International Journal of Pediatric Otorhinolaryngology 116 (2019) 135–140

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International Journal of Pediatric Otorhinolaryngology

journal homepage: www.elsevier.com/locate/ijporl

Review Article

Probiotics in the treatment of otitis media. The past, the present and the T
future
Andrea Colemana,c,∗, Anders Cervinb,c
a
The Centre for Children's Health Research, 62 Graham Street, South Brisbane, QLD, 4101, Australia
b
The Royal Brisbane and Women's Hospital, Brisbane, Australia
c
The University of Queensland Centre for Clinical Research, Herston, Australia

A R T I C LE I N FO A B S T R A C T

Keywords: Otitis media (OM) is one of the most common infectious diseases in children and the leading cause for medical
Otitis media consultations and antibiotic prescription in this population. The burden of disease associated with OM is greater
Probiotics in developing nations and indigenous populations where the associated hearing loss contributes to poor edu-
Microbiota cation and employment outcomes. Current treatment and prevention is largely focused on vaccination and
Upper respiratory tract
antibiotics. However, rates of OM, particularly in indigenous populations, remain high. With growing concerns
Bacterial interference
regarding antibiotic resistance and antibiotic-associated complications, an alternative, more effective treatment
Pediatrics
is required. Administration of probiotics, both locally and systemically have been investigated for their ability to
treat and prevent OM in children. This review explores the theoretical bases of probiotics, successful application
of probiotics in medicine, and their use in the treatment and prevention of OM. We conclude that local ad-
ministration of niche-specific probiotic bacteria that demonstrates the ability to inhibit the growth of oto-
pathogens in vitro shows promise in the prevention and treatment of OM and warrants further investigation.

1. Introduction bacterial load, and genetic and environmental factors [11]. Otopatho-
gens, most commonly Streptococcus pneumoniae, Moraxella catarrhalis,
Otitis media (OM) refers to inflammation and/or infection in the Haemophilus influenzae and/or respiratory viruses, colonize and pro-
middle ear and encompasses a continuum of acute and chronic diseases, liferate in the nasopharynx (NP), where they travel up the eustachian
clinically characterized by fluid in the middle ear (See Table 1 for de- tube to infect the middle ear and cause OM [1]. Management depends
finitions) [1,2]. OM is one of the most common infectious diseases in on the type and severity of OM and include watchful waiting, anti-
children [3]. There are approximately 709 million cases of acute OM biotics and surgery [12,13]. A Cochrane review which included 1483
(acute OM (AOM)) per year worldwide, with the highest disease burden otitis-prone children or children at increased risk of OM from around
in developing nations and indigenous populations [4–6]. Although most the world showed that long-term antibiotics reduced the number of
episodes of OM resolve quickly without complication, the disease can episodes of AOM, with a number needed to treat of five to prevent one
be associated with significant health and developmental sequelae. It is case of AOM [14]. For every 12 months of antibiotic treatment per
estimated that approximately 21 000 people die from OM-related child, 1.5 episodes of AOM were prevented [14]. None of the included
complications around the world each year, the highest mortality rate is studies reported on AOM with perforated tympanic membrane
in the first year of life [4]. Complications can include mastoiditis, (AOMwP) or chronic suppurative OM (CSOM). Long-term treatment
cholesteatoma, meningitis, brain abscess and lateral sinus thrombosis regimens with antibiotics can be difficult for families to adhere to,
[7]. OM often results in conductive hearing loss, which can impact on leading to increased risk of antibiotic-resistant pathogens. Furthermore,
speech, language and cognitive development [8,9]. In Indigenous po- despite liberal use of antibiotics, the prevalence of OM, particularly in
pulations, OM and its sequelae contribute to poor education and em- Australian Indigenous communities, remain unchanged [15,16].
ployment outcomes and greater contact with the criminal justice system Alternatively, attempts to prevent OM via vaccination has been
[10]. widely trialed with mixed results. Pneumococcal conjugate vaccines
The pathogenesis of OM is multifactorial and involves the adaptive demonstrated a modest reduction in episodes of AOM in healthy in-
and native immune systems, eustachian tube dysfunction, viral and fants, and no benefit for high-risk infants or older children with a

