31 January. Year of study not provided. Presented in 1984, published 1985
Children aged 6 mo to 5 y with rAOM. Free of AOM at randomisation. Exclusion - not
Varsano 1985a (Continued)
eligible for TTs

Number entered 40, 32 completed (8 not co-operative or non-compliant). 17 placebo,
15 sulfisoxazole
Interventions 10 weeks
Sulfisoxazole (250 mg tablet if less than 2 y; 500 mg if 2 to 5 y BD)
Placebo
Outcomes Measured in 32/40 (80%)

Format of reporting - proportion of children with AOM, total number of episodes, and
rate of AOM per patient per 10-week period
Diagnostic criteria - AOM = erythema or white-yellow opacification plus bulging and
poor mobility, or acute perforation with pus in canal
Subgroups - age (less than 2 versus 2 to 5 yrs), OME at entry
Microbiology - none
Notes Q: BBACBA
Risk of bias
Allocation concealment (selection bias) Unclear risk B - Unclear
All outcomes
istration
METHODS: Blinding. Randomisation method. Stratified. Review schedule. Group similarity reported.
PARTICIPANTS: Country, city. Dates of study. Eligibility (age, inclusion). Numbers eligible, enrolled, allocated by group. Baseline
characteristics by group.
INTERVENTIONS: Duration of therapy, Active and Control group dose and schedule.
OUTCOMES: Proportion with at least one follow-up assessment. Format of reporting. Diagnostic criteria. Subgroups. Microbiology
(carriage and resistance outcomes)
NOTES: Q: Quality scores for 1) Randomisation (A: Randomisation & Blinding clear, or R&B stated AND group similarity reported);
2) Allocation concealment (A: adequate); 3) Blinding (A: double-blind or outcome assessor blinded); 4) Participant reporting by
allocated group (A: progress of all randomized children reported); 5) Follow up (A: > 90%); 6) Standardised outcome assessments (A:
described and used for all participants)
AOM = acute otitis media
BD = twice-daily
CI = confidence interval
d = day
ENT = ear, nose and throat
Hi = Haemophilus influenzae
LRI = lower respiratory infection
M. cat = Moraxella catarrhalis
MEE = middle ear effusion
MEF = middle ear fluid
mo = months
NP = nasopharynx
OD = daily
OM = otitis media
OME = otitis media with effusion
OP = oropharynx
rAOM = recurrent acute otitis media
Rx = treatment
SD = standard deviation
SOM = suppurative otitis media
Spn = Streptococcus pneumoniae
TM = tympanic membrane
TTs = tympanostomy tubes
URTI = upper respiratory tract infection
y = year
TMP = trimethoprim
SMX = sulfamethoxasole
SX = sulfasoxasole
RAD = reactive airway disease
(AOM)woP = acute otitis media without perforation
(AOM)wiP = acute otitis media with perforation
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Berman 1992 Cases of AOM not reported. No placebo (treatment of URTI symptoms)
De Diego 2001 No placebo group
Donaldson 1990 Children with AOM withdrawn
Harrison 1999 No placebo group. Intervention not antibiotics or therapy thought to be effective (homeopathic)
Koivunen 2004 All children received tympanostomy tubes at time of randomisation
AOM = acute otitis media

URTI = upper respiratory tract infection
DATA AND ANALYSES
Comparison 1. Antibiotic versus control - primary outcomes
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Prevention - any AOM or 14 1461 Risk Ratio (M-H, Random, 95% CI) 0.65 [0.53, 0.79]
CSOM during intervention
2 Prevention - episodes of AOM 13 1327 Incidence Rate Ratio (Random, 95% CI) 0.51 [0.39, 0.66]
or CSOM during intervention
Comparison 2. Antibiotic versus control - secondary outcomes
No. of No. of
1 Prevention - any rAOM or 5 329 Risk Ratio (M-H, Fixed, 95% CI) 0.45 [0.20, 1.01]
2 Prevention - any AOM or 1 103 Risk Ratio (M-H, Fixed, 95% CI) 0.74 [0.46, 1.18]
CSOM at end of intervention
3 Prevention - any AOM or 1 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
CSOM following cessation of
intervention
3.1 More than three months 1 117 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.69, 1.08]
3.2 Six to 11 months 1 117 Risk Ratio (M-H, Fixed, 95% CI) 0.86 [0.69, 1.08]
4 Prevention - episodes of illness 1 224 incidence rate ratio (Fixed, 95% CI) 0.84 [0.72, 0.97]
during intervention
5 Side effects - any clinical side 12 817 Risk Ratio (M-H, Random, 95% CI) 1.99 [0.25, 15.89]
effects during intervention
6 Side effects - any antibiotic 2 181 Risk Ratio (M-H, Fixed, 95% CI) 1.37 [0.83, 2.26]
resistance during intervention
Comparison 3. Antibiotic versus control - subgroup analyses
No. of No. of
1 Prevention - any AOM or 14 Risk Ratio (M-H, Random, 95% CI) Subtotals only
CSOM during intervention:
children < 12 months, more
than 12 months, or not
separated
1.1 Less than 12 months 2 220 Risk Ratio (M-H, Random, 95% CI) 0.81 [0.45, 1.44]
1.2 More than 12 months 1 21 Risk Ratio (M-H, Random, 95% CI) 0.06 [0.00, 0.99]
1.3 Not separated 11 1190 Risk Ratio (M-H, Random, 95% CI) 0.70 [0.59, 0.84]
2 Prevention - episodes of AOM 13 Incidence Rate Ratio (Random, 95% CI) Subtotals only
in children less than 12 months
2.1 Less than 12 months 2 248 Incidence Rate Ratio (Random, 95% CI) 1.00 [0.60, 1.67]
2.2 More than 12 months 2 33 Incidence Rate Ratio (Random, 95% CI) 0.56 [0.09, 3.67]
2.3 Not separated 10 1046 Incidence Rate Ratio (Random, 95% CI) 0.45 [0.35, 0.57]
CSOM during intervention:
otitis prone, non-otitis-prone,
or not separated
3.1 Otitis prone 7 636 Risk Ratio (M-H, Random, 95% CI) 0.73 [0.61, 0.88]
3.2 Non-otitis prone 1 117 Risk Ratio (M-H, Random, 95% CI) 0.60 [0.42, 0.84]
3.3 Not separated 6 706 Risk Ratio (M-H, Random, 95% CI) 0.51 [0.30, 0.87]
in OP, non-OP or separated
4.1 Otitis-prone 8 796 Incidence Rate Ratio (Random, 95% CI) 0.52 [0.37, 0.73]
4.2 Non-otitis prone 0 0 Incidence Rate Ratio (Random, 95% CI) 0.0 [0.0, 0.0]
4.3 Not separated 5 531 Incidence Rate Ratio (Random, 95% CI) 0.47 [0.29, 0.76]
in high-risk or not high-risk
populations
5.1 High-risk populations 2 467 Risk Ratio (M-H, Random, 95% CI) 0.81 [0.44, 1.50]
5.2 Not high-risk populations 12 994 Risk Ratio (M-H, Random, 95% CI) 0.62 [0.51, 0.76]
in high-risk or not high-risk
population
6.1 High-risk populations 2 439 Incidence Rate Ratio (Random, 95% CI) 0.67 [0.42, 1.08]
6.2 Not high-risk populations 11 888 Incidence Rate Ratio (Random, 95% CI) 0.51 [0.30, 0.87]
Comparison 4. Antibiotic versus control - sensitivity analyses
No. of No. of
CSOM during intervention by
study quality
1.1 High-quality 8 780 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.59, 0.95]
randomisation and allocation
concealment
1.2 Not high-quality 6 681 Risk Ratio (M-H, Random, 95% CI) 0.53 [0.40, 0.69]
concealment
1.3 High-quality for blinding 12 1380 Risk Ratio (M-H, Random, 95% CI) 0.68 [0.56, 0.82]
of outcome assessment
1.4 High-quality for all six 4 492 Risk Ratio (M-H, Random, 95% CI) 0.69 [0.48, 1.01]
criteria
by study quality
2.1 High quality for 6 667 Incidence Rate Ratio (Random, 95% CI) 0.63 [0.45, 0.88]
concealment
2.2 Not high quality for 7 660 Incidence Rate Ratio (Random, 95% CI) 0.43 [0.31, 0.59]
concealment
2.3 High quality for blinding 10 1036 Incidence Rate Ratio (Random, 95% CI) 0.58 [0.46, 0.74]
of outcome assessment
2.4 High quality for all six 3 499 Incidence Rate Ratio (Random, 95% CI) 0.54 [0.33, 0.90]
criteria
study size
3.1 Fewer than 100 7 339 Risk Ratio (M-H, Random, 95% CI) 0.49 [0.30, 0.81]
participants
3.2 Greater than 100 7 1122 Risk Ratio (M-H, Random, 95% CI) 0.72 [0.57, 0.89]
participants
by study size
4.1 Fewer than 100 8 548 Incidence Rate Ratio (Random, 95% CI) 0.42 [0.30, 0.61]
participants
4.2 Greater than 100 5 779 Incidence Rate Ratio (Random, 95% CI) 0.62 [0.44, 0.87]
participants
inclusion criteria
5.1 Excluded age greater than 4 494 Risk Ratio (M-H, Random, 95% CI) 0.75 [0.57, 0.98]
36 months
5.2 Included age greater than 10 967 Risk Ratio (M-H, Random, 95% CI) 0.58 [0.43, 0.77]
36 months
5.3 Otitis-prone at entry (2/6 6 595 Risk Ratio (M-H, Random, 95% CI) 0.68 [0.54, 0.85]
or 3/12)
5.4 Less otitis-prone at entry 5 293 Risk Ratio (M-H, Random, 95% CI) 0.50 [0.29, 0.88]
(2/6 or 3/18; 1 before 6 months
of age or 2/12)
5.5 Free of MEE at entry 3 332 Risk Ratio (M-H, Random, 95% CI) 0.53 [0.35, 0.80]
5.6 Free of MEE at entry not 5 225 Risk Ratio (M-H, Random, 95% CI) 0.57 [0.33, 0.99]
required
5.7 Excluded congenital 9 798 Risk Ratio (M-H, Random, 95% CI) 0.65 [0.46, 0.91]
abnormalities
5.8 Exclusion criteria not 5 681 Risk Ratio (M-H, Random, 95% CI) 0.61 [0.51, 0.71]
described
5.9 Conducted in USA 8 1021 Risk Ratio (M-H, Random, 95% CI) 0.65 [0.52, 0.81]
5.10 Not conducted in USA 5 399 Risk Ratio (M-H, Random, 95% CI) 0.58 [0.37, 0.90]
by inclusion criteria
6.1 Excluded age greater than 3 509 Incidence Rate Ratio (Random, 95% CI) 0.70 [0.52, 0.94]
36 months
6.2 Included age greater than 10 818 Incidence Rate Ratio (Random, 95% CI) 0.44 [0.31, 0.61]
36 months
6.3 Otitis-prone at entry (2/6 6 657 Incidence Rate Ratio (Random, 95% CI) 0.47 [0.30, 0.72]
or 3/12)
6.4 Less otitis-prone at entry 4 171 Incidence Rate Ratio (Random, 95% CI) 0.59 [0.38, 0.91]
(2/6 or 3/18; 1 before 6 months
of age or 2/12)
6.5 Free of MEE at entry 3 306 Incidence Rate Ratio (Random, 95% CI) 0.39 [0.22, 0.67]
6.6 Free of MEE at entry not 7 526 Incidence Rate Ratio (Random, 95% CI) 0.44 [0.30, 0.65]
required
6.7 Excluded congenital 8 722 Incidence Rate Ratio (Random, 95% CI) 0.58 [0.42, 0.80]
abnormalities
6.8 Exclusion criteria not 5 605 Incidence Rate Ratio (Random, 95% CI) 0.41 [0.27, 0.64]
described
6.9 Conducted in USA 8 946 Incidence Rate Ratio (Random, 95% CI) 0.50 [0.36, 0.70]
6.10 Not conducted in USA 4 312 Incidence Rate Ratio (Random, 95% CI) 0.44 [0.23, 0.85]
medication
7.1 Amoxicillin, penicillin 9 1189 Risk Ratio (M-H, Random, 95% CI) 0.64 [0.50, 0.82]
7.2 Sulfisoxazole, 8 363 Risk Ratio (M-H, Random, 95% CI) 0.58 [0.40, 0.84]
trimethoprim sulfamethoxazole
7.3 Not placebo-controlled 2 129 Risk Ratio (M-H, Random, 95% CI) 0.28 [0.02, 3.69]
7.4 Once daily 8 1131 Risk Ratio (M-H, Random, 95% CI) 0.61 [0.52, 0.72]
7.5 Twice daily 7 389 Risk Ratio (M-H, Random, 95% CI) 0.78 [0.56, 1.09]
7.6 Less than 3 months 2 190 Risk Ratio (M-H, Random, 95% CI) 0.67 [0.26, 1.72]
therapy
7.7 Three to six months 9 635 Risk Ratio (M-H, Random, 95% CI) 0.64 [0.48, 0.86]
therapy
7.8 More than six months 3 636 Risk Ratio (M-H, Random, 95% CI) 0.62 [0.50, 0.76]
therapy
by medication
8.1 Amoxicillin, penicillin 7 846 Incidence Rate Ratio (Random, 95% CI) 0.55 [0.40, 0.76]
8.2 Sulfisoxazole, 7 503 Incidence Rate Ratio (Random, 95% CI) 0.52 [0.28, 0.96]
trimethoprim sulfamethoxazole
8.3 Not placebo-controlled 2 269 Incidence Rate Ratio (Random, 95% CI) 0.27 [0.19, 0.39]
8.4 Once daily 7 701 Incidence Rate Ratio (Random, 95% CI) 0.53 [0.39, 0.71]
8.5 Twice daily 7 682 Incidence Rate Ratio (Random, 95% CI) 0.54 [0.33, 0.90]
8.6 Less than three months 2 86 Incidence Rate Ratio (Random, 95% CI) 0.62 [0.15, 2.53]
therapy
8.7 Three to six months 6 404 Incidence Rate Ratio (Random, 95% CI) 0.54 [0.36, 0.81]
therapy
8.8 More than six months 5 837 Incidence Rate Ratio (Random, 95% CI) 0.45 [0.32, 0.63]
therapy
outcome measure
9.1 Monthly active 9 1100 Risk Ratio (M-H, Random, 95% CI) 0.71 [0.58, 0.86]
surveillance
9.2 Greater than one 5 311 Risk Ratio (M-H, Random, 95% CI) 0.45 [0.28, 0.72]
to three-monthly active
surveillance
by outcome measure
10.1 Monthly active 8 913 Incidence Rate Ratio (Random, 95% CI) 0.59 [0.45, 0.77]
surveillance
10.2 Four to six-weekly, 5 414 Incidence Rate Ratio (Random, 95% CI) 0.32 [0.19, 0.56]
or three-monthly active
surveillance
date of study
11.1 Completed in 1970s 4 474 Risk Ratio (M-H, Random, 95% CI) 0.56 [0.34, 0.94]
by date of study
12.1 Completed in 1970s 1 43 Incidence Rate Ratio (Random, 95% CI) 0.50 [0.26, 0.98]
13 Prevention - any AOM or 1 364 Risk Ratio (M-H, Fixed, 95% CI) 0.61 [0.44, 0.84]
compliance
13.1 High compliance 1 171 Risk Ratio (M-H, Fixed, 95% CI) 0.47 [0.29, 0.76]
13.2 Not high compliance 1 193 Risk Ratio (M-H, Fixed, 95% CI) 0.77 [0.50, 1.19]
by compliance
14.1 High compliance 2 140 Incidence Rate Ratio (Random, 95% CI) 0.36 [0.24, 0.54]
14.2 Not high compliance 2 153 Incidence Rate Ratio (Random, 95% CI) 0.87 [0.62, 1.22]
Analysis 1.1. Comparison 1 Antibiotic versus control - primary outcomes, Outcome 1 Prevention - any
AOM or CSOM during intervention.
Review: Antibiotics for the prevention of acute and chronic suppurative otitis media in children
Comparison: 1 Antibiotic versus control - primary outcomes
Outcome: 1 Prevention - any AOM or CSOM during intervention
Study or subgroup Antibiotic Control Risk Ratio Weight Risk Ratio

