Accepted Manuscript

A Systematic Review and Meta-Analysis of Antimicrobial Resistance in Paediatric

Acute Otitis Media

Michael W. Mather, MRes, Michael Drinnan, PhD, John D. Perry, PhD, Steven
Powell, MRes, Janet A. Wilson, MD, Jason Powell, PhD

PII: S0165-5876(19)30211-3
DOI: https://doi.org/10.1016/j.ijporl.2019.04.041
Reference: PEDOT 9490

To appear in: International Journal of Pediatric Otorhinolaryngology

Received Date: 4 December 2018

Revised Date: 16 March 2019
Accepted Date: 30 April 2019

Please cite this article as: M.W. Mather, M. Drinnan, J.D. Perry, S. Powell, J.A. Wilson, J. Powell, A
Systematic Review and Meta-Analysis of Antimicrobial Resistance in Paediatric Acute Otitis Media,
International Journal of Pediatric Otorhinolaryngology, https://doi.org/10.1016/j.ijporl.2019.04.041.

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 ACCEPTED MANUSCRIPT
A Systematic Review and Meta-Analysis of

Antimicrobial Resistance in Pediatric Acute Otitis Media

Michael W. Mather1,2 MRes, Michael Drinnan1 PhD, John D. Perry3 PhD,

Steven Powell2 MRes, Janet A. Wilson2,4 MD, Jason Powell*1,2 PhD

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Affiliations:

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1
Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon

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Tyne, NE2 4HH, UK.

2
Department of Otolaryngology, Freeman Hospital, Freeman Road, Newcastle upon Tyne,

NE7 7DN, UK.

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3
Department of Microbiology, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7
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7DN, UK.

4
Institute of Health and Society, Newcastle University, Richardson Road, Newcastle upon
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Tyne, NE2 4AX, UK.

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*Correspondence to: Jason Powell at Institute of Cellular Medicine, Newcastle University,

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Framlington Place, Newcastle upon Tyne, NE2 4HH, UK [jason.powell@newcastle.ac.uk]

Telephone: +44 191 208 6000

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Competing interests Statement: The authors have no conflicts of interest relevant to this

article to disclose.
 ACCEPTED MANUSCRIPT
Full title: A Systematic Review and Meta-Analysis of Antimicrobial Resistance in

Paediatric Acute Otitis Media

Short running title: A Systematic Review and Meta-Analysis of Antimicrobial Resistance

in Paediatric Acute Otitis Media

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Michael W. Mather1,2 MRes, Michael Drinnan1 PhD, John D. Perry3 PhD,

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Steven Powell2 MRes, Janet A. Wilson2,4 MD, Jason Powell*1,2 PhD

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Affiliations:
1
Institute of Cellular Medicine, Newcastle University, Framlington Place, Newcastle upon

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Tyne, NE2 4HH, UK.
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2
Department of Otolaryngology, Freeman Hospital, Freeman Road, Newcastle upon Tyne,

NE7 7DN, UK.

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3
Department of Microbiology, Freeman Hospital, Freeman Road, Newcastle upon Tyne, NE7
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7DN, UK.
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4
Institute of Health and Society, Newcastle University, Richardson Road, Newcastle upon
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Tyne, NE2 4AX, UK.

*Correspondence to: Jason Powell at Institute of Cellular Medicine, Newcastle University,

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Framlington Place, Newcastle upon Tyne, NE2 4HH, UK [jason.powell@newcastle.ac.uk]

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Telephone: +44 191 208 6000

Acknowledgements: Not applicable

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Abstract:

Objective of review: Acute otitis media (AOM) is the largest cause of antimicrobial

prescriptions amongst children in developed countries. Excessive and inappropriate

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prescribing is known to drive antimicrobial resistance, but less is known of antimicrobial

resistance in AOM-associated bacteria.

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Type of review & search strategy: We conducted a systematic review and meta-analysis of

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bacterial prevalence and antimicrobial resistance in studies of paediatric AOM identified

from Ovid Medline, Embase and the Cochrane library.