∗
Corresponding author. The Centre for Children's Health Research, 62 Graham Street, South Brisbane, QLD, 4101, Australia.
E-mail addresses: [email protected] (A. Coleman), [email protected] (A. Cervin).

https://doi.org/10.1016/j.ijporl.2018.10.023
Received 29 August 2018; Received in revised form 16 October 2018; Accepted 16 October 2018
Available online 19 October 2018
0165-5876/ © 2018 Elsevier B.V. All rights reserved.
A. Coleman, A. Cervin International Journal of Pediatric Otorhinolaryngology 116 (2019) 135–140

Table 1
Otitis media definitions.
Adapted from Kong et al. [2].
Type of OM Definition

Acute otitis media (AOM) without perforation Presence of middle ear fluid with symptoms or signs of suppurative infection, which may include otalgia, fever, irritability,
vomiting or diarrhoea.
AOM with perforation Acute suppurative infection with recent discharge from the middle ear or through a tympanostomy tube (within the past 7 days).
Recurrent AOM (rAOM) Recurrent bouts of AOM — three episodes in 6 months or four to five in 12 months.
Otitis media with effusion (OME) Presence of middle ear fluid without symptoms or signs of suppurative infection.
Chronic suppurative otitis media (CSOM) A persistent discharge from the middle ear through a tympanic membrane perforation for more than 6 weeks. CSOM may include
a chronic perforation with or without acute or chronic otorrhoea.

history of OM [17]. Furthermore, disease displacement with non-vac- 3. The microbiota and development of respiratory immunity
cine S. pneumoniae serotypes and H. influenzae have been widely re-
ported [1,18,19]. The outcomes of vaccination targeting both S. pneu- To determine potential candidates for probiotic therapy in OM, a
moniae and H. influenzae (PHiD-CV10) are also equivocal. In Australian comprehensive understanding of the development of the healthy URT
Indigenous children PHiD-CV10 has resulted in some reduction in rates microbiota is required. The URT is colonized by commensal flora during
of suppurative OM, however these coincided with an increase in OME birth [29,30]. Soon afterwards the URT microbiota rapidly changes to
[20,21]. In Finnish children there was a non-significant trend towards develop niche-differentiation. Henceforth, one of several microbial
reduction in the number of AOM episodes [22]. In contrast, im- profiles develop, defined by dominant key species [30,31]. Profiles
plementation of PHiD-CV10 did not change the prevalence of the three dominated by early colonization with Moraxella and Corynebacterium/
main otopathogens in middle ear fluid or NP of New Zealand children Dolosigranulum are more stable than those dominated by Haemophilus or
with recurrent AOM or OME [23]. Streptococcus, and appear to protect against URT infections (URTI)
OM treatment and prevention continues to provide a great challenge [31,32]. The healthy URT microbiota has greater richness and diversity
for researchers and clinicians. An emerging field of research aims at when compared to patients with pneumonia, URTIs and AOM [33,34].
treating and preventing OM using probiotics. Effective probiotic treat- For example, healthy children had twice (n = 15) the number of op-
ment is based on a comprehensive understanding the microbiota in erations taxonomic units (OTUs) identified in the URT compared to
healthy and OM states, and how this can be manipulated to treat and children with pneumonia (n = 8) [33].
prevent OM. This review explores the history of successful applications Resident microbial flora contributes to the protection of the host
of probiotics in medicine, the development of the upper respiratory against pathogen proliferation, but is also integral to the development
tract (URT) microbiota, bacterial interference and probiotics in OM, of a competent immune system [35,36]. Experiments using germ-free
and finally highlights future opportunities for the use of probiotics in mice have demonstrated the importance of the bacterial microbiota on
OM. mediation of immune cell differentiation and subsequent modulation of
inflammation [36]. It is now well established that birth via caesarian
section is related to a higher risk of inflammatory disease, where the
2. Probiotic success in medicine immune system have difficulties distinguishing self from non-self or
where external antigens elicit an over the top response such as seen in
Probiotics are “live microorganisms which, when administered in food allergy, atopy, allergic rhinitis, and asthma [36]. There is spec-
adequate amounts, confer a health benefit on the host” [24]. In 1958, a ulation that the respiratory microbiota, shaped by method of delivery,
landmark paper described the use of fecal transplantation to treat pa- may be contributing to this disruption to the developing immune
tients with Clostridium difficile enterocolitis, restoring the dysbiosis system [29,30,36]. Disruption of the respiratory microbiota can impact
caused by antibiotics, and resulting in dramatic health improvement local immunity, infection susceptibility and the development of chronic
[25]. Despite this success, no further research was conducted on fecal respiratory inflammatory diseases [37]. It is believed that there is a
transplantation for another 50 years. Recently, fecal transplantation critical period in infancy/childhood when the influence of microbes on
was tested in a randomized control trial (RCT) for the treatment of C. the developing immune system establishes a system of homeostasis, this
difficile enterocolitis against vancomycin and vancomycin plus bowel is likely to happen during the first year of life [36]. The local admin-
lavage [26]. This study was stopped after the interim analysis. Of the 16 istration of probiotics in the upper airways in infancy/childhood may
patients who received the fecal transplantation, 13 had resolution of enable the development of a stable, resilient microbiota, and promote
symptoms after the first infusion, another two after second transfusion the establishment of a healthy immune system with the ability to dis-
from a different donor. This compared to resolution of symptoms in just tinguish self from non-self as well as deliver a measured response to
four of the 13 patients receiving vancomycin and three of the 13 re- external antigens.
ceiving vancomycin and bowel lavage [26]. This results has been re-
plicated in a number of RCTs [27], and is now offered as treatment for
4. Bacterial interference of the upper respiratory tract
appropriate patients. This is a striking example of where the use of
probiotics has been more effective than antibiotics.
Bacterial interference as a means of preventing disease has been
Probiotics have also demonstrated impressive results when used in
reported since the late 1800s [38], however, it has struggled to trans-
premature infants. Prophylactic administration of probiotics containing
late into clinical practice. Bacterial interference is defined as “a dy-
Lactobacillus spp. alone or in combination with Bifidobacterium spp via
namic antagonistic interaction between at least two different strains of
enteral feeding has been shown to significantly reduced the incidence of
bacteria that affects the life cycle of each” [39]. Microorganisms on the
severe necrotizing enterocolitis and all causes of mortality in preterm
mucosal surface of the URT interact in a multitude of ways, one of
infants [28]. There were no reports of systemic infection with probiotic
which is antagonistically, competing for ecological space and inter-
species [28]. Probiotic prophylaxis is now routinely used in many
fering with each other's growth [40]. It is believed that this ‘bacterial
neonatal intensive care units around the world.
interference’ by normal mucosal flora prevents colonization and pro-
liferation of respiratory pathogens, thereby maintaining respiratory
health [40].