M- M-
H,Random,95% H,Random,95%
n/N n/N CI CI
Casselbrant 1992a 36/86 48/80 9.7 % 0.70 [ 0.51, 0.95 ]
Gaskins 1982a 0/10 8/11 0.5 % 0.06 [ 0.00, 0.99 ]
Gonzalez 1986a 16/21 17/20 9.8 % 0.90 [ 0.66, 1.21 ]
Leach 2008 40/52 37/51 10.8 % 1.06 [ 0.85, 1.33 ]
Liston 1983a 11/19 11/16 7.0 % 0.84 [ 0.51, 1.40 ]
Mandel 1996a 13/55 27/51 6.6 % 0.45 [ 0.26, 0.77 ]
Maynard 1972a 42/173 76/191 9.6 % 0.61 [ 0.44, 0.84 ]
Perrin 1974a 4/28 12/26 3.1 % 0.31 [ 0.11, 0.84 ]
Persico 1985a 34/60 41/48 10.5 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 18/66 19/30 7.3 % 0.43 [ 0.27, 0.70 ]
Roark 1997a 37/99 22/59 8.1 % 1.00 [ 0.66, 1.52 ]
Sih 1993a 7/40 10/20 4.2 % 0.35 [ 0.16, 0.78 ]
Teele 2000a 31/76 28/41 9.2 % 0.60 [ 0.42, 0.84 ]
Varsano 1985a 4/15 12/17 3.6 % 0.38 [ 0.15, 0.92 ]
Total (95% CI) 800 661 100.0 % 0.65 [ 0.53, 0.79 ]

Total events: 293 (Antibiotic), 368 (Control)
Heterogeneity: Tau2 = 0.08; Chi2 = 40.84, df = 13 (P = 0.00010); I2 =68%
Test for overall effect: Z = 4.21 (P = 0.000025)
Test for subgroup differences: Not applicable
0.1 0.2 0.5 1 2 5 10

Favours antibiotic Favours control
Analysis 1.2. Comparison 1 Antibiotic versus control - primary outcomes, Outcome 2 Prevention - episodes
of AOM or CSOM during intervention.
Comparison: 1 Antibiotic versus control - primary outcomes
Outcome: 2 Prevention - episodes of AOM or CSOM during intervention
log
[Incidence Incidence Incidence
Study or subgroup Antibiotic Control Rate Ratio] Rate Ratio Weight Rate Ratio
N N (SE) IV,Random,95% CI IV,Random,95% CI
Casselbrant 1992a 88 136 -0.588 (0.137) 11.2 % 0.56 [ 0.42, 0.73 ]
Gaskins 1982a 1 9 -2.1 (1.47) 0.8 % 0.12 [ 0.01, 2.18 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 8.6 % 0.69 [ 0.42, 1.15 ]
Gray 1981 31 39 -0.31 (0.256) 8.7 % 0.73 [ 0.44, 1.21 ]
Leach 2008 104 111 -0.1597 (0.141) 11.1 % 0.85 [ 0.65, 1.12 ]
Liston 1983a 16 27 -0.695 (0.342) 7.0 % 0.50 [ 0.26, 0.98 ]
Mandel 1996a 14 46 -1.313 (0.33) 7.2 % 0.27 [ 0.14, 0.51 ]
Maynard 1972a 73 151 -0.635 (0.146) 11.0 % 0.53 [ 0.40, 0.71 ]
Principi 1989a 20 25 -1.012 (0.324) 7.3 % 0.36 [ 0.19, 0.69 ]
Roark 1997a 36 20 0.1823 (0.3) 7.8 % 1.20 [ 0.67, 2.16 ]
Schuller 1983a 38 221 -1.3 (0.184) 10.2 % 0.27 [ 0.19, 0.39 ]
Sih 1993a 8 14 -1.253 (0.497) 4.7 % 0.29 [ 0.11, 0.76 ]
Varsano 1985a 6 24 -1.253 (0.514) 4.5 % 0.29 [ 0.10, 0.78 ]
Total (95% CI) 464 863 100.0 % 0.51 [ 0.39, 0.66 ]

Test for overall effect: Z = 5.03 (P < 0.00001)
0.1 0.2 0.5 1 2 5 10

Analysis 2.1. Comparison 2 Antibiotic versus control - secondary outcomes, Outcome 1 Prevention - any
rAOM or CSOM during intervention.
Comparison: 2 Antibiotic versus control - secondary outcomes
Outcome: 1 Prevention - any rAOM or CSOM during intervention

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Gaskins 1982a 0/10 0/11 Not estimable
Liston 1983a 1/19 5/16 34.0 % 0.17 [ 0.02, 1.30 ]
Principi 1989a 0/66 1/30 12.9 % 0.15 [ 0.01, 3.68 ]
Sih 1993a 0/40 1/20 12.4 % 0.17 [ 0.01, 4.01 ]
Teele 2000a 8/76 5/41 40.7 % 0.86 [ 0.30, 2.47 ]
Total (95% CI) 211 118 100.0 % 0.45 [ 0.20, 1.01 ]

Heterogeneity: Chi2 = 3.17, df = 3 (P = 0.37); I2 =5%
0.1 0.2 0.5 1 2 5 10

AOM or CSOM at end of intervention.
Outcome: 2 Prevention - any AOM or CSOM at end of intervention

Leach 2008 18/52 24/51 100.0 % 0.74 [ 0.46, 1.18 ]
Total (95% CI) 52 51 100.0 % 0.74 [ 0.46, 1.18 ]

Heterogeneity: not applicable
0.1 0.2 0.5 1 2 5 10

AOM or CSOM following cessation of intervention.
Outcome: 3 Prevention - any AOM or CSOM following cessation of intervention

1 More than three months

Teele 2000a 51/76 32/41 100.0 % 0.86 [ 0.69, 1.08 ]
Subtotal (95% CI) 76 41 100.0 % 0.86 [ 0.69, 1.08 ]

2 Six to 11 months
Teele 2000a 51/76 32/41 100.0 % 0.86 [ 0.69, 1.08 ]
Subtotal (95% CI) 76 41 100.0 % 0.86 [ 0.69, 1.08 ]

0.1 0.2 0.5 1 2 5 10

Analysis 2.4. Comparison 2 Antibiotic versus control - secondary outcomes, Outcome 4 Prevention -
episodes of illness during intervention.
Outcome: 4 Prevention - episodes of illness during intervention
log
[incidence incidence incidence
Study or subgroup Antibiotic Control rate ratio] rate ratio Weight rate ratio
N N (SE) IV,Fixed,95% CI IV,Fixed,95% CI
Maynard 1972a 73 151 -0.1779 (0.0761) 100.0 % 0.84 [ 0.72, 0.97 ]
Total (95% CI) 73 151 100.0 % 0.84 [ 0.72, 0.97 ]

0.1 0.2 0.5 1 2 5 10

Analysis 2.5. Comparison 2 Antibiotic versus control - secondary outcomes, Outcome 5 Side effects - any
clinical side effects during intervention.
Outcome: 5 Side effects - any clinical side effects during intervention