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Results: From 48 unique studies, 15,871 samples were included. Only 0.67 (CI 0.63–0.71) of
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all ear samples grew a bacterial pathogen. The most common bacterial causes of AOM in
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children were Streptococcus pneumoniae 0.30 (CI 0.27-0.32), Haemophilus influenza 0.23

(CI 0.20–0.26), and Moraxella catarrhalis 0.05 (CI 0.04–0.06). Resistance patterns varied
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amongst organisms and antimicrobial agents. The pooled proportion of bacterial culture-
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positive episodes of AOM that could be effectively treated with amoxicillin was 0.85 (CI

0.76–0.94), erythromycin was 0.64 (0.48–0.78) and amoxicillin-clavulanate was 0.95 (CI
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0.85–0.98).
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Conclusion: We have demonstrated the bacteriology and antimicrobial resistance patterns of

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AOM. Of samples which grew bacteria, on average approximately 15% of isolates

demonstrated resistance to amoxicillin; a typical first-line agent. Greater understanding of

local bacteriology and resistance patterns is needed to enable improved antimicrobial

stewardship.

Key words: Otitis media, antimicrobial resistance, bacteriology

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Five succinct key points:

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1. Two in three samples from middle ear sampling in AOM grew a bacterial pathogen

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2. Common bacterial causes of AOM include Streptococcus pneumoniae, Haemophilus

influenzae, and Moraxella catarrhalis

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3. Antimicrobial resistance to first-line antibiotics is common
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4. Amoxicillin-clavulanate offers a higher chance of bacterial eradication than current
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first-line agents
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5. A greater understanding of local bacteriology and resistance patterns is needed to

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enable improved antimicrobial stewardship

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Main text –

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Introduction

Acute otitis media (AOM) is defined as the presence of inflammation in the middle ear

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associated with an effusion, and accompanied by the rapid onset of signs and symptoms of an
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ear infection1. It is the single largest cause of infections amongst children 2
and is the most
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common cause for antimicrobial prescriptions for children in economically developed

countries 1.
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Many national guidelines for AOM recommend either immediate or delayed antimicrobial
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3 4 5 6
prescribing (amoxicillin in most circumstances), or observation with close follow-up .
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These guidelines are, in part, based on work which has shown that after two to three days of

watchful waiting approximately 80% of children will spontaneously recover 7. Important

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exceptions to this include; children younger than 2 years, those with bilateral AOM, and
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those with AOM and otorrhoea, where antibiotics may be more beneficial 8. Despite these
9 10 11
evidence-based guidelines, large scale studies from North America , Europe , and the
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UK have demonstrated excessive and inconsistent antimicrobial prescribing in paediatric

AOM in general practice and secondary care.

There is a clear association between antimicrobial prescribing and the development of

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antimicrobial resistance , and the World Health Organisation (WHO) calculated that in

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Europe alone infections due to drug-resistant bacteria cause in excess of 25,000 deaths and
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cost at least 1.5 billion euros each year in direct healthcare costs and lost productivity .

Furthermore, there is also evidence that specifically associates antimicrobial use to the

development of antimicrobial resistance in AOM, and demonstrates that this increases the

likelihood of treatment failure 15.

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Recent studies have sought to identify the pathogens responsible for paediatric acute otitis

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media , and older studies have also investigated the overall effectiveness of antibiotics in

children with acute otitis media 8. We present a comprehensive review and meta-analysis, of

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both the microbiology and antimicrobial resistance of AOM organisms to commonly used

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antimicrobial agents, with the aim of informing responsible antimicrobial stewardship.
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Methods

Systematic review
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A comprehensive literature search was performed using Medline, Embase and the Cochrane
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library up to and including January 2017. A keyword search was undertaken using the search
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terms ‘otitis media’ AND each of the following search terms: ‘aetiology’, ‘otopathogens’,

‘pathogens’, ‘microbiology’, ‘bacteria’, ‘anti-bacterial agents’, and ‘antibiotic resistance’.

