Current Advances in Otitis Media

Bench to Bedside and Back

Joseph E. Kerschner, MD, FACS, FAAP
jkerschner@mcw.edu
Dean and Executive Vice President
Medical College of Wisconsin
Professor, Pediatric Otolaryngology
Childrens Hospital of Wisconsin and Medical College
of Wisconsin

Topics
Guidelines
Antimicrobials
Hearing loss and speech development
Vaccines
Eustachian Tube
Biofilms
Translational research
Pathogen resistance
Host-pathogen interactions

Knowledge Base Check

We are all at different levels
Expert
Very comfortable with all aspects of OM management
Need to learn more

Show of Hands
I have read the AAP (AAO-HNS) guidelines on acute
otitis media (AOM)
There exist more than one set of guidelines
I am not interested in the publication of guidelines
because they do not help with the management of
individual patients

Guideline Quiz
The AAO (AAP) guidelines contain 6 recommendations?
True = Raise Your Hand
2 of these 7 recommendations relate to the use of
antibiotics for AOM? True = Raise Your Hand
The strongest recommendation from the guidelines
relates to how practitioners should use antibiotics to treat
AOM? True = Raise Your Hand

http://pediatrics.aappublications.org/
cgi/reprint/113/5/1451

World-wide = 15 AOM
guidelines
Australia
Canada
South Africa
USA - 2004
Europe

AOM Guidelines
Diagnosis
Treatment of pain
Antimicrobial use
Observation option
First-line, second-line therapy
Failure to respond to therapy
Risk factor reduction
Alternative therapy

Diagnosis
Huge problem in otitis media
Impacts treatment When and If
Has seriously flawed research into this disease
NEJM papers in ABX section

Will be the cornerstone of new concepts in treatment

Clinical history is a poor predictor
80% of Dx can be made by history
Not true for OM
Huge overlap with viral URI
Need diagnostic skills

Diagnosis: US vs. Dutch

Acute onset of signs
and symptoms
Presence of middle ear
effusion (MEE)
Signs or symptoms of
middle ear inflammation
Erythema of the TM
Otalgia clearly referable
to the ear

Pneumatic otoscopy
Tympanometry

Symptoms: otalgia,
otorrhea, fever, or
irritablity and
Signs: red, opaque or
bulging tympanic
membrane or
Difference in redness
right and left tympanic
membrane or
Acute otorrhea

AOM verses OME

Major challenge
OME is more common than AOM and does not
need Rx
May accompany viral URI
May be a residual of a resolved AOM

Signs and symptoms

Acute onset
Distinct erythema
Otalgia
Interfering with normal activity and/or sleep

Asymptomatic purulent otitis

Pain
The management of AOM should
include an assessment of pain
If present it should be treated
Only STRONG recommendation from
panel

Present with most AOM

In past was seen as a peripheral
concern

Treatment of Pain in AOM

Analgesics
Acetaminophen
Ibuprofen

Myringotomy
Topical Agents (Benzocaine)
Little additional benefit

Homeopathic treatments
No controlled studies

Narcotics
Effective
Increased risk profile

Antibiotics Why do We
Treat?
George saved his
brothers life that
day. But he caught a
bad cold which
infected his left ear.
Cost him his hearing
in that ear.

Antibiotic Usage
Amoxicillin
Still best drug (?)
Efficacy
Safety
Cost
Compliance

Efficacy
90mg/kg/day
Most effective against intermediate and highly
resistant S. pneumoniae (SP)

Vaccines & Antibiotic Usage

Pneumococcal Vaccine changing story
PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, 23F)
Introduction
Decrease in SP prevalence
Increase NTHI
Subsequently
Increase in serotypes not covered
Increasing resistance in these
With over 90 serotypes we can expect this to will be
played into the future
PCV13 serotypes (1, 3, 4, 5, 6A, 6B, 7F, 9V, 14,
18C, 19A, 19F, and 23F)
Consider broader spectrum for more severe illness,
recent antibiotic usage, higher NTHI percentage,
daycare
High-dose amoxicillin-clavulanate has become
drug of choice in these settings
Cost
Casey, JR Ped Inf Dis J, 2010
Safety profile