M- M-
n/N n/N CI CI
Casselbrant 1992a 6/86 0/80 28.5 % 12.10 [ 0.69, 211.45 ]
Gaskins 1982a 0/10 0/11 Not estimable
Gonzalez 1986a 0/21 0/20 Not estimable
Gray 1981 0/26 0/24 Not estimable
Leach 2008 0/52 0/51 Not estimable
Liston 1983a 0/19 0/16 Not estimable
Perrin 1974a 1/28 0/26 25.5 % 2.79 [ 0.12, 65.66 ]
Principi 1989a 0/66 0/30 Not estimable
Schuller 1983a 0/18 0/24 Not estimable
Sih 1993a 0/40 0/20 Not estimable
Teele 2000a 3/76 3/41 46.0 % 0.54 [ 0.11, 2.55 ]
Varsano 1985a 0/15 0/17 Not estimable
Total (95% CI) 457 360 100.0 % 1.99 [ 0.25, 15.89 ]

0.1 0.2 0.5 1 2 5 10

Analysis 2.6. Comparison 2 Antibiotic versus control - secondary outcomes, Outcome 6 Side effects - any
antibiotic resistance during intervention.
Outcome: 6 Side effects - any antibiotic resistance during intervention

Casselbrant 1992a 16/52 8/38 46.2 % 1.46 [ 0.70, 3.06 ]
Mandel 1996a 15/49 10/42 53.8 % 1.29 [ 0.65, 2.55 ]
Total (95% CI) 101 80 100.0 % 1.37 [ 0.83, 2.26 ]

Heterogeneity: Chi2 = 0.06, df = 1 (P = 0.80); I2 =0.0%
0.1 0.2 0.5 1 2 5 10

Analysis 3.1. Comparison 3 Antibiotic versus control - subgroup analyses, Outcome 1 Prevention - any
AOM or CSOM during intervention: children < 12 months, more than 12 months, or not separated.
Comparison: 3 Antibiotic versus control - subgroup analyses
Outcome: 1 Prevention - any AOM or CSOM during intervention: children < 12 months, more than 12 months, or not separated

M- M-
n/N n/N CI CI
1 Less than 12 months
Leach 2008 40/52 37/51 52.4 % 1.06 [ 0.85, 1.33 ]
Teele 2000a 31/76 28/41 47.6 % 0.60 [ 0.42, 0.84 ]
Subtotal (95% CI) 128 92 100.0 % 0.81 [ 0.45, 1.44 ]

2 More than 12 months
Gaskins 1982a 0/10 8/11 100.0 % 0.06 [ 0.00, 0.99 ]
Subtotal (95% CI) 10 11 100.0 % 0.06 [ 0.00, 0.99 ]

3 Not separated
Casselbrant 1992a 36/86 48/80 13.5 % 0.70 [ 0.51, 0.95 ]
Gonzalez 1986a 16/21 17/20 13.6 % 0.90 [ 0.66, 1.21 ]
Liston 1983a 11/19 11/16 7.9 % 0.84 [ 0.51, 1.40 ]
Mandel 1996a 13/25 27/51 9.0 % 0.98 [ 0.62, 1.55 ]
Maynard 1972a 42/173 76/191 13.1 % 0.61 [ 0.44, 0.84 ]
Perrin 1974a 4/28 4/26 1.7 % 0.93 [ 0.26, 3.34 ]
Persico 1985a 34/60 41/48 15.6 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 18/66 19/30 8.4 % 0.43 [ 0.27, 0.70 ]
Roark 1997a 37/99 22/59 9.9 % 1.00 [ 0.66, 1.52 ]
Sih 1993a 7/40 10/20 3.9 % 0.35 [ 0.16, 0.78 ]
Varsano 1985a 4/15 12/17 3.3 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 632 558 100.0 % 0.70 [ 0.59, 0.84 ]

0.1 0.2 0.5 1 2 5 10

Analysis 3.2. Comparison 3 Antibiotic versus control - subgroup analyses, Outcome 2 Prevention - episodes
of AOM or CSOM during intervention in children less than 12 months.
Outcome: 2 Prevention - episodes of AOM or CSOM during intervention in children less than 12 months
log
1 Less than 12 months

Leach 2008 104 111 -0.1597 (0.141) 72.5 % 0.85 [ 0.65, 1.12 ]
Roark 1997a 23 10 0.4272 (0.418) 27.5 % 1.53 [ 0.68, 3.48 ]
Subtotal (95% CI) 127 121 100.0 % 1.00 [ 0.60, 1.67 ]

2 More than 12 months
Gaskins 1982a 1 9 -2.1 (1.47) 28.5 % 0.12 [ 0.01, 2.18 ]
Roark 1997a 13 10 0.0253 (0.469) 71.5 % 1.03 [ 0.41, 2.57 ]
Subtotal (95% CI) 14 19 100.0 % 0.56 [ 0.09, 3.67 ]

3 Not separated
Casselbrant 1992a 88 136 -0.588 (0.137) 15.8 % 0.56 [ 0.42, 0.73 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 10.6 % 0.69 [ 0.42, 1.15 ]
Gray 1981 31 39 -0.31 (0.256) 10.7 % 0.73 [ 0.44, 1.21 ]
Liston 1983a 16 27 -0.695 (0.342) 7.9 % 0.50 [ 0.26, 0.98 ]
Mandel 1996a 14 46 -1.313 (0.33) 8.2 % 0.27 [ 0.14, 0.51 ]
Maynard 1972a 73 151 -0.635 (0.146) 15.4 % 0.53 [ 0.40, 0.71 ]
Principi 1989a 20 25 -1.012 (0.324) 8.4 % 0.36 [ 0.19, 0.69 ]
Schuller 1983a 38 221 -1.3 (0.184) 13.7 % 0.27 [ 0.19, 0.39 ]
Sih 1993a 8 14 -1.253 (0.497) 4.7 % 0.29 [ 0.11, 0.76 ]
Varsano 1985a 6 24 -1.2533 (0.514) 4.5 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 323 723 100.0 % 0.45 [ 0.35, 0.57 ]

0.1 0.2 0.5 1 2 5 10

AOM or CSOM during intervention: otitis prone, non-otitis-prone, or not separated.
Outcome: 3 Prevention - any AOM or CSOM during intervention: otitis prone, non-otitis-prone, or not separated

M- M-
n/N n/N CI CI
1 Otitis prone
Casselbrant 1992a 36/86 48/80 19.6 % 0.70 [ 0.51, 0.95 ]
Gonzalez 1986a 16/21 17/20 19.9 % 0.90 [ 0.66, 1.21 ]
Liston 1983a 11/19 11/16 9.9 % 0.84 [ 0.51, 1.40 ]
Persico 1985a 34/60 41/48 24.2 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 18/66 16/30 9.5 % 0.51 [ 0.30, 0.86 ]
Roark 1997a 37/99 22/59 13.1 % 1.00 [ 0.66, 1.52 ]
Varsano 1985a 4/15 12/17 3.7 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 366 270 100.0 % 0.73 [ 0.61, 0.88 ]

2 Non-otitis prone
Teele 2000a 31/76 28/41 100.0 % 0.60 [ 0.42, 0.84 ]
Subtotal (95% CI) 76 41 100.0 % 0.60 [ 0.42, 0.84 ]

3 Not separated
Gaskins 1982a 0/10 8/11 3.3 % 0.06 [ 0.00, 0.99 ]
Leach 2008 40/52 37/51 24.0 % 1.06 [ 0.85, 1.33 ]
Mandel 1996a 13/55 27/51 20.0 % 0.45 [ 0.26, 0.77 ]
Maynard 1972a 42/171 76/191 23.1 % 0.62 [ 0.45, 0.85 ]
Perrin 1974a 4/28 12/26 13.4 % 0.31 [ 0.11, 0.84 ]
Sih 1993a 7/40 10/20 16.1 % 0.35 [ 0.16, 0.78 ]
Subtotal (95% CI) 356 350 100.0 % 0.51 [ 0.30, 0.87 ]

0.1 0.2 0.5 1 2 5 10

of AOM or CSOM during intervention in OP, non-OP or separated.
Outcome: 4 Prevention - episodes of AOM or CSOM during intervention in OP, non-OP or separated
log
1 Otitis-prone
Casselbrant 1992a 88 136 -0.588 (0.137) 16.7 % 0.56 [ 0.42, 0.73 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 13.2 % 0.69 [ 0.42, 1.15 ]
Gray 1981 31 39 -0.31 (0.256) 13.3 % 0.73 [ 0.44, 1.21 ]
Liston 1983a 16 27 -0.695 (0.342) 10.9 % 0.50 [ 0.26, 0.98 ]
Principi 1989a 20 25 -1.012 (0.324) 11.4 % 0.36 [ 0.19, 0.69 ]
Roark 1997a 36 20 0.1823 (0.3) 12.0 % 1.20 [ 0.67, 2.16 ]
Schuller 1983a 38 221 -1.291 (0.184) 15.4 % 0.27 [ 0.19, 0.39 ]
Varsano 1985a 6 24 -1.386 (0.514) 7.2 % 0.25 [ 0.09, 0.68 ]
Subtotal (95% CI) 264 532 100.0 % 0.52 [ 0.37, 0.73 ]

2 Non-otitis prone
Subtotal (95% CI) 0 0 Not estimable
Test for overall effect: not applicable
3 Not separated
Gaskins 1982a 1 9 -2.1 (1.47) 2.7 % 0.12 [ 0.01, 2.18 ]
Leach 2008 104 111 -0.1597 (0.141) 30.8 % 0.85 [ 0.65, 1.12 ]
Mandel 1996a 14 46 -1.313 (0.33) 21.4 % 0.27 [ 0.14, 0.51 ]
Maynard 1972a 73 151 -0.635 (0.146) 30.6 % 0.53 [ 0.40, 0.71 ]
Sih 1993a 8 14 -1.253 (0.497) 14.5 % 0.29 [ 0.11, 0.76 ]
Subtotal (95% CI) 200 331 100.0 % 0.47 [ 0.29, 0.76 ]

0.1 0.2 0.5 1 2 5 10

AOM or CSOM during intervention in high-risk or not high-risk populations.
Outcome: 5 Prevention - any AOM or CSOM during intervention in high-risk or not high-risk populations

M- M-
n/N n/N CI CI
1 High-risk populations
Leach 2008 40/52 37/51 51.6 % 1.06 [ 0.85, 1.33 ]
Maynard 1972a 42/173 76/191 48.4 % 0.61 [ 0.44, 0.84 ]
Subtotal (95% CI) 225 242 100.0 % 0.81 [ 0.44, 1.50 ]

2 Not high-risk populations
Casselbrant 1992a 36/86 48/80 12.7 % 0.70 [ 0.51, 0.95 ]
Gaskins 1982a 0/10 8/11 0.5 % 0.06 [ 0.00, 0.99 ]
Gonzalez 1986a 16/21 17/20 12.8 % 0.90 [ 0.66, 1.21 ]
Liston 1983a 11/19 11/16 8.5 % 0.84 [ 0.51, 1.40 ]
Mandel 1996a 13/55 27/51 7.9 % 0.45 [ 0.26, 0.77 ]
Perrin 1974a 4/28 12/26 3.4 % 0.31 [ 0.11, 0.84 ]
Persico 1985a 34/60 41/48 14.0 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 18/66 19/30 9.0 % 0.43 [ 0.27, 0.70 ]
Roark 1997a 37/99 22/59 10.2 % 1.00 [ 0.66, 1.52 ]
Sih 1993a 7/40 10/20 4.8 % 0.35 [ 0.16, 0.78 ]
Teele 2000a 31/76 28/41 11.9 % 0.60 [ 0.42, 0.84 ]
Varsano 1985a 4/15 12/17 4.1 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 575 419 100.0 % 0.62 [ 0.51, 0.76 ]