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Search results were limited to those that were in the English language, human-only studies,

and published from 1980 onwards. Duplicated articles were removed and abstracts were
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screened for relevance to bacteriology and/or antimicrobial resistance in acute otitis media in
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children (less than 18 years old).

Relevant articles were read in full to extract data for the meta-analysis. Inclusion criteria

comprised all studies which provided original, non-duplicated quantitative data about the

prevalence of bacteria with or without the number of susceptible, intermediate, and resistant

strains of each species. Sampling methods included those obtained by tympanocentesis and

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otorrhoea from an acute tympanic membrane perforation, or combination of these sampling

techniques.

Notable exclusions comprised absence of original data, investigations of native flora,

investigations specifically considering recurrent or ‘treatment-failure’ acute otitis media,

studies with overlapping data (in which case we include the most recent report), studies

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exclusively sampling tympanostomy tube otorrhoea (except in mixed methods studies in

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which we only included series where tympanostomy tube otorrhoea comprised a small,

<20%, proportion of samples), nasopharyngeal swab data, or omission of fundamental

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demographic information (e.g. number of participants in study). No studies were excluded on

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the basis of their chosen method of culturing pathogens. Where AOM data was part of a
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larger study, only data relating to AOM was extracted. In drug trials, only the initial

tympanocentesis data (i.e. before participants received the antimicrobial drug under
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investigation) was included.

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Meta-analysis
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All extracted data from the literature was included in the quantitative analysis. Data was

tabulated in Microsoft Excel, then analysed using R (Vienna, Austria), version 3.3.1. Meta-
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analysis was performed using function metaprop and reported using function forest from the

meta library.
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Pooled statistics were created from random-effects and fixed effects (inverse variance) meta-

analyses. Heterogeneity was consistently extremely high (median I2 > 90%), and therefore we

discuss results on the basis of the random-effects meta-analysis. Each study is given a similar

weight, whereas in the fixed-effects analysis all patients are weighted equally and large

studies dominate the analysis. The random effect analysis is the more conservative approach,

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with wider confidence intervals. The methods are described below, with notes on the specific

complicating factors:

Positive culture: For each species separately and for all species together, we report the

number of positive cultures as a proportion of all children assessed. Since some children are

positive for more than one species, or are positive for a rare bacterial species not included in

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our data, the species totals are not necessarily additive to give the overall total.

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Antimicrobial susceptibility: We calculated the antimicrobial susceptibility of three bacterial

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strains, to four common antimicrobials: penicillin; amoxicillin; amoxicillin-clavulanate; and

erythromycin. For the relevant subset of species we also assessed beta-lactamase production

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as a surrogate for resistance to penicillin and amoxicillin.
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In a number of studies, only a subgroup of all positive cultures was assessed for antimicrobial

susceptibility; the size of this subgroup was used as the denominator in the meta-analysis.
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Overall antimicrobial effectiveness: In almost all cases of AOM the decision on

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antimicrobial choice will be made without any prior knowledge of the organism involved. We
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therefore assessed the potential effectiveness of each common antimicrobial agent against an

unknown pathogen. For each study, we estimated the overall susceptibility to a specific
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antimicrobial as reported in that study. This was estimated as the susceptibility of a given
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pathogen, weighted by the proportion of cases where that pathogen was present. We
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acknowledge that under this model, bias can be introduced where a particular antimicrobial

agent is not used uniformly against all pathogens, or where multiple pathogens are present in

the same sample.

Results

The literature search yielded 7,598 articles following the key-word search. Studies were

limited to English language, human only studies, and studies from 1980-present day.