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A. Coleman, A. Cervin International Journal of Pediatric Otorhinolaryngology 116 (2019) 135–140

Fig. 1. Possible mechanisms in which probiotics/commensal flora maintain a healthy upper respiratory tract; 1) commensal flora/probiotics bind to respiratory
epithelium thereby preventing pathogens from adhering; 2) they change the mucosal environment, for example by reducing pH; 3) they release bacteriocins and
other inhibitory substances which target pathogenic bacteria: 4) they stimulate local mucosal immunity; 5) complete for nutritional substances; and 6) simulate
systemic immune response.

Table 2
Randomized controlled trials investigating local (intranasal) administration of probiotics to prevent/treat otitis media.
Study n Age Population Treatment Primary Outcome Results P value
Measure(s)

Roos 2001 [45] 108 6 months–6 Otitis-prone Local: Streptococcus mitis, S. No AOM + normal TM Treatment (n = 53) = 42% 0.02
years sanguinis, Streptococci oralis Placebo (n = 55) = 22%
OME Treatment = 31% 0.05
Placebo = 56%
Tano 2002 [46] 36 < 4 years Otitis-prone Local: S. mitis, S. sanguinis, S. oralis Recurrence of AOM Treatment (n = 16) = 44% n.s
Placebo (n = 20) = 40%
Skovbjerg 2008 54 1–8 years Otitis-prone Local: S. sanguinis OR L. rhamnosus Resolution OME S. sanguinis (n = 19) = 37% 0.05
[49] L. rhamnosus (n = 18) = 17%
Placebo (n = 17) = 6% 0.06
Marchisio 2015 97 1–5 years Otitis-prone Local: Streptococcus salivarius Recurrence of AOM Treatment (n = 50) = 70% 0.08
[47] 24SMB Placebo (n = 47) = 85%
NP colonized (n = 28) = 57% not 0.03
colonized (n = 22) = 86%

Note: AOM, acute otitis media; NP, nasopharynx; n.s., non-significant (no p value reported); TM, tympanic membrane.