0.2 0.5 1 2 5
of AOM or CSOM during intervention in high-risk or not high-risk population.
Outcome: 6 Prevention - episodes of AOM or CSOM during intervention in high-risk or not high-risk population
log
1 High-risk populations
Leach 2008 104 111 -0.1597 (0.141) 50.3 % 0.85 [ 0.65, 1.12 ]
Maynard 1972a 73 151 -0.645 (0.146) 49.7 % 0.52 [ 0.39, 0.70 ]
Subtotal (95% CI) 177 262 100.0 % 0.67 [ 0.42, 1.08 ]

2 Not high-risk populations
Casselbrant 1992a 88 136 0.588 (0.137) 10.9 % 1.80 [ 1.38, 2.35 ]
Gaskins 1982a 1 9 -2.1 (1.47) 2.7 % 0.12 [ 0.01, 2.18 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 10.2 % 0.69 [ 0.42, 1.15 ]
Gray 1981 31 39 -0.31 (0.256) 10.2 % 0.73 [ 0.44, 1.21 ]
Liston 1983a 16 27 -0.659 (0.342) 9.6 % 0.52 [ 0.26, 1.01 ]
Mandel 1996a 14 46 -1.313 (0.33) 9.7 % 0.27 [ 0.14, 0.51 ]
Principi 1989a 20 25 -1.012 (0.324) 9.7 % 0.36 [ 0.19, 0.69 ]
Roark 1997a 36 20 0.1823 (0.3) 9.9 % 1.20 [ 0.67, 2.16 ]
Schuller 1983a 38 221 -1.3 (0.184) 10.7 % 0.27 [ 0.19, 0.39 ]
Sih 1993a 8 14 -1.253 (0.497) 8.2 % 0.29 [ 0.11, 0.76 ]
Varsano 1985a 6 24 -1.253 (0.514) 8.1 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 287 601 100.0 % 0.51 [ 0.30, 0.87 ]

Heterogeneity: Tau2 = 0.67; Chi2 = 97.99, df = 10 (P<0.00001); I2 =90%
0.1 0.2 0.5 1 2 5 10

Analysis 4.1. Comparison 4 Antibiotic versus control - sensitivity analyses, Outcome 1 Prevention - any
AOM or CSOM during intervention by study quality.
Comparison: 4 Antibiotic versus control - sensitivity analyses
Outcome: 1 Prevention - any AOM or CSOM during intervention by study quality

M- M-
n/N n/N CI CI
1 High-quality randomisation and allocation concealment
Casselbrant 1992a 36/86 48/80 15.3 % 0.70 [ 0.51, 0.95 ]
Gonzalez 1986a 16/21 17/20 15.5 % 0.90 [ 0.66, 1.21 ]
Leach 2008 40/52 37/51 17.4 % 1.06 [ 0.85, 1.33 ]
Liston 1983a 11/19 11/16 10.6 % 0.84 [ 0.51, 1.40 ]
Mandel 1996a 13/55 27/51 9.9 % 0.45 [ 0.26, 0.77 ]
Perrin 1974a 4/28 12/26 4.4 % 0.31 [ 0.11, 0.84 ]
Roark 1997a 37/99 22/59 12.5 % 1.00 [ 0.66, 1.52 ]
Teele 2000a 31/76 28/41 14.4 % 0.60 [ 0.42, 0.84 ]
Subtotal (95% CI) 436 344 100.0 % 0.75 [ 0.59, 0.95 ]

2 Not high-quality randomisation and allocation concealment
Gaskins 1982a 0/10 8/11 0.9 % 0.06 [ 0.00, 0.99 ]
Maynard 1972a 42/173 76/191 29.1 % 0.61 [ 0.44, 0.84 ]
Persico 1985a 34/60 41/48 34.3 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 18/66 19/30 19.0 % 0.43 [ 0.27, 0.70 ]
Sih 1993a 7/40 10/20 9.0 % 0.35 [ 0.16, 0.78 ]
Varsano 1985a 4/15 12/17 7.5 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 364 317 100.0 % 0.53 [ 0.40, 0.69 ]

3 High-quality for blinding of outcome assessment
Casselbrant 1992a 36/86 48/80 10.3 % 0.70 [ 0.51, 0.95 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
M- M-
n/N n/N CI CI
Gonzalez 1986a 16/21 17/20 10.4 % 0.90 [ 0.66, 1.21 ]
Leach 2008 40/52 37/51 11.8 % 1.06 [ 0.85, 1.33 ]
Liston 1983a 11/19 11/16 7.1 % 0.84 [ 0.51, 1.40 ]
Mandel 1996a 13/55 27/51 6.7 % 0.45 [ 0.26, 0.77 ]
Maynard 1972a 42/173 76/191 10.2 % 0.61 [ 0.44, 0.84 ]
Perrin 1974a 4/28 12/26 2.9 % 0.31 [ 0.11, 0.84 ]
Persico 1985a 34/60 41/48 11.3 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 18/66 19/30 7.5 % 0.43 [ 0.27, 0.70 ]
Roark 1997a 37/99 22/59 8.5 % 1.00 [ 0.66, 1.52 ]
Teele 2000a 31/76 28/41 9.7 % 0.60 [ 0.42, 0.84 ]
Varsano 1985a 4/15 12/17 3.5 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 750 630 100.0 % 0.68 [ 0.56, 0.82 ]

4 High-quality for all six criteria
Casselbrant 1992a 36/86 48/80 26.5 % 0.70 [ 0.51, 0.95 ]
Leach 2008 40/52 37/51 28.8 % 1.06 [ 0.85, 1.33 ]
Mandel 1996a 13/55 27/51 19.4 % 0.45 [ 0.26, 0.77 ]
Teele 2000a 31/76 28/41 25.4 % 0.60 [ 0.42, 0.84 ]
Subtotal (95% CI) 269 223 100.0 % 0.69 [ 0.48, 1.01 ]

0.1 0.2 0.5 1 2 5 10

Analysis 4.2. Comparison 4 Antibiotic versus control - sensitivity analyses, Outcome 2 Prevention -
episodes of AOM or CSOM during intervention by study quality.
Outcome: 2 Prevention - episodes of AOM or CSOM during intervention by study quality
log
1 High quality for randomisation and allocation concealment

Casselbrant 1992a 88 136 -0.588 (0.137) 22.1 % 0.56 [ 0.42, 0.73 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 16.1 % 0.69 [ 0.42, 1.15 ]
Leach 2008 104 111 -0.1597 (0.141) 21.9 % 0.85 [ 0.65, 1.12 ]
Liston 1983a 16 27 -0.695 (0.342) 12.6 % 0.50 [ 0.26, 0.98 ]
Mandel 1996a 14 46 -1.313 (0.33) 13.0 % 0.27 [ 0.14, 0.51 ]
Roark 1997a 36 20 0.1823 (0.3) 14.3 % 1.20 [ 0.67, 2.16 ]
Subtotal (95% CI) 287 380 100.0 % 0.63 [ 0.45, 0.88 ]

2 Not high quality for randomisation and allocation concealment
Gaskins 1982a 1 9 -2.1 (1.47) 1.2 % 0.12 [ 0.01, 2.18 ]
Gray 1981 31 39 -0.31 (0.256) 20.4 % 0.73 [ 0.44, 1.21 ]
Maynard 1972a 73 151 -0.635 (0.146) 30.9 % 0.53 [ 0.40, 0.71 ]
Principi 1989a 20 25 -1.01 (0.324) 15.6 % 0.36 [ 0.19, 0.69 ]
Schuller 1983a 38 221 -1.3 (0.33) 15.3 % 0.27 [ 0.14, 0.52 ]
Sih 1993a 8 14 -1.253 (0.497) 8.5 % 0.29 [ 0.11, 0.76 ]
Varsano 1985a 6 24 -1.253 (0.514) 8.1 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 177 483 100.0 % 0.43 [ 0.31, 0.59 ]

3 High quality for blinding of outcome assessment
Casselbrant 1992a 88 136 -0.588 (0.137) 14.8 % 0.56 [ 0.42, 0.73 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 10.0 % 0.69 [ 0.42, 1.15 ]
Gray 1981 31 39 -0.31 (0.256) 10.1 % 0.73 [ 0.44, 1.21 ]
Leach 2008 104 111 -0.1597 (0.141) 14.6 % 0.85 [ 0.65, 1.12 ]
Liston 1983a 16 27 -0.695 (0.342) 7.5 % 0.50 [ 0.26, 0.98 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
log
Mandel 1996a 14 46 -1.313 (0.33) 7.8 % 0.27 [ 0.14, 0.51 ]
Maynard 1972a 73 151 -0.635 (0.146) 14.4 % 0.53 [ 0.40, 0.71 ]
Principi 1989a 20 25 -1.012 (0.324) 7.9 % 0.36 [ 0.19, 0.69 ]
Roark 1997a 36 20 0.1823 (0.3) 8.6 % 1.20 [ 0.67, 2.16 ]
Varsano 1985a 6 24 -1.253 (0.514) 4.3 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 417 619 100.0 % 0.58 [ 0.46, 0.74 ]

4 High quality for all six criteria
Casselbrant 1992a 88 136 -0.588 (0.137) 37.7 % 0.56 [ 0.42, 0.73 ]
Leach 2008 104 111 -0.1597 (0.141) 37.4 % 0.85 [ 0.65, 1.12 ]
Mandel 1996a 14 46 -1.313 (0.33) 24.9 % 0.27 [ 0.14, 0.51 ]
Subtotal (95% CI) 206 293 100.0 % 0.54 [ 0.33, 0.90 ]

0.1 0.2 0.5 1 2 5 10

AOM or CSOM during intervention by study size.
Outcome: 3 Prevention - any AOM or CSOM during intervention by study size

M- M-
n/N n/N CI CI
1 Fewer than 100 participants
Gaskins 1982a 0/10 8/11 0.5 % 0.06 [ 0.00, 0.99 ]
Gonzalez 1986a 16/21 17/20 9.8 % 0.90 [ 0.66, 1.21 ]
Liston 1983a 11/19 11/16 7.0 % 0.84 [ 0.51, 1.40 ]
Perrin 1974a 4/28 12/26 3.1 % 0.31 [ 0.11, 0.84 ]
Principi 1989a 18/66 19/30 7.3 % 0.43 [ 0.27, 0.70 ]
Sih 1993a 7/40 10/20 4.2 % 0.35 [ 0.16, 0.78 ]
Varsano 1985a 4/15 12/17 3.6 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 199 140 35.5 % 0.49 [ 0.30, 0.81 ]

2 Greater than 100 participants
Casselbrant 1992a 36/86 48/80 9.7 % 0.70 [ 0.51, 0.95 ]
Leach 2008 40/52 37/51 10.8 % 1.06 [ 0.85, 1.33 ]
Mandel 1996a 13/55 27/51 6.6 % 0.45 [ 0.26, 0.77 ]
Maynard 1972a 42/173 76/191 9.6 % 0.61 [ 0.44, 0.84 ]
Persico 1985a 34/60 41/48 10.5 % 0.66 [ 0.52, 0.85 ]
Roark 1997a 37/99 22/59 8.1 % 1.00 [ 0.66, 1.52 ]
Teele 2000a 31/76 28/41 9.2 % 0.60 [ 0.42, 0.84 ]
Subtotal (95% CI) 601 521 64.5 % 0.72 [ 0.57, 0.89 ]

Total (95% CI) 800 661 100.0 % 0.65 [ 0.53, 0.79 ]
Test for subgroup differences: Chi2 = 1.81, df = 1 (P = 0.18), I2 =45%
0.1 0.2 0.5 1 2 5 10

episodes of AOM or CSOM during intervention by study size.
Outcome: 4 Prevention - episodes of AOM or CSOM during intervention by study size
log
1 Fewer than 100 participants