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Following deduplication this provided 4,249 unique articles. Abstracts were screened for

relevance to bacteriology or antimicrobial resistance in acute otitis media in children, which

identified 204 articles. The full texts and bibliographies were read, and 48 articles 17, 18, 19, 20,
21 22 23 24 25 26 27 28
, , , , , , , , 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,
53 54 55 56 57 58 59 60 61 62 63 64
, , , , , , , , , , , had quantitative data that could be included in the analysis

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(Figure 1, Table 1). Of these, 8 were retrospective studies, 27 were prospective studies, 4

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were a combination of both prospective and retrospective analysis, and 9 were drug trials. In

total these articles provided data for 15,871 unique episodes of AOM.

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Microbiology

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Our best estimate demonstrated a positive culture in 0.67 (CI 0.63 – 0.71) of all samples. The
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most commonly isolated bacterial species was Streptococcus pneumoniae; a Gram-positive

diplococcus well-known to colonize upper respiratory tract mucosa 65, found in 0.30 (CI 0.27
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- 0.32) of samples. The second most prevalent species was Haemophilus influenzae, a Gram-
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negative coccobacillus 66, which was isolated in 0.23 (CI 0.20 – 0.26) of samples. At 0.05 (CI
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0.04 – 0.06) of samples Moraxella catarrhalis, a Gram-negative diplococcus, was a less

frequent participant, but was the third most commonly isolated species. These are
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summarised in Fig. 2. The frequency of co-detection of multiple species for each sample was

rarely reported in the original studies thereby precluding further analysis of this.
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Antimicrobial susceptibility
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Streptococcus pneumoniae

For Gram-positive bacteria, such as Streptococcus pneumoniae, most of the literature

reported the proportion of samples resistant to penicillin. Testing for other specific drugs,

even commonly used compounds such as amoxicillin, was much less frequent. It is important

to note that whilst amoxicillin is a penicillin-based compound, some work suggests penicillin

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resistance is not fully predictive of resistance to related drugs, such as amoxicillin 40, which

we also found in our results (Table 2).

Haemophilus influenzae & Moraxella catarrhalis

For Gram-negative bacteria, such as Haemophilus influenzae and Moraxella catarrhalis,

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resistance was most often reported as the proportion of isolates capable of beta-lactamase

production. Beta-lactamase is an enzyme produced by bacteria which hydrolyses the beta-

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lactam ring structure of commonly used penicillin-based drugs, including amoxicillin,

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thereby conferring a resistant phenotype 67 (Table 2).

Overall antimicrobial effectiveness in AOM

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We have demonstrated variable resistance against commonly used antimicrobial agents by
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different AOM-causing bacteria. In most cases antimicrobial prescription decisions will be
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made without knowledge of the causative organism. We therefore assessed the effectiveness

of each antimicrobial agent against all positive bacterial cultures (Table 2). We also examined
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a pooled estimate of non-susceptibility to penicillin over time and found no statistically

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significant trend (Figure 3).

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Factors affecting antimicrobial effectiveness in AOM

We were unable to identify any obvious trends towards changes in antimicrobial resistance or
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bacteriology of AOM over the period covered in this meta-analysis. Subgroup analysis of
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study cohort age, sampling method and geographical location was severely limited by the

data available.

Discussion

Even when a bacteriological cause for AOM is confirmed, many first-line antimicrobial

treatments for AOM demonstrate drug-resistance. Whilst the analysed data indicates a

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pathogenic bacterial species was isolated in two out of every three cases of AOM, it is

possible that the children in the studies analysed are at the more severe end of the AOM

spectrum as they have engaged with medical services and had an intervention, such as

tympanocentesis.

Of the positive cultures the bacteriology of AOM was dominated by Streptococcus

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pneumoniae and Haemophilus influenzae. Non-susceptibility to commonly used first-line

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agents was found to be high in both Streptococcus pneumoniae and Haemophilus influenzae.

Of particular concern, Moraxella catarrhalis, though less prevalent, demonstrated near

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universal production of beta-lactamase and resistance to amoxicillin. Streptococcus

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pneumoniae demonstrated high resistance to erythromycin; a common first-line agent in
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penicillin allergy. A promising finding was that, whilst studies were limited, susceptibility of

all three organisms to amoxicillin-clavulanate, commonly used as a second-line agent,

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remains very high at >90% of culture positive isolates.