As early as the 1970s Viridians Streptococci (part of the alpha he- Local administration of probiotics is the application of bacterial inter-
molytic streptococcus (AHS) group) were shown to inhibit a range of ference to treat and prevent infections in vivo.
potential pathogens in vitro including Neisseria meningitides, Moraxella
spp., Beta-hemolytic Streptococci, Corynebacterium diphtheriae, S.
pneumoniae, S. aureus, and Escherichia coli [40,41]. In vitro studies have 5. Probiotics in the upper respiratory tract, past and present
confirmed significant bactericidal effects from various strains of AHS evidence for local administration
against S. pneumoniae, NTHi, and M. catarrhalis, which are strain spe-
cific [39]. In vivo, bacterial interference is thought to be achieved by Roos et al. provided the proof of concept that commensal flora from
several mechanisms. These mechanisms include occupying specific sites URT of healthy individuals can prevent recurrence of streptococcal
on the epithelial cell surfaces, thus preventing the adherence of pa- tonsillitis [43]. The authors isolated four strains of AHS from the throats
thogens, changes in the microenvironment by, for example, lowering of of healthy individuals that had a strong ability to inhibit the growth of
pH, production of antagonistic substances, and competition for nutri- Group A Streptococcus in vitro. One hundred and thirty children with
tional substances (Fig. 1) [40]. AHS owe their inhibitory potential to recurrent streptococcal tonsillitis were treated with antibiotics and then
their production of bacteriocins (peptide toxins) which have inhibitory randomized to receive a daily throat spray containing either the pro-
activity against gram-positive and gram-negative bacteria [40]. Cor- biotic strains or a placebo for 10 days [44]. In the eight weeks post
ynebacterium spp., a URT commensal, is more often found in the URT in baseline, bacteriologically-verified tonsillitis recurrence occurred in
children who aren't colonized by S. pneumoniae [42]. In vitro, Cor- only 2% (1/50) of the children in the probiotic treatment group, whilst
ynebacterium accolens was shown to inhibit the growth of S. pneumoniae it occurred in a much larger proportion, 23% (14/61), of children in the
by hydrolyzing skin surface triacylglycerols to produce anti-pneumo- placebo group [44]. Having demonstrated such efficacy in recurrent
coccal free fatty acids [42]. This is an example how a commensal mi- streptococcal tonsillitis, the authors applied the concept to OM.
crobe uses human resources to positively shape the URT microbiota. There have been several RCTs investigating the local administration
of probiotics to treat/prevent OM in otitis-prone children (see Table 2).

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Table 3
Randomized controlled trials investigating systemic (oral) administration of probiotics to prevent/treat otitis media.
Study n Age Population Treatment Primary Outcome Result(s) P value
Measure(s)