Gaskins 1982a 1 9 -2.1 (1.47) 0.8 % 0.12 [ 0.01, 2.18 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 8.6 % 0.69 [ 0.42, 1.15 ]
Gray 1981 31 39 -0.31 (0.256) 8.7 % 0.73 [ 0.44, 1.21 ]
Liston 1983a 16 27 -0.695 (0.342) 7.0 % 0.50 [ 0.26, 0.98 ]
Principi 1989a 20 25 -1.012 (0.324) 7.3 % 0.36 [ 0.19, 0.69 ]
Schuller 1983a 38 221 -1.3 (0.184) 10.2 % 0.27 [ 0.19, 0.39 ]
Sih 1993a 8 14 -1.253 (0.497) 4.7 % 0.29 [ 0.11, 0.76 ]
Varsano 1985a 6 24 -1.253 (0.514) 4.5 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 149 399 51.7 % 0.42 [ 0.30, 0.61 ]

2 Greater than 100 participants
Casselbrant 1992a 88 136 -0.588 (0.137) 11.2 % 0.56 [ 0.42, 0.73 ]
Leach 2008 104 111 -0.1597 (0.141) 11.1 % 0.85 [ 0.65, 1.12 ]
Mandel 1996a 14 46 -1.31 (0.33) 7.2 % 0.27 [ 0.14, 0.52 ]
Maynard 1972a 73 151 -0.635 (0.146) 11.0 % 0.53 [ 0.40, 0.71 ]
Roark 1997a 36 20 0.1823 (0.3) 7.8 % 1.20 [ 0.67, 2.16 ]
Subtotal (95% CI) 315 464 48.3 % 0.62 [ 0.44, 0.87 ]

Total (95% CI) 464 863 100.0 % 0.51 [ 0.39, 0.66 ]
0.1 0.2 0.5 1 2 5 10

AOM or CSOM during intervention by inclusion criteria.
Outcome: 5 Prevention - any AOM or CSOM during intervention by inclusion criteria

M- M-
n/N n/N CI CI
1 Excluded age greater than 36 months
Casselbrant 1992a 36/86 48/80 23.8 % 0.70 [ 0.51, 0.95 ]
Leach 2008 40/52 37/51 27.5 % 1.06 [ 0.85, 1.33 ]
Persico 1985a 34/60 41/48 26.4 % 0.66 [ 0.52, 0.85 ]
Teele 2000a 31/76 28/41 22.2 % 0.60 [ 0.42, 0.84 ]
Subtotal (95% CI) 274 220 100.0 % 0.75 [ 0.57, 0.98 ]

2 Included age greater than 36 months
Gaskins 1982a 0/10 8/11 1.1 % 0.06 [ 0.00, 0.99 ]
Gonzalez 1986a 16/21 17/20 15.3 % 0.90 [ 0.66, 1.21 ]
Liston 1983a 11/19 11/16 11.8 % 0.84 [ 0.51, 1.40 ]
Mandel 1996a 13/55 27/51 11.2 % 0.45 [ 0.26, 0.77 ]
Maynard 1972a 42/173 76/191 15.1 % 0.61 [ 0.44, 0.84 ]
Perrin 1974a 4/28 12/26 5.8 % 0.31 [ 0.11, 0.84 ]
Principi 1989a 18/66 19/30 12.2 % 0.43 [ 0.27, 0.70 ]
Roark 1997a 37/99 22/59 13.3 % 1.00 [ 0.66, 1.52 ]
Sih 1993a 7/40 10/20 7.6 % 0.35 [ 0.16, 0.78 ]
Varsano 1985a 4/15 12/17 6.7 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 526 441 100.0 % 0.58 [ 0.43, 0.77 ]

3 Otitis-prone at entry (2/6 or 3/12)
Casselbrant 1992a 36/86 48/80 23.0 % 0.70 [ 0.51, 0.95 ]
Liston 1983a 11/19 11/16 13.4 % 0.84 [ 0.51, 1.40 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
M- M-
n/N n/N CI CI
Persico 1985a 34/60 41/48 26.6 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 18/66 19/30 14.4 % 0.43 [ 0.27, 0.70 ]
Roark 1997a 37/99 22/59 17.0 % 1.00 [ 0.66, 1.52 ]
Varsano 1985a 4/15 12/17 5.6 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 345 250 100.0 % 0.68 [ 0.54, 0.85 ]

4 Less otitis-prone at entry (2/6 or 3/18; 1 before 6 months of age or 2/12)
Gaskins 1982a 0/10 8/11 3.8 % 0.06 [ 0.00, 0.99 ]
Gonzalez 1986a 16/21 17/20 30.4 % 0.90 [ 0.66, 1.21 ]
Perrin 1974a 4/28 12/26 16.3 % 0.31 [ 0.11, 0.84 ]
Sih 1993a 7/40 10/20 19.8 % 0.35 [ 0.16, 0.78 ]
Teele 2000a 31/76 28/41 29.7 % 0.60 [ 0.42, 0.84 ]
Subtotal (95% CI) 175 118 100.0 % 0.50 [ 0.29, 0.88 ]

5 Free of MEE at entry
Casselbrant 1992a 36/86 48/80 49.5 % 0.70 [ 0.51, 0.95 ]
Mandel 1996a 13/55 27/51 31.4 % 0.45 [ 0.26, 0.77 ]
Sih 1993a 7/40 10/20 19.1 % 0.35 [ 0.16, 0.78 ]
Subtotal (95% CI) 181 151 100.0 % 0.53 [ 0.35, 0.80 ]

6 Free of MEE at entry not required
Gaskins 1982a 0/10 8/11 3.6 % 0.06 [ 0.00, 0.99 ]
Gonzalez 1986a 16/21 17/20 28.9 % 0.90 [ 0.66, 1.21 ]
Liston 1983a 11/19 11/16 24.9 % 0.84 [ 0.51, 1.40 ]
Principi 1989a 18/66 19/30 25.5 % 0.43 [ 0.27, 0.70 ]
Varsano 1985a 4/15 12/17 17.2 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 131 94 100.0 % 0.57 [ 0.33, 0.99 ]

7 Excluded congenital abnormalities
0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
M- M-
n/N n/N CI CI
Casselbrant 1992a 36/86 48/80 14.1 % 0.70 [ 0.51, 0.95 ]
Gaskins 1982a 0/10 8/11 1.4 % 0.06 [ 0.00, 0.99 ]
Gonzalez 1986a 16/21 17/20 14.1 % 0.90 [ 0.66, 1.21 ]
Leach 2008 40/52 37/51 14.9 % 1.06 [ 0.85, 1.33 ]
Liston 1983a 11/19 11/16 11.8 % 0.84 [ 0.51, 1.40 ]
Mandel 1996a 13/55 27/51 11.3 % 0.45 [ 0.26, 0.77 ]
Perrin 1974a 4/28 12/26 6.7 % 0.31 [ 0.11, 0.84 ]
Principi 1989a 18/66 41/48 12.9 % 0.32 [ 0.21, 0.48 ]
Roark 1997a 37/99 22/59 12.8 % 1.00 [ 0.66, 1.52 ]
Subtotal (95% CI) 436 362 100.0 % 0.65 [ 0.46, 0.91 ]

8 Exclusion criteria not described
Maynard 1972a 42/173 76/191 26.9 % 0.61 [ 0.44, 0.84 ]
Persico 1985a 34/60 41/48 42.7 % 0.66 [ 0.52, 0.85 ]
Sih 1993a 7/40 10/20 4.2 % 0.35 [ 0.16, 0.78 ]
Teele 2000a 31/76 28/41 22.9 % 0.60 [ 0.42, 0.84 ]
Varsano 1985a 4/15 12/17 3.4 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 364 317 100.0 % 0.61 [ 0.51, 0.71 ]

Heterogeneity: Tau2 = 0.0; Chi2 = 3.51, df = 4 (P = 0.48); I2 =0.0%
9 Conducted in USA
Casselbrant 1992a 36/86 48/80 19.6 % 0.70 [ 0.51, 0.95 ]
Gaskins 1982a 0/10 8/11 0.7 % 0.06 [ 0.00, 0.99 ]
Liston 1983a 11/19 11/16 12.0 % 0.84 [ 0.51, 1.40 ]
Mandel 1996a 13/55 27/51 11.1 % 0.45 [ 0.26, 0.77 ]
Maynard 1972a 42/173 76/191 19.2 % 0.61 [ 0.44, 0.84 ]
Perrin 1974a 4/28 12/26 4.4 % 0.31 [ 0.11, 0.84 ]
Roark 1997a 37/99 22/59 15.0 % 1.00 [ 0.66, 1.52 ]
Teele 2000a 31/76 28/41 18.0 % 0.60 [ 0.42, 0.84 ]
Subtotal (95% CI) 546 475 100.0 % 0.65 [ 0.52, 0.81 ]

0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
M- M-
n/N n/N CI CI
10 Not conducted in USA

Leach 2008 40/52 37/51 26.0 % 1.06 [ 0.85, 1.33 ]
Persico 1985a 34/60 41/48 25.6 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 18/66 19/30 21.0 % 0.43 [ 0.27, 0.70 ]
Sih 1993a 7/40 10/20 14.5 % 0.35 [ 0.16, 0.78 ]
Varsano 1985a 4/15 12/17 13.0 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 233 166 100.0 % 0.58 [ 0.37, 0.90 ]

0.1 0.2 0.5 1 2 5 10

episodes of AOM or CSOM during intervention by inclusion criteria.
Outcome: 6 Prevention - episodes of AOM or CSOM during intervention by inclusion criteria
log
1 Excluded age greater than 36 months

Casselbrant 1992a 88 136 -0.588 (0.137) 39.5 % 0.56 [ 0.42, 0.73 ]
Gray 1981 31 39 -0.31 (0.256) 21.8 % 0.73 [ 0.44, 1.21 ]
Leach 2008 104 111 -0.1597 (0.141) 38.7 % 0.85 [ 0.65, 1.12 ]
Subtotal (95% CI) 223 286 100.0 % 0.70 [ 0.52, 0.94 ]

2 Included age greater than 36 months
Gaskins 1982a 1 9 -2.1 (1.47) 1.2 % 0.12 [ 0.01, 2.18 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 12.4 % 0.69 [ 0.42, 1.15 ]
Liston 1983a 16 27 -0.695 (0.342) 10.2 % 0.50 [ 0.26, 0.98 ]
Mandel 1996a 14 46 -1.313 (0.33) 10.5 % 0.27 [ 0.14, 0.51 ]
Maynard 1972a 73 151 -0.635 (0.146) 15.4 % 0.53 [ 0.40, 0.71 ]
Principi 1989a 20 25 -1.012 (0.324) 10.7 % 0.36 [ 0.19, 0.69 ]
Roark 1997a 36 20 0.1823 (0.3) 11.3 % 1.20 [ 0.67, 2.16 ]
Schuller 1983a 38 221 -1.3 (0.184) 14.5 % 0.27 [ 0.19, 0.39 ]
Sih 1993a 8 14 -1.253 (0.497) 7.0 % 0.29 [ 0.11, 0.76 ]
Varsano 1985a 6 24 -1.253 (0.514) 6.7 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 241 577 100.0 % 0.44 [ 0.31, 0.61 ]