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The strengths of this meta-analysis include its comprehensive nature. We included 48 studies
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and some 15,871 unique episodes of AOM. However, there are a number of considerations

required when interpreting these finding. The International Organisation for Standardisation
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(ISO) has divided classification of Streptococcus pneumoniae resistance into susceptible,

intermediate, and resistant categories 68. ‘Susceptible’ bacteria are inhibited in vitro by a drug
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concentration associated with a high probability of therapeutic cure. ‘Intermediate’ varieties

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are associated with an uncertain clinical effect. ‘Resistant’ bacteria are associated with a high

likelihood of therapeutic failure. Based on these definitions, we took all samples reported in

the AOM literature as intermediate or resistant as being ‘non-susceptible’ isolates, as even

intermediately susceptible bacteria in AOM have been shown to have impaired

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bacteriological clearance in response to antimicrobial drugs . These ISO classifications are

defined by points on a spectrum known as minimum inhibitory concentration (MIC)

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‘breakpoints’. However, as there is geographical variation in these breakpoints comparison

between studies from different locations is subject to variability.

In terms of sampling, most (n=30, 62.5%) studies sampled exclusively via tympanocentesis,
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which has been identified as the ‘gold standard’ for middle ear fluid culture . Some (n=3,

6.3%) studies also identified bacteria exclusively by sampling otorrhoea from the external

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auditory canal following acute tympanic perforation; which potentially risks contamination

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with the native flora of the external auditory canal . The remaining 15 studies (31.3%)

involved mixed sampling methods.

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Studies exclusively examining tympanostomy tube otorrhoea were excluded on the basis that

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they reflect a chronically perforated tympanic membrane and will likely be contaminated
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with migration of commensal species from the external auditory canal . Data from

nasopharyngeal swabs were also excluded as they are felt to be unrepresentative of the
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middle ear70: indeed a recent systematic review found a wide range of concordance between
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nasopharyngeal samples and middle ear samples - from 68 up to 97% 73. Studies specifically
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investigating recurrent or ‘treatment failure’ AOM were excluded on the basis that they

introduce a confounding variable to the analysis and would likely warrant specific
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investigation in a separate study.

Whilst most studies to date utilised culture-based methods of bacterial identification, one
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more recent study (Yatyshina et al. 2016) used polymerase chain reaction (PCR) technology
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. This study appeared to have higher rates of bacterial detection compared to the average

over all studies, which suggests that culture-dependent detection might underestimate the

prevalence of positive bacterial infection. Whilst changing from culture-based methods to

PCR may alter the detection of bacteria, this technique will not alter the ways in which

antimicrobial resistance is assessed.

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There is also inconsistency between included studies in terms of diagnostic criteria for AOM.

Other studies have found that diagnoses of AOM are not always supported by positive

physical examination findings74; and therefore it is plausible that a number of studies which

did not demonstrate a positive bacterial culture result were not in fact AOM. The possibility

of this is an inherent weakness of a retrospective study on the subject.

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Consideration also ought to be given to the lack of quantification of variables known to alter

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antimicrobial resistance, such as previous antimicrobial therapy13. Indeed, a substantial

problem affecting all studies of antimicrobial resistance is that whilst a prescription may have

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been provided to a patient; few studies confirm that the antibiotics were actually dispensed

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and administered. As such, the stated rates of antimicrobial prescribing may be overstated
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compared to the true figures.

Further confounding factors include the different geographical locations of the studies; each
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with differing rates of prescribing and unique epidemiology of bacteria75. We attempted to

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perform subgroup analysis of antimicrobial resistance by continent but, whilst effects were
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suggested, the small group sizes and potential confounding factors preclude drawing reliable

conclusions. Similarly, the heterogeneity of guidelines for the management of AOM in

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different locations at different points in time precluded further analysis of this, but would be

valuable topics for future research.