Hatakka 2001 [50] 513 1–6 years Healthy Systemic: Lactobacillus rhamnosus GG Incidence AOM Treatment 0.08
(n = 252) = 31%
Placebo (n = 261) = 39%
Hatakka 2007 [57] 269 10 mo-6 Otitis-prone Systemic: L. rhamnosus GG and LC705, Bifidobacterium Incidence AOM Treatment n.s
years breve 99 and Propionibacterium freudenreichii JS (n = 135) = 72%
Placebo (n = 134) = 65%
Rautava 2008 [52] 72 <2 Healthy Systemic: L. rhamnosus GG & Bifidobacterium lactis BB-12 Incidence AOM 1st 7 Treatment 0.01
months months (n = 32) = 22%
Placebo (n = 40) = 50%
Recurrent (> 3) AOM Treatment = 13% 0.18
in 1st year Placebo = 25%
Stecksen-Blicks 186 1–5 years Healthy Systemic: L. rhamnosus LB21, fluoride No. days with AOM Treatment < 0.01
2009 [51] (n = 110) = 0.5
Placebo (n = 76) = 1.0
Taipale 2011 [53] 69 1–2 months Healthy Systemic: B. lactis BB-12 Incidence AOM Treatment 0.50
(n = 34) = 26%
Placebo (n = 35) = 17%
Cohen 2013 [58] 166 7–13 Healthy Systemic: Streptococcus thermophiles, S. salivarius, L. No. episodes of AOM Treatment (n = 83) = 249 0.80
months rhamnosus + preB Raftilose/Raftiline Placebo (n = 83) = 237
Incidence recurrent Treatment = 30% 0.90
AOM Placebo = 30%
Di Peirro 2016 [56] 222 3 years Healthy Systemic: S. salivarius K12 (BLIS K12) Incidence AOM Treatment < 0.01
(n = 111) = 44%
Placebo (n = 111) = 80%

Note: AOM, acute otitis media; n.s., non-significant (no p value reported).

Roos et al. appear to be the first to investigate the use of a probiotic nose of a healthy child and shown to produce bacteriocin-like sub-
treatment made of bacterial strains with a demonstrated ability to in- stances with activity against otopathogens [48]. The children were
hibit the growth of otopathogens [45]. Roos and colleagues isolated treated with antibiotics and then randomized to receive either the
AHS from the opening of the eustachian tube of healthy children and probiotic or placebo nasal spray twice daily for five consecutive days
identified five strains that were powerful inhibitors of S. pneumoniae, M. each month for three consecutive months. Quantitative PCR of NP swab
catarrhalis, and S. pyogenes [45]. They developed a probiotic nasal spray samples was used to detect the presence of S. salivarius 24SMB. After
containing two strains of Streptococcus sanguinis, two strains of Strep- treatment, the proportion of children who did not experience AOM in
tococcus mitis and one strain of Streptococcus oralis. One-hundred and the probiotic group (30%; 15/50) was double what it was in the control
eight otitis-prone children were randomized to receive either the pro- group (15%; 7/47) (p = 0.075) [47]. When the authors limited their
biotic or a placebo. All children received 10 days of antibiotics, fol- analysis to children in the treatment group who yielded an NP swab
lowed by either the probiotic or placebo nasal spray twice daily for 10 sample that contained the probiotic, they found that children who were
days, then for another 10 days after 55–60 days. There was a significant successfully colonized with S. salivarius 24SMB were significantly more
reduction in the rate of recurrence amongst those who received the likely to have no episodes of AOM (43%; 12/28); compared to those
probiotic, with 42% (22/53) children in the treatment group experi- who were not colonized with S. salivarius 24SMB (14%; 3/22)
encing no AOM and having healthy tympanic membranes, compared to (p = 0.03) [47]. These data suggest that colonization with the probiotic
22% (12/55) in the placebo group [45]. Significantly less children strain may be playing a role in treatment efficacy.
without recurrence of AMO in treatment group had OM with effusion The above studies focused on the prevention of AOM, one study by
(OME) at the last visit (31%; 10/32), compared to those in the placebo Skovbjerg et al., explored the use of probiotics to treat OME [49]. A
group (56%; 15/27) [45]. double-blinded pilot study was conducted on 60 children with OME,
An attempt to replicate the Roos result by Tano et al., whom did not using a nasal spray containing either S. sanguinis, Lactobacillus rham-
pre-treat participants with antibiotics, was unsuccessful [46]. Specifi- nosus or placebo for 10 days; no antibiotics were given prior to the
cally, Tano et al. conducted a smaller RCT (n = 36) testing a probiotic commencement of the treatment [49]. There were significantly more
treatment comprised of a mixture of AHS strains that had demonstrated children with complete or significant clinical recovery following
in vitro a good ability to inhibit the growth of otopathogens, as well as treatment with S. sanguinis (7/19) compared to placebo (1/17)
good adherence to adenoid epithelial cells [46]. The study recruited (p= < 0.05), but not for those who received L. rhamnosus (3/18)
children with a history of recurrent AOM. Despite four months of compared to placebo (p = 0.60) [49]. Interestingly, there was no evi-
treatment, there was no difference in the number of children with AOM, dence of colonization with S. sanguinis in the NP following treatment,
44% (7/16) in the treatment groups vs. 40% (8/20) in the placebo although culture-bases analysis was used, which may not have suffi-
group [46]. Prior dosing with antibiotics may be required to reduce the cient sensitivity. Alternatively, the probiotic may have been exerting its
bacterial load, allowing the probiotic strains more ecological space to action via the immune system.
adhere to the mucosal epithelial cells and proliferate. Testing the NP for
the presence and abundance of the probiotic strains after treatment
would have informed on whether this contributed to the failure of the 5.1. Probiotics in the upper respiratory tract, past and present evidence for
treatment. systemic administration
A noteworthy RCT conducted by Marchisio et al. [47] provides in-
sight into the ability of a probiotic treatment to colonize the participant. These studies have explored local probiotic administration. Other
Otitis-prone children were randomized to test a probiotic treatment studies have investigated the systemic probiotic administration on the
consisting of Streptococcus salivarius 24SMB; a strain obtained from the prevention of OM (Table 3). In healthy children, several RCTs used L.
rhamnosus GG and/or Bifidobacterium lactis BB-12 orally to investigate