3 Otitis-prone at entry (2/6 or 3/12)
Casselbrant 1992a 88 136 -0.588 (0.137) 21.8 % 0.56 [ 0.42, 0.73 ]
Liston 1983a 16 27 -0.695 (0.342) 15.1 % 0.50 [ 0.26, 0.98 ]
Principi 1989a 20 25 -1.012 (0.324) 15.7 % 0.36 [ 0.19, 0.69 ]
Roark 1997a 36 20 0.1823 (0.3) 16.5 % 1.20 [ 0.67, 2.16 ]
Schuller 1983a 38 221 -1.3 (0.184) 20.4 % 0.27 [ 0.19, 0.39 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
log
Varsano 1985a 6 24 -1.253 (0.514) 10.4 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 204 453 100.0 % 0.47 [ 0.30, 0.72 ]

4 Less otitis-prone at entry (2/6 or 3/18; 1 before 6 months of age or 2/12)
Gaskins 1982a 1 9 -2.1 (1.47) 2.3 % 0.12 [ 0.01, 2.18 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 40.3 % 0.69 [ 0.42, 1.15 ]
Gray 1981 31 39 -0.31 (0.256) 40.8 % 0.73 [ 0.44, 1.21 ]
Sih 1993a 8 14 -1.253 (0.497) 16.6 % 0.29 [ 0.11, 0.76 ]
Subtotal (95% CI) 69 102 100.0 % 0.59 [ 0.38, 0.91 ]

5 Free of MEE at entry
Casselbrant 1992a 88 136 -0.588 (0.137) 48.3 % 0.56 [ 0.42, 0.73 ]
Mandel 1996a 14 46 -1.313 (0.33) 31.3 % 0.27 [ 0.14, 0.51 ]
Sih 1993a 8 14 -1.253 (0.497) 20.4 % 0.29 [ 0.11, 0.76 ]
Subtotal (95% CI) 110 196 100.0 % 0.39 [ 0.22, 0.67 ]

6 Free of MEE at entry not required
Gaskins 1982a 1 9 -2.1 (1.47) 1.7 % 0.12 [ 0.01, 2.18 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 18.3 % 0.69 [ 0.42, 1.15 ]
Gray 1981 31 39 -0.31 (0.256) 18.4 % 0.73 [ 0.44, 1.21 ]
Liston 1983a 16 27 -0.695 (0.342) 14.9 % 0.50 [ 0.26, 0.98 ]
Principi 1989a 20 25 -1.012 (0.324) 15.6 % 0.36 [ 0.19, 0.69 ]
Schuller 1983a 38 221 -1.3 (0.184) 21.5 % 0.27 [ 0.19, 0.39 ]
Varsano 1985a 6 24 -1.253 (0.514) 9.6 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 141 385 100.0 % 0.44 [ 0.30, 0.65 ]

7 Excluded congenital abnormalities
Casselbrant 1992a 88 136 -0.588 (0.137) 19.0 % 0.56 [ 0.42, 0.73 ]
Gaskins 1982a 1 9 -2.1 (1.47) 1.2 % 0.12 [ 0.01, 2.18 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 14.1 % 0.69 [ 0.42, 1.15 ]
Leach 2008 104 111 -0.1597 (0.141) 18.8 % 0.85 [ 0.65, 1.12 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
log
Liston 1983a 16 27 -0.695 (0.342) 11.1 % 0.50 [ 0.26, 0.98 ]
Mandel 1996a 14 46 -1.313 (0.33) 11.5 % 0.27 [ 0.14, 0.51 ]
Principi 1989a 20 25 -1.012 (0.324) 11.7 % 0.36 [ 0.19, 0.69 ]
Roark 1997a 36 20 0.1823 (0.3) 12.6 % 1.20 [ 0.67, 2.16 ]
Subtotal (95% CI) 308 414 100.0 % 0.58 [ 0.42, 0.80 ]

8 Exclusion criteria not described
Gray 1981 31 39 -0.31 (0.256) 22.3 % 0.73 [ 0.44, 1.21 ]
Maynard 1972a 73 151 -0.635 (0.146) 28.0 % 0.53 [ 0.40, 0.71 ]
Schuller 1983a 38 221 -1.3 (0.184) 26.1 % 0.27 [ 0.19, 0.39 ]
Sih 1993a 8 14 -1.253 (0.497) 12.1 % 0.29 [ 0.11, 0.76 ]
Varsano 1985a 6 24 -1.253 (0.514) 11.6 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 156 449 100.0 % 0.41 [ 0.27, 0.64 ]

9 Conducted in USA
Casselbrant 1992a 88 136 -0.588 (0.137) 17.5 % 0.56 [ 0.42, 0.73 ]
Gaskins 1982a 1 9 -2.1 (1.47) 1.2 % 0.12 [ 0.01, 2.18 ]
Gray 1981 31 39 -0.31 (0.256) 13.6 % 0.73 [ 0.44, 1.21 ]
Liston 1983a 16 27 -0.695 (0.342) 10.9 % 0.50 [ 0.26, 0.98 ]
Mandel 1996a 14 46 -1.313 (0.33) 11.3 % 0.27 [ 0.14, 0.51 ]
Maynard 1972a 73 151 -0.635 (0.146) 17.2 % 0.53 [ 0.40, 0.71 ]
Roark 1997a 36 20 0.1823 (0.3) 12.2 % 1.20 [ 0.67, 2.16 ]
Schuller 1983a 38 221 -1.3 (0.184) 16.0 % 0.27 [ 0.19, 0.39 ]
Subtotal (95% CI) 297 649 100.0 % 0.50 [ 0.36, 0.70 ]

10 Not conducted in USA

Leach 2008 104 111 -0.1597 (0.141) 33.5 % 0.85 [ 0.65, 1.12 ]
Principi 1989a 20 25 -1.012 (0.324) 26.8 % 0.36 [ 0.19, 0.69 ]
Sih 1993a 8 14 -1.253 (0.497) 20.1 % 0.29 [ 0.11, 0.76 ]
Varsano 1985a 6 24 -1.253 (0.514) 19.5 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 138 174 100.0 % 0.44 [ 0.23, 0.85 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
log
0.1 0.2 0.5 1 2 5 10

AOM or CSOM during intervention by medication.
Outcome: 7 Prevention - any AOM or CSOM during intervention by medication

M- M-
n/N n/N CI CI
1 Amoxicillin, penicillin
Casselbrant 1992a 36/86 48/80 13.7 % 0.70 [ 0.51, 0.95 ]
Leach 2008 40/52 37/51 15.2 % 1.06 [ 0.85, 1.33 ]
Mandel 1996a 13/55 27/51 9.4 % 0.45 [ 0.26, 0.77 ]
Maynard 1972a 42/173 76/191 13.5 % 0.61 [ 0.44, 0.84 ]
Persico 1985a 34/60 41/48 14.8 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 9/33 19/30 8.3 % 0.43 [ 0.23, 0.80 ]
Roark 1997a 37/99 22/59 11.6 % 1.00 [ 0.66, 1.52 ]
Sih 1993a 3/20 10/20 3.7 % 0.30 [ 0.10, 0.93 ]
Teele 2000a 12/40 28/41 9.8 % 0.44 [ 0.26, 0.74 ]
Subtotal (95% CI) 618 571 100.0 % 0.64 [ 0.50, 0.82 ]

0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
M- M-
n/N n/N CI CI
2 Sulfisoxazole, trimethoprim sulfamethoxazole
Gaskins 1982a 0/10 8/11 1.7 % 0.06 [ 0.00, 0.99 ]
Gonzalez 1986a 16/21 17/20 20.5 % 0.90 [ 0.66, 1.21 ]
Liston 1983a 11/19 11/16 16.5 % 0.84 [ 0.51, 1.40 ]
Perrin 1974a 4/28 12/26 8.8 % 0.31 [ 0.11, 0.84 ]
Principi 1989a 9/33 19/30 14.3 % 0.43 [ 0.23, 0.80 ]
Sih 1993a 4/20 10/20 9.0 % 0.40 [ 0.15, 1.07 ]
Teele 2000a 19/36 28/41 19.2 % 0.77 [ 0.53, 1.12 ]
Varsano 1985a 4/15 12/17 10.0 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 182 181 100.0 % 0.58 [ 0.40, 0.84 ]

3 Not placebo-controlled
Gaskins 1982a 0/10 8/11 37.0 % 0.06 [ 0.00, 0.99 ]
Persico 1985a 34/60 41/48 63.0 % 0.66 [ 0.52, 0.85 ]
Subtotal (95% CI) 70 59 100.0 % 0.28 [ 0.02, 3.69 ]

4 Once daily
Casselbrant 1992a 36/86 48/80 17.2 % 0.70 [ 0.51, 0.95 ]
Mandel 1996a 13/55 27/51 7.5 % 0.45 [ 0.26, 0.77 ]
Maynard 1972a 42/173 76/191 16.6 % 0.61 [ 0.44, 0.84 ]
Persico 1985a 34/60 41/48 21.6 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 18/66 19/30 9.2 % 0.43 [ 0.27, 0.70 ]
Roark 1997a 20/55 22/59 9.1 % 0.98 [ 0.60, 1.58 ]
Sih 1993a 7/40 10/20 3.8 % 0.35 [ 0.16, 0.78 ]
Teele 2000a 31/76 28/41 15.0 % 0.60 [ 0.42, 0.84 ]
Subtotal (95% CI) 611 520 100.0 % 0.61 [ 0.52, 0.72 ]

5 Twice daily
Gaskins 1982a 0/10 8/11 1.4 % 0.06 [ 0.00, 0.99 ]
Gonzalez 1986a 16/21 17/20 22.5 % 0.90 [ 0.66, 1.21 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
M- M-
n/N n/N CI CI
Leach 2008 40/52 37/51 24.5 % 1.06 [ 0.85, 1.33 ]
Liston 1983a 11/19 11/16 16.9 % 0.84 [ 0.51, 1.40 ]
Perrin 1974a 4/28 12/26 8.0 % 0.31 [ 0.11, 0.84 ]
Roark 1997a 18/44 22/59 17.4 % 1.10 [ 0.68, 1.78 ]
Varsano 1985a 4/15 12/17 9.3 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 189 200 100.0 % 0.78 [ 0.56, 1.09 ]

6 Less than 3 months therapy
Roark 1997a 37/99 22/59 58.5 % 1.00 [ 0.66, 1.52 ]
Varsano 1985a 4/15 12/17 41.5 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 114 76 100.0 % 0.67 [ 0.26, 1.72 ]

7 Three to six months therapy
Gaskins 1982a 0/10 8/11 1.1 % 0.06 [ 0.00, 0.99 ]
Gonzalez 1986a 16/21 17/20 15.1 % 0.90 [ 0.66, 1.21 ]
Leach 2008 40/52 37/51 16.3 % 1.06 [ 0.85, 1.33 ]
Liston 1983a 11/19 11/16 11.7 % 0.84 [ 0.51, 1.40 ]
Perrin 1974a 4/28 12/26 5.8 % 0.31 [ 0.11, 0.84 ]
Persico 1985a 34/60 41/48 15.9 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 18/66 19/30 12.1 % 0.43 [ 0.27, 0.70 ]
Sih 1993a 7/40 10/20 7.6 % 0.35 [ 0.16, 0.78 ]
Teele 2000a 31/76 28/41 14.4 % 0.60 [ 0.42, 0.84 ]
Subtotal (95% CI) 372 263 100.0 % 0.64 [ 0.48, 0.86 ]

8 More than six months therapy
Casselbrant 1992a 36/86 48/80 44.1 % 0.70 [ 0.51, 0.95 ]
Mandel 1996a 13/55 27/51 14.3 % 0.45 [ 0.26, 0.77 ]
Maynard 1972a 42/173 76/191 41.6 % 0.61 [ 0.44, 0.84 ]
Subtotal (95% CI) 314 322 100.0 % 0.62 [ 0.50, 0.76 ]