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Another consideration is the variable rates of, and often lack of documentation of,
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pneumococcal (PCV) and Haemophilus influenzae type B (Hib) vaccination and the impact

on resistance. Although we were unable to control for this variable in countries with universal

vaccination against Haemophilus influenzae it may be that other species are relatively more

prevalent causes of AOM, which will have correspondingly different levels of antimicrobial

resistance. Similarly, countries in which antimicrobial drugs, such as amoxicillin, are

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available without prescription, one may find higher levels of drug-resistant bacteria compared

to our pooled data, however we were unable to control for these factors.

There is also the challenge of consistent patient selection across so many studies. Although a

definition of AOM is provided1, not all papers had identical inclusion criteria. Two large

trials (Hoberman NEJM 2016 & Tahtinen NEJM 2011) suggested that use of very stringent

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inclusion criteria revealed a high percentage of pathogen isolated compared to the mean

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values reported in this analysis.

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Whilst we were unable to identify a statistically significant rise in non-susceptibility to

penicillin over time amongst all species tested (Figure 3) factors such as disparate geography

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and variable vaccination schedules may reduce the reliability of this for any one specific
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location and time point. The introduction of different guidelines over time may also affect the

estimate.
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We include children and adolescents up to 18 years because many of the published studies
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presented this range as their inclusion criteria. Furthermore, patient age was often not defined
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beyond the descriptor of less than 18 years so further data extraction and subgroup analysis

was not possible. AOM is most commonly a disease of early childhood 1. As anatomy and
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immunology changes during childhood, it is possible that these factors alter AOM

bacteriology and antimicrobial resistance patterns as a child ages, however such data was not
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available for analysis.

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Other important considerations are the paucity of data on biofilms in the included studies,

which have known importance in OM76. One must also consider the selection of only English

language studies which may have excluded relevant articles in other languages.

Implications of the findings

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It was been well-described that acute otitis media may be associated with diagnostic

uncertainty. Emphasis must therefore be made on treating true episodes of AOM with an

effective antimicrobial agent for an appropriate duration. However, this data suggests many

prescriptions adhering to present guidelines are likely to be microbiologically ineffective and

therefore of no clinical benefit. For example, our global estimates suggest that Erythromycin

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is frequently ineffective – and yet still confers risks of adverse drug reactions. This therefore

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suggests its role as a first line agent may be limited.

A meta-analysis by Rosenfeld et al. demonstrated that over 60% of cases of AOM resolve

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spontaneously after 24 hours, and 80% within 2-3 days, when not treated with antimicrobial

drugs 7. Some clinicians might consider prescribing them in an attempt to mitigate the risk of

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developing serious complications of AOM. However, a retrospective analysis of the records

of 2.5 million children found that while administration of antimicrobial therapy in primary
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care reduced the incidence of mastoiditis, 4,831 episodes of otitis media needed to be treated

with antimicrobial drugs to prevent 1 case of mastoiditis77.

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Ineffective treatment of resistant bacteria confers all the risks of drug side-effects for the

patient without providing any benefits. These risks are not inconsiderable; a recent Cochrane
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review found that one in fourteen patients will experience an adverse event, including

vomiting, diarrhoea, or a rash78. Furthermore, continued use of these agents may continue to
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drive further selection of resistant bacteria.

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Conclusions

Commonly used first-line antimicrobial agents are unlikely to confer any positive effect in

many cases of paediatric AOM. Firstly, due to the frequently non-bacterial nature of the

condition; and secondly, the evidence of bacterial resistance to commonly used first-line

antimicrobial agents.

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Author contributions: MM was responsible for the conception and content of the article,

the database searches, data interpretation, and preparation of the manuscript. MD performed

the statistical analysis, data interpretation, and assisted in manuscript preparation. JDP

assisted with microbiological data interpretation and manuscript preparation. SP contributed

clinical interpretation of data and manuscript preparation. JW contributed clinical

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interpretation of data and manuscript preparation. JP was responsible for the conception and

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content of the article, data interpretation, and preparation of the manuscript. All authors

approved the final manuscript.