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whether OM could be prevented. Milk supplemented with L. rhamnosus prevention and treatment of all types of OM, and particularly in de-
GG was given to 513 day care children for seven months and showed no veloping nations and indigenous communities. To facilitate such re-
significant differences in the number of episodes of AOM in the pro- search agreement on how to define the diagnosis of different middle ear
biotic (31%; 79/252) compared to placebo groups (39%; 101/261) infections is paramount. It is equally important to investigate the
(p = 0.08) [50]. Stecksen-Blicks et al. gave 186 healthy children milk complete microbiome in the upper respiratory tract, not only the pa-
with L. rhamnosus GG for 21 months and measured the number of days thogens as in the past. Infection is a sign of dysbiosis and pathogens in
with OM [51]. They found children who received the probiotic milk isolation can no longer be considered as solely responsible.
(n = 110) had fewer days with OM (0.5) compared to placebo (n = 76) Microbiological methods, both culture dependent and molecular
(1.0) (p = 0.003) [51]. In a younger cohort of infants < 2 months old, methods, need to be aligned across the OM research community. This
L. rhamnosus GG + B. lactis BB-12 supplemented infant formula was should be a priority agenda for interest groups such as the International
given for 12 months and shown to significantly reduce the incidence of Society for Otitis Media.
AOM in the first 7 months of life, 22% (7/32) had AOM in treatment Another area for consideration, particularly in the prevention of
group vs. 50% (20/40) in the placebo group (p = 0.014) [52]. How- OM, is the influence that the mother and ingestion of breastmilk may
ever, there were no statistically significant differences in the number of have on the development of the URT microbiota in infants. Breastmilk
children who suffered recurrent AOM (≥3 episodes); four (13%) in the has demonstrated protection against AOM in children under two year of
treatment group and 10 (25%) in the placebo group (p = 0.183) [52]. age [59]. It may exert as least some of its effect through manipulating
Another study gave B. lactis BB-12 to infants via slow-release tablets for commensal flora of the URT and gut as a probiotic and prebiotic
seven months and showed no significant difference in the incidence of [59,60]. Breastmilk has its own microbiome which may influence the
self-reported OM compared to placebo; (26%; 9/34 and 17%; 6/35 infant's microbiome, particularly gut microbiome, and confer health
respectively (p = 0.455)) [53]. Whether L. rhamnosus GG and B. lactis benefits without supplementation [61]. Research is beginning to
BB-12 can prevent OM in healthy children is equivocal. L. rhamnosus GG emerge into whether the health of the infant can be influenced by de-
was originally isolated from the healthy gastrointestinal system [54] livering probiotics to the mother prenatally and whilst breastfeeding. In
and B. lactis BB-12 was a dairy culture [55]. Therefore, their poor ef- randomized controlled trials, providing probiotics to mothers in their
ficacy in preventing disease from respiratory pathogens may be due to last trimester of pregnancy and through the breastfeeding infants' first
them being used beyond their niche environment. 3–6 months of life has demonstrated reduced risk of atopic dermatitis
One study by Di Pierro et al. investigated whether oral adminis- [62,63]. However, this effect does not appear to be mediated by the
tration of a probiotic strain niche to the URT, S. salivarius K12, could probiotic strains being delivered through the breastmilk [64]. The
prevent AOM in healthy children attending kindergarten [56]. They provision of probiotics prenatally and in breastfeeding mothers in the
delivered the probiotics via dissolving oral tablet and found a sig- prevention of OM, particularly in high risk populations should be
nificant reduction in the incidence of AOM in the treatment (44%; 49/ considered.