0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
M- M-
n/N n/N CI CI
0.1 0.2 0.5 1 2 5 10

episodes of AOM or CSOM during intervention by medication.
Outcome: 8 Prevention - episodes of AOM or CSOM during intervention by medication
log
1 Amoxicillin, penicillin
Casselbrant 1992a 88 136 -0.588 (0.137) 19.1 % 0.56 [ 0.42, 0.73 ]
Leach 2008 104 111 -0.1597 (0.141) 18.9 % 0.85 [ 0.65, 1.12 ]
Mandel 1996a 14 46 -1.313 (0.33) 11.6 % 0.27 [ 0.14, 0.51 ]
Maynard 1972a 73 151 -0.635 (0.146) 18.7 % 0.53 [ 0.40, 0.71 ]
Principi 1989a 20 25 -1.012 (0.324) 11.8 % 0.36 [ 0.19, 0.69 ]
Roark 1997a 36 20 0.1823 (0.3) 12.6 % 1.20 [ 0.67, 2.16 ]
Sih 1993a 8 14 -1.253 (0.497) 7.2 % 0.29 [ 0.11, 0.76 ]
Subtotal (95% CI) 343 503 100.0 % 0.55 [ 0.40, 0.76 ]

2 Sulfisoxazole, trimethoprim sulfamethoxazole
Gaskins 1982a 1 9 -2.1 (1.47) 3.7 % 0.12 [ 0.01, 2.18 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 17.6 % 0.69 [ 0.42, 1.15 ]
0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
log
Gray 1981 31 39 -0.31 (0.256) 17.6 % 0.73 [ 0.44, 1.21 ]
Liston 1983a 16 27 0.695 (0.342) 16.1 % 2.00 [ 1.02, 3.92 ]
Schuller 1983a 38 221 -1.3 (0.184) 18.7 % 0.27 [ 0.19, 0.39 ]
Sih 1993a 8 14 -1.253 (0.497) 13.3 % 0.29 [ 0.11, 0.76 ]
Varsano 1985a 6 24 -1.253 (0.514) 13.0 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 129 374 100.0 % 0.52 [ 0.28, 0.96 ]

3 Not placebo-controlled
Gaskins 1982a 1 9 -2.1 (1.47) 1.5 % 0.12 [ 0.01, 2.18 ]
Schuller 1983a 38 221 -1.3 (0.184) 98.5 % 0.27 [ 0.19, 0.39 ]
Subtotal (95% CI) 39 230 100.0 % 0.27 [ 0.19, 0.39 ]

4 Once daily
Casselbrant 1992a 88 136 -0.588 (0.137) 21.2 % 0.56 [ 0.42, 0.73 ]
Gray 1981 31 39 -0.31 (0.256) 14.9 % 0.73 [ 0.44, 1.21 ]
Mandel 1996a 14 46 -1.313 (0.33) 11.6 % 0.27 [ 0.14, 0.51 ]
Maynard 1972a 73 151 -0.635 (0.146) 20.7 % 0.53 [ 0.40, 0.71 ]
Principi 1989a 20 25 -1.012 (0.324) 11.9 % 0.36 [ 0.19, 0.69 ]
Roark 1997a 36 20 0.1823 (0.3) 12.8 % 1.20 [ 0.67, 2.16 ]
Sih 1993a 8 14 -1.253 (0.497) 6.9 % 0.29 [ 0.11, 0.76 ]
Subtotal (95% CI) 270 431 100.0 % 0.53 [ 0.39, 0.71 ]

5 Twice daily
Gaskins 1982a 1 9 -2.1 (1.47) 2.7 % 0.12 [ 0.01, 2.18 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 17.0 % 0.69 [ 0.42, 1.15 ]
Leach 2008 104 111 -0.1597 (0.141) 19.3 % 0.85 [ 0.65, 1.12 ]
Liston 1983a 16 27 -0.695 (0.342) 15.1 % 0.50 [ 0.26, 0.98 ]
Roark 1997a 36 20 0.1823 (0.3) 16.1 % 1.20 [ 0.67, 2.16 ]
Schuller 1983a 38 221 -1.3 (0.184) 18.6 % 0.27 [ 0.19, 0.39 ]
Varsano 1985a 6 24 -1.253 (0.514) 11.3 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 230 452 100.0 % 0.54 [ 0.33, 0.90 ]

0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
log
6 Less than three months therapy
Roark 1997a 36 20 0.1823 (0.3) 54.2 % 1.20 [ 0.67, 2.16 ]
Varsano 1985a 6 24 -1.253 (0.514) 45.8 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 42 44 100.0 % 0.62 [ 0.15, 2.53 ]

7 Three to six months therapy
Gaskins 1982a 1 9 -2.1 (1.47) 1.8 % 0.12 [ 0.01, 2.18 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 22.0 % 0.69 [ 0.42, 1.15 ]
Leach 2008 104 111 -0.1597 (0.141) 29.4 % 0.85 [ 0.65, 1.12 ]
Liston 1983a 16 27 -0.695 (0.342) 17.3 % 0.50 [ 0.26, 0.98 ]
Principi 1989a 20 25 -1.012 (0.324) 18.3 % 0.36 [ 0.19, 0.69 ]
Sih 1993a 8 14 -1.253 (0.497) 11.2 % 0.29 [ 0.11, 0.76 ]
Subtotal (95% CI) 178 226 100.0 % 0.54 [ 0.36, 0.81 ]

8 More than six months therapy
Casselbrant 1992a 88 136 -0.588 (0.137) 23.8 % 0.56 [ 0.42, 0.73 ]
Gray 1981 31 39 -0.31 (0.256) 17.5 % 0.73 [ 0.44, 1.21 ]
Mandel 1996a 14 46 -1.313 (0.33) 14.1 % 0.27 [ 0.14, 0.51 ]
Maynard 1972a 73 151 -0.635 (0.146) 23.3 % 0.53 [ 0.40, 0.71 ]
Schuller 1983a 38 221 -1.3 (0.184) 21.3 % 0.27 [ 0.19, 0.39 ]
Subtotal (95% CI) 244 593 100.0 % 0.45 [ 0.32, 0.63 ]

0.1 0.2 0.5 1 2 5 10

AOM or CSOM during intervention by outcome measure.
Outcome: 9 Prevention - any AOM or CSOM during intervention by outcome measure

M- M-
n/N n/N CI CI
1 Monthly active surveillance

Casselbrant 1992a 36/86 48/80 9.6 % 0.70 [ 0.51, 0.95 ]
Gonzalez 1986a 16/21 17/20 9.7 % 0.90 [ 0.66, 1.21 ]
Leach 2008 40/52 37/51 10.9 % 1.06 [ 0.85, 1.33 ]
Liston 1983a 11/19 11/16 6.6 % 0.84 [ 0.51, 1.40 ]
Mandel 1996a 13/55 27/51 6.2 % 0.45 [ 0.26, 0.77 ]
Maynard 1972a 42/173 76/191 9.4 % 0.61 [ 0.44, 0.84 ]
Roark 1997a 37/60 41/48 10.8 % 0.72 [ 0.57, 0.91 ]
Sih 1993a 7/40 10/20 3.8 % 0.35 [ 0.16, 0.78 ]
Teele 2000a 31/76 28/41 9.0 % 0.60 [ 0.42, 0.84 ]
Subtotal (95% CI) 582 518 76.0 % 0.71 [ 0.58, 0.86 ]

2 Greater than one to three-monthly active surveillance
Gaskins 1982a 0/10 8/11 0.5 % 0.06 [ 0.00, 0.99 ]
Perrin 1974a 4/28 12/26 2.8 % 0.31 [ 0.11, 0.84 ]
Persico 1985a 34/60 41/48 10.5 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 18/66 19/30 7.0 % 0.43 [ 0.27, 0.70 ]
Varsano 1985a 4/15 12/17 3.3 % 0.38 [ 0.15, 0.92 ]
Subtotal (95% CI) 179 132 24.0 % 0.45 [ 0.28, 0.72 ]

Total (95% CI) 761 650 100.0 % 0.64 [ 0.53, 0.77 ]
0.1 0.2 0.5 1 2 5 10

episodes of AOM or CSOM during intervention by outcome measure.
Outcome: 10 Prevention - episodes of AOM or CSOM during intervention by outcome measure
log
1 Monthly active surveillance

Casselbrant 1992a 88 136 -0.588 (0.137) 10.3 % 0.56 [ 0.42, 0.73 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 8.3 % 0.69 [ 0.42, 1.15 ]
Leach 2008 104 111 -0.1597 (0.141) 10.2 % 0.85 [ 0.65, 1.12 ]
Liston 1983a 16 27 -0.695 (0.342) 6.9 % 0.50 [ 0.26, 0.98 ]
Mandel 1996a 14 46 -1.313 (0.33) 7.1 % 0.27 [ 0.14, 0.51 ]
Maynard 1972a 73 151 -0.635 (0.146) 10.1 % 0.53 [ 0.40, 0.71 ]
Roark 1997a 36 20 0.1823 (0.3) 7.6 % 1.20 [ 0.67, 2.16 ]
Sih 1993a 8 14 -1.253 (0.497) 4.8 % 0.29 [ 0.11, 0.76 ]
Subtotal (95% CI) 368 545 65.2 % 0.59 [ 0.45, 0.77 ]

2 Four to six-weekly, or three-monthly active surveillance
Gaskins 1982a 1 9 -2.1 (0.47) 5.1 % 0.12 [ 0.05, 0.31 ]
Gray 1981 31 39 -0.31 (0.256) 8.3 % 0.73 [ 0.44, 1.21 ]
Principi 1989a 20 25 -1.012 (0.324) 7.2 % 0.36 [ 0.19, 0.69 ]
Schuller 1983a 38 221 -1.3 (0.184) 9.5 % 0.27 [ 0.19, 0.39 ]
Varsano 1985a 6 24 -1.253 (0.514) 4.6 % 0.29 [ 0.10, 0.78 ]
Subtotal (95% CI) 96 318 34.8 % 0.32 [ 0.19, 0.56 ]

Total (95% CI) 464 863 100.0 % 0.47 [ 0.36, 0.63 ]
0.1 0.2 0.5 1 2 5 10

AOM or CSOM during intervention by date of study.
Outcome: 11 Prevention - any AOM or CSOM during intervention by date of study

M- M-
n/N n/N CI CI
1 Completed in 1970s
Gaskins 1982a 0/10 8/11 0.6 % 0.06 [ 0.00, 0.99 ]
Liston 1983a 11/19 11/16 8.1 % 0.84 [ 0.51, 1.40 ]
Maynard 1972a 42/173 76/191 10.9 % 0.61 [ 0.44, 0.84 ]
Perrin 1974a 4/28 12/26 3.6 % 0.31 [ 0.11, 0.84 ]
Subtotal (95% CI) 230 244 23.3 % 0.56 [ 0.34, 0.94 ]

Casselbrant 1992a 36/86 48/80 11.1 % 0.70 [ 0.51, 0.95 ]
Gonzalez 1986a 16/21 17/20 11.1 % 0.90 [ 0.66, 1.21 ]
Persico 1985a 34/60 41/48 11.9 % 0.66 [ 0.52, 0.85 ]
Principi 1989a 18/66 19/30 8.5 % 0.43 [ 0.27, 0.70 ]
Subtotal (95% CI) 233 178 42.5 % 0.68 [ 0.53, 0.87 ]

Mandel 1996a 13/55 27/51 7.6 % 0.45 [ 0.26, 0.77 ]
Roark 1997a 37/99 22/59 9.4 % 1.00 [ 0.66, 1.52 ]
Sih 1993a 7/40 10/20 4.9 % 0.35 [ 0.16, 0.78 ]
Subtotal (95% CI) 194 130 21.9 % 0.57 [ 0.29, 1.11 ]