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Data availability: The datasets generated during and/or analysed during the current study are

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available from the corresponding author on reasonable request.
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Funding source: This work received no specific funding.

Competing financial interests disclosure: The authors have no financial relationships

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relevant to this article to disclose.

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Competing interests Statement: The authors have no conflicts of interest relevant to this
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article to disclose.
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Figure and table legends:

Figure 1 - PRIMSA flow diagram of literature search strategy

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Figure 2 – Bacterial prevalence Forrest plots

Figure 3 – Time course of non-susceptibility to penicillin amongst all bacterial isolates

Table 1 - Descriptive statistics of studies included in quantitative analysis (ND=Not

documented)

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Table 2 - Measures of antibiotic effectiveness for commonly tested antibiotic agents against

the most common acute otitis media pathogens. Each cell shows: (top) estimate of

effectiveness; (centre) 95% confidence intervals; (bottom) number of studies (st) and patients

(px) pooled.

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Table 1 - Descriptive statistics of studies included in quantitative analysis (ND=Not
documented)

Percentage (%) tympanostomy tube otorrhoea sampling

Percentage (%) tympanocentesis sampling

Upper age limit of participants (months)

Lower age limit of participants (months)
Percentage (%) otorrhoea sampling

PT Number of samples in study

Year study commenced

Year study ended

Country of origin

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Reference

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Douglas 1980 Australia 100.0 0.0 - 1977 1978 4 168 103

Karma 1987 Finland 100 - - 1980 1985 0 2 155
Trujillo 1989 Colombia 100 - - 1979 1985 0.1 132 111
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Arguedas 1991 USA 100 - - ND ND ND ND 122

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Rodriguez 1995 USA 97.5 2.5 - 1994 1995 12 72 159

Aronovitz 1996 USA 100 - - 1996 1996 24 180 169
Gehanno 1996 France 100.0 0.0 - 1992 1993 0 71 303
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Arguedas 1998 Costa Rica 100 - - 1992 1997 4 144 398

Jacobs 1998 International 80 18 2 1994 1995 3 60 915
Heikkinen 1999 USA 100 - - 1989 1993 2 84 815
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Block 2000 USA 100 - - 1996 1996 6 144 177

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Dagan 2000 International 100 - - 1997 1998 3.9 106.6 238

Commisso 2000 Argentina 100 - - 1996 1997 1 24 367
Dagan 2001 International 100 - - 1999 1999 3 48 521
Gehanno 2001 France 86.6 13.4 - 1987 1997 3 36 2149
Kilpi 2001 Finland 100 - - 1994 1995 2 24 772
Leiberman 2001 Israel 100 - - 1998 1999 3 32 73
Rosenblut 2001 Chile 100 - - 1998 1999 3 ND 170
Sih 2001 Brazil 100 - - 1990 1995 2 60 300
Broides 2002 Israel 100 - - 1998 2000 3 36 145
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Turner 2002 Israel 100 - - 1995 1999 0 2 137
Arguedas 2003 Costa Rica 81 19 - 1999 2001 4 123 102
Piglansky 2003 Israel 100 - - 1999 2001 3 36 78
Oguz 2003 Turkey 100 - - 1998 2000 6 144 78
Hoberman 2005 International 100 - - 2001 2002 6 30 730
Guven 2006 Turkey 98.1 1.9 - 2002 2004 6 144 180
Rosenblut 2006 Chile 100 - - 1998 2002 3 108 543

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Sakran 2006 Israel 100 - - 2002 2004 0 2 68
Patel 2007 USA 100 - - 1989 1998 2 84 982
Aguilar 2009 Costa Rica 100 - - 2002 2007 2 92 880

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Brook 2009 USA - 100 - 1998 2006 5 144 124
Yano 2009 Japan 100 - - 2002 2004 0 120 1092

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Grubb 2010 USA 100 - - 2005 2009 ND ND 184
Parra 2011 Mexico 82 18 - 2008 2009 3 60 121
Sierra 2011 Colombia 85 15 - 2008 2009 3 60 99