111) compared to placebo group (80%; 89/111) and the number of There is a significant, ongoing burden of disease caused by OM in
episodes of AOM, 53 in the treatment group vs 101 in the placebo group developing nations and Indigenous populations, despite vaccinations
[56]. S. salivarius has been shown to adhere to the URT and strongly and antibiotic treatment. The causes are multi-factorial and include
inhibit the growth of the main respiratory pathogens in vitro. This study social, environmental, biomedical and possible immune and genetic
suggests that there may be a role for niche specific probiotic strains in factors [65]. A multi-pronged approach to the treatment and prevention
preventing AOM in healthy children and further research is required. of OM is required, however from a biomedical perspective “strategies to
In otitis-prone children a range of probiotic mixtures have been reduce the exposure to high doses of multiple OM causing bacteria are
administered systemically to determine whether recurrence of OM can urgently needed” [65]. Antibiotics may temporarily resolve OM and
be prevented. Two hundred and sixty-nine otitis-prone children were reduce the number of otopathogens, however they likely disrupt the
given a probiotic capsule containing two strains of L. rhamnosus GG, normal protective flora and allow for recolonization with otopathogens
Bifidobacterium breve 99, and Propionibacterium freudenreichii spp. sher- and recurrent infections. In addition to growing global concerns re-
mani JS [57]. There were no differences in the incidence of AOM; 72% garding antibiotics resistance, an alternative, more effective treatment
(n = 135) vs. 65% (n = 134) for treatment vs. placebo (OR = 1.48 is required. Local administration of a probiotic that is niche-specific for
(95% CI 0.87–2.52)) or recurrent AOM (18% vs 17% respectively; the URT and demonstrates the ability to interfere with the growth of
OR = 1.04 (95% CI 0.55–1.96)) [57]. Correspondingly, 166 “high-risk” otopathogens needs to be evaluated as an alternative treatment for the
children were given formula supplemented with Streptococcus thermo- refractory problem of OM, particularly in developing nations and In-
philus, S. salivarius, L. rhamnosus LPR and a prebiotic for 12 months and digenous populations.
found no difference in the number of episodes of AOM in the treatment
(249) (n = 83) compared to control (237) (n = 83) [58]. Cumulatively,
these results demonstrate that ingestion of non-specific systemic pro- Funding
biotics does not prevent AOM in healthy children or reduce the number
of episodes in otitis-prone/“high-risk” children, regardless of the This work was supported by the National Health and Medical
duration of treatment. In contrast, local administration using strains Research Council [APP1133366]; Queensland Health Junior Doctor
isolated from the URT of healthy children showed more promising re- Fellowship; and Garnett Passe & Rodney Williams Memorial
sults in preventing OM in otitis-prone children. Foundation.

6. The future, opportunities ahead

Conflicts of interest
The use of probiotics to prevent and treat OM shows promise and
proof of concept exists. For such a probiotic to be effective it likely None.
needs to be niche-specific, demonstrate in vitro bacterial inference
against the main respiratory pathogens, and able to colonize the NP.
Although, there may also be a systemic effect through activation of the Acknowledgements
immune system. In otitis-prone children, antibiotics may be required
prior to giving the probiotic to reduce the overall bacterial load and We would like to thank Dr. Diane Maresco-Pennisi for her con-
facilitate colonization. Further research is required in both the tribution in editing the manuscript.

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A. Coleman, A. Cervin International Journal of Pediatric Otorhinolaryngology 116 (2019) 135–140

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