0.1 0.2 0.5 1 2 5 10

(Continued . . . )
(. . . Continued)
M- M-
n/N n/N CI CI
Leach 2008 40/52 37/51 12.3 % 1.06 [ 0.85, 1.33 ]
Subtotal (95% CI) 52 51 12.3 % 1.06 [ 0.85, 1.33 ]

Total (95% CI) 709 603 100.0 % 0.67 [ 0.53, 0.83 ]
0.1 0.2 0.5 1 2 5 10

episodes of AOM or CSOM during intervention by date of study.
Outcome: 12 Prevention - episodes of AOM or CSOM during intervention by date of study
log
Liston 1983a 16 27 -0.695 (0.342) 10.6 % 0.50 [ 0.26, 0.98 ]
Subtotal (95% CI) 16 27 10.6 % 0.50 [ 0.26, 0.98 ]

Casselbrant 1992a 88 136 -0.588 (0.137) 17.7 % 0.56 [ 0.42, 0.73 ]
Gonzalez 1986a 29 40 -0.37 (0.259) 13.3 % 0.69 [ 0.42, 1.15 ]
Principi 1989a 20 25 -1.012 (0.324) 11.1 % 0.36 [ 0.19, 0.69 ]
Subtotal (95% CI) 137 201 42.1 % 0.55 [ 0.42, 0.71 ]

Mandel 1996a 14 46 -1.313 (0.33) 10.9 % 0.27 [ 0.14, 0.51 ]
Roark 1997a 36 20 0.1823 (0.3) 11.9 % 1.20 [ 0.67, 2.16 ]
Sih 1993a 8 14 -1.253 (0.497) 6.9 % 0.29 [ 0.11, 0.76 ]
Subtotal (95% CI) 58 80 29.7 % 0.47 [ 0.16, 1.35 ]

Leach 2008 104 111 -0.1597 (0.141) 17.6 % 0.85 [ 0.65, 1.12 ]
Subtotal (95% CI) 104 111 17.6 % 0.85 [ 0.65, 1.12 ]

Total (95% CI) 315 419 100.0 % 0.56 [ 0.41, 0.77 ]
0.1 0.2 0.5 1 2 5 10

AOM or CSOM during intervention by compliance.
Outcome: 13 Prevention - any AOM or CSOM during intervention by compliance

1 High compliance
Maynard 1972a 17/79 42/92 54.0 % 0.47 [ 0.29, 0.76 ]
Subtotal (95% CI) 79 92 54.0 % 0.47 [ 0.29, 0.76 ]

2 Not high compliance
Maynard 1972a 25/94 34/99 46.0 % 0.77 [ 0.50, 1.19 ]
Subtotal (95% CI) 94 99 46.0 % 0.77 [ 0.50, 1.19 ]

Total (95% CI) 173 191 100.0 % 0.61 [ 0.44, 0.84 ]
Heterogeneity: Chi2 = 2.29, df = 1 (P = 0.13); I2 =56%
0.1 0.2 0.5 1 2 5 10

episodes of AOM or CSOM during intervention by compliance.
Outcome: 14 Prevention - episodes of AOM or CSOM during intervention by compliance
log
1 High compliance
Gray 1981 11 19 -0.7696 (0.4178) 19.9 % 0.46 [ 0.20, 1.05 ]
Maynard 1972a 24 86 -1.12 (0.2448) 27.6 % 0.33 [ 0.20, 0.53 ]
Subtotal (95% CI) 35 105 47.5 % 0.36 [ 0.24, 0.54 ]

2 Not high compliance
Gray 1981 20 19 0.138 (0.3478) 22.9 % 1.15 [ 0.58, 2.27 ]
Maynard 1972a 49 65 -0.2308 (0.1985) 29.6 % 0.79 [ 0.54, 1.17 ]
Subtotal (95% CI) 69 84 52.5 % 0.87 [ 0.62, 1.22 ]

Total (95% CI) 104 189 100.0 % 0.61 [ 0.35, 1.07 ]
0.1 0.2 0.5 1 2 5 10

ADDITIONAL TABLES
Table 1. Quality of studies included in the review
Quality component High quality Agreement Kappa
Randomisation 9/17 75% 0.48
Allocation concealment 9/17 69% 0.35
Blinding 14/17 94% 0.76
Reporting by allocated group 9/17 88% 0.75
Table 1. Quality of studies included in the review (Continued)
Follow up 10/17 81% 0.63
Outcome assessments 14/17 81% -0.1
Table 2. AOM episodes per child year
Study Antibiotic Control
Casselbrant 0.6 (n = 86) 1.08 (n = 80)
Gaskins 0 (n = 10) 2.0 (n = 11)
Gonzalez 2.8 (n = 21) 4 (n = 80)
Gray 1.2 (n = 26) 1.6 (n = 24)
Leach 4.25 (n = 52) 5.0 (n = 51)
Liston 3.6 (n = 19) 6.7 (n = 16)
Mandel 0.28 (n = 55) 1.04 (n = 51)
Maynard 0.42 (n = 173) 0.74 (n = 191)
Principi 0.66 (n = 66) 1.68 (n = 30)
Roark 2.6(n = 99) 2.95 (n = 59)
Schuller 1.15 (n = 18) 4.9 (n = 20)
Sih 0.8 (n = 40) 2.6 (n = 20)
Varsano 2.08 (n = 15) 7.3 (n = 17)
APPENDICES
Appendix 1. Embase.com search strategy

18. #14 AND #17
17. #15 OR #16
16. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR ’cross-over’:ab,ti OR ’cross over’:ab,ti OR volunteer*:
ab,ti OR assign*:ab,ti OR allocat*:ab,ti OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti
15. ’randomized controlled trial’/exp OR ’single blind procedure’/exp OR ’double blind procedure’/exp OR ’crossover procedure’/exp
14. #3 AND #13
13. #11 OR #12
12. ’antibiotic prophylaxis’/de
11. #7 AND #10
10. #8 OR #9
9. chemoprevent*:ab,ti OR chemoprophyla*:ab,ti OR prophyla*:ab,ti OR prevent*:ab,ti
8. ’chemoprophylaxis’/de
7. #4 OR #5 OR #6
6. amoxicillin:ab,ti OR amoxycillin:ab,ti OR ampicillin:ab,ti OR azithromycin:ab,ti OR azithromicin:ab,ti OR cefaclor:ab,ti OR
penicillin:ab,ti OR sulphamethoxazole:ab,ti OR sulphisoxazole:ab,ti OR cotrimoxazole:ab,ti
5. antibiotic*:ab,ti
4. ’antibiotic agent’/exp
3. #1 OR #2
2. ’otitis media’:ab,ti OR aom:ab,ti OR ome:ab,ti OR csom:ab,ti
1. ’otitis media’/exp
WHAT’S NEW
Last assessed as up-to-date: 6 August 2010.
Date Event Description
29 July 2013 Amended We have corrected in the Footnotes of the Characteristics of included study table for Roark 1997a. The
intervention described “Amoxicillin 20 mg/kg/d QD or BD” with QD defined in the Footnotes as “four
times daily”. The original study states once daily versus twice daily, and the text of the review also reports
this correctly
HISTORY
Protocol first published: Issue 3, 2003
Review first published: Issue 4, 2006
Date Event Description
6 August 2010 New search has been performed Searches conducted. One new study identified (Leach 2008). Conclusions of
review unchanged. New conflict of interest as the review authors are investigators
in the new included study
20 June 2008 Amended Converted to new review format.
28 March 2006 New search has been performed Searches conducted.
CONTRIBUTIONS OF AUTHORS
Amanda Leach (AL) was responsible for designing the study, searching the literature, identifying the relevant studies, extracting the
data, analysing the results and writing the review. Peter Morris (PM) extracted data independently and assisted with the design, analysis
and writing of the review.
DECLARATIONS OF INTEREST
Both review authors were investigators on a randomized controlled trial of antibiotics to prevent otitis media in remote Australian
Aboriginal children. This study was funded by the Australian National Health and Medical Research Council.
SOURCES OF SUPPORT
Internal sources
• No sources of support supplied
External sources
• National Health and Medical Research Council, Australia.
Both authors received individual and project grant research support
NOTES
Protocol amendment: the outcome colonised with resistant Streptococcus pneumoniae or Haemophilus influenzae was limited to the first
follow-up visit following treatment, and at least six weeks after starting treatment. Although this meant that some of the data from some
studies that measured antibiotic resistance at multiple time points was not used, we decided that the estimates of antibiotic resistance
would become more comparable across a range of studies (27 August 2003).
INDEX TERMS
Medical Subject Headings (MeSH)

Acute Disease; Anti-Bacterial Agents [∗ therapeutic use]; Chronic Disease; Infant, Newborn; Otitis Media [drug therapy]; Otitis Media,
Suppurative [∗ prevention & control]; Randomized Controlled Trials as Topic; Recurrence [prevention & control]; Tympanic Membrane
Perforation [prevention & control]
MeSH check words

Adolescent; Child; Child, Preschool; Humans; Infant

Antibiotik OMSK (Cochrane)

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Antibiotik OMSK (Cochrane)

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Antibiotics for the prevention of acute and chronic

suppurative otitis media in children (Review)

Leach AJ, Morris PS

Antibiotics for the prevention of acute and chronic

Amanda J Leach1 , Peter S Morris2

Menzies School of Health Research, Darwin, Australia

Editorial group: Cochrane Acute Respiratory Infections Group.

PLAIN LANGUAGE SUMMARY

Assumed risk Corresponding risk

Control Antibiotic versus control

Prevention - any AOM or Low risk population RR 0.65 1461 ⊕⊕⊕

Medium risk population

550 per 1000 358 per 1000

High risk population

800 per 1000 520 per 1000

GRADE Working Group grades of evidence

METHODS Types of outcome measures

Dealing with missing data Subgroup analysis and investigation of heterogeneity

proportion of children with recurrent AOM or CSOM at end of

02 Secondary outcomes - first primary outcome (any

1. Children less than 12 months or age, older than 12

2. Otitis-prone children, non-otitis prone, or not separated

Assumed risk Corresponding risk

Control Antibiotic versus control

GRADE Working Group grades of evidence

Characteristics of included studies [ordered by study ID]

Participants Pittsburgh, USA

Outcomes Measured in more than 90%

Bias Authors’ judgement Support for judgement

Other bias Low risk No other potential source of bias identified

Methods Not blinded

Participants San Juan, Puerto Rico

Outcomes Measured in more than 90%

Bias Authors’ judgement Support for judgement

Allocation concealment (selection bias) Unclear risk B - unclear

Blinding (performance bias and detection Unclear risk C - unclear

Other bias Unclear risk No other potential source of bias identified

Participants Aurora CO and Tacoma WA, USA

Outcomes Measured in less than 90%

Bias Authors’ judgement Support for judgement

Other bias Unclear risk No other potential source of bias identified

Participants Alabama, USA

Outcomes Measured in more than 90%

Bias Authors’ judgement Support for judgement

Other bias Unclear risk No other potential source of bias identified

Methods Double-blind, placebo-controlled

Participants Australia. 3 remote Aboriginal communities 70 km from Darwin in tropical northern

Outcomes Measured and analysed in all children

Bias Authors’ judgement Support for judgement

Other bias Low risk No other potential source of bias identified

Participants San Antonio, Texas, USA

Outcomes Measured in less than 90%

Bias Authors’ judgement Support for judgement

Other bias Unclear risk No other potential source of bias identified

Participants Pittsburgh, USA

Outcomes Measured in more than 90%

Bias Authors’ judgement Support for judgement

Other bias Unclear risk No other potential source of bias identified

Participants West Alaskan villages, USA

Outcomes Measured in more than 90%

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk D - randomisation not mentioned

Allocation concealment (selection bias) Unclear risk B - unclear

and side effects were categorised as treat-