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Grevers 2012 Germany 24 76 - 2008 2010 3 60 100
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Naranjo 2012 Venezuela 90.1 9.9 - 2008 2009 0 60 91
Casey 2013 USA 100 - - 2008 2010 6 36 208
Chen 2013 Taiwan - 100 - 2011 2012 0 215 69
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Falup-Pecurariu
Romania 67.0 33.0 - 2009 2011 0 59 212
2013
Al-Mazrou 2014 Saudi Arabia 69 31.0 - 2009 2011 3 60 75
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Intakorn 2014 Thailand 91 9 - 2008 2009 5 59 118

Kung 2014 Taiwan 100 - - 2009 2011 4 213 151
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Abdelnour 2015 Costa Rica 90.1 9.9 - 2010 2012 3 59 456

Ding 2015 China - 100 - 2011 2013 0 216 229
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Tamir 2015 Israel 76 24 - 2008 2013 0 72 295

Sillanpaa 2016 Finland 78 5 17 2010 2011 6 39 91
Yatsyshina 2016 Russia 100 - - 2011 2013 0 59 216
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Amoxicillin- Beta lactamase

Amoxicillin Penicillin Erythromycin
clavulanate non-producer
0.86 0.60 0.93 0.64

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Streptococcus [0.69 to 0.95] [0.51 to 0.68] [0.81 to 0.98] [0.48 to 0.78]
pneumoniae

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9 st, 1121 px 29 st, 2704 px 8 st, 888 px 14 st, 976 px
0.82 0.43 0.98 0.53 0.71

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Haemophilus [0.67 to 0.92] [0.05 to 0.92] [0.88 to 1.00] [0.30 to 0.74] [0.61 to 0.79]
influenza
5 st, 238 px 3 st, 46 px 7 st, 564 px 1 st, 17 px *** 25 st, 2280 px

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0.12 0.13 0.98 0.07

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Moraxella catarrhalis [0.01 to 0.65] [0.01 to 0.63] [0.91 to 1.00] [0.03 to 0.17]
3 st, 58 px 3 st, 63 px 3 st, 77 px 0 st, 0 px 13 st, 205 px

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0.85 0.56 0.95 0.64
All samples (excluding [0.73 to 0.93] [0.47 to 0.65] [0.85 to 0.98] [0.48 to 0.78]

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negative cultures)
11 st, 1417 px 29 st, 2813 px 10 st, 1529 px 14 st, 993 px

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Table 2 - Measures of antibiotic effectiveness for commonly tested antibiotic agents against the most common acute otitis media pathogens.
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Each cell shows: (top) estimate of effectiveness; (centre) 95% confidence intervals; (bottom) number of studies (st) and patients (px) pooled.

*** Data based on the single study entered into the meta-analysis.
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PRISMA 2009 Flow Diagram

Fig. 1 - PRIMSA flow diagram of literature search strategy

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Identification

Records identified through Additional records identified

database searching through other sources

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(n = 7598) (n = 0)

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Records after duplicates removed
(n = 4249)

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Screening

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Abstracts screened Abstracts excluded
(n = 4249) (n = 4045)
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Full-text articles assessed

Full-text articles excluded
for eligibility
Eligibility

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(n = 156)
(n =204)
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Studies included in
qualitative synthesis
(n = N/A)
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Included

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Studies included in
quantitative synthesis
(meta-analysis)
(n = 48)

From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-
Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. doi:10.1371/journal.pmed1000097

For more information, visit www.prisma-statement.org.

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Fig. 2 – Bacterial prevalence Forrest plots
A: Any bacterial growth B: Streptococcus pneumoniae

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C: Haemophilus influenzae D: Moraxella catarrhalis

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Figure 3: Time course of non-susceptibility to penicillin amongst all bacterial isolates (p=0.756, r2=0.003
37 studies; n=15,073 patients). Size of dot equates to number of participants in study.