Penicillin (PCN) Allergy

Not type I hypersensitivity to PCN
(urticaria/anaphylaxis)
Cefdinir drug of choice
Cefuroxime compliance concerns
Ceftriaxone compliance concerns

Type I hypersensitivity to PCN

Quinolones
Clindamycin
Macrolides

2nd-Line Therapy
Of 16 FDA approved ABX for OM in children - only 5 have
demonstrated much efficacy against resistant S. pneumo
High dose Amoxicillin - most effective
Cefdinir (Omnicef)
Cefuroxime (Ceftin) (compliance)
IM ceftriaxone (Rocephin) (invasive)
Clindamycin
Quinolones not approved

Amoxicillin failure
High dose amoxicillin/clavulanate

Amoxicillin/clavulanate failure
3-day parenteral ceftriaxone
Cefdinir
Cefuroxime

PCN allergy very poor choices for Type I hypersensitivity

Quinolones
Clindamycin

3rd-Line Therapy
Tympanocentesis
We will see these patients ASAP
Significant past history of AOM consider tube
placement

Dutch Model
Low use of antibiotics
High rate of tympanostomy tube placement

Observation Option
Treatment of OM is the most common reason
for an antibiotic to be prescribed for children
in the US
Began in 1989 in Netherlands
Selective antibiotic therapy
Withhold antibiotic treatment for 48 to 72 hours to
allow for spontaneous resolution of OM
Rationale
Reduce antibiotic pressure
Reduce development of resistant organisms

Observation Option
Age
<6 months
6-23 months
>24 months

Severity
Non-severe Disease
T<102F (39 C) orally
Mild or no otalgia
Non-toxic appearing

Certainty of Diagnosis
Follow-up and Communication

Observation Option
Age
<6 mos.

Certain AOM

Uncertain AOM

Antibiotics

Antibiotics
Antibiotics if severe
Observe if non-severe

6-23 mos. Antibiotics

24 mos.

Antibiotics if severe
Observe if non-severe

Observe

Rosenfeld R, IJPORL, 2001

This algorithm still will treat most episodes of real

bacterial OM will help limit treatment of less severe
and episodes that are not real OM
Diagnosis is key

Evidence For
Observation Option
Most episodes of OM will resolve without antibiotic
treatment
~80% (Rosenfeld, J Pediatr, 1994)
Between 7-20 children must be treated for each child who receives
a benefit

Selective therapy is not equivalent to placebo trials regarding

risks of complications from OM
Allows treatment in cases not spontaneously resolving
Allows treatment before complications arise
Pre-antibiotic era
Significant complications and death
Placebo studies - 17% incidence of mastoiditis (Rudberg, 1954)

AHRQ Review and agreed that there was not an increase in

suppurative complications

Evidence For
Observation Option
Selective therapy reduces costs, morbidity
associated with antibiotic use and antimicrobial
resistance
Penicillin-resistant Streptococcus pneumoniae in the
Netherlands only 1.1% - (Hermans, J Infect Dis, 1997)
Prescriptions these are in study populations real
world?
49% reduction in antibiotic use with no increased adverse events
(Spiro DM, et al. JAMA. 2006)
Trial of initial versus deferred antibiotics: only 24% of latter group
filled prescription (Little, et al BMJ 2001)

Observation Option
Evidence ??
Hoberman A, et al NEJM 2011
Excellent study
Examined young children < 2 years
Demonstrated that antibiotics helped regardless of severity
First study to demonstrate this question likely will impact
new guidelines with respect to severity

Overall modest impact of antibiotics

Used stringent criteria for diagnosis
This speaks to the need for accurate diagnosis
Real world
But if we are sure about the diagnosis there is a greater positive
impact on treatment

Evidence Against
Observation Option
Lack of rigor in studies demonstrating limited
benefit from antibiotics (Wald, Ped Infect Dis
J, 2003)
Complication rate increased versus universal
antibiotic treatment
Mastoiditis
3.8/100 000 per year in Netherlands
1.2-2 /100 000 per year in higher prescribing
nations (Van Zuijlen, Ped Inf Dis J, 2001)

Evidence Against
Observation Option
Antibiotic treatment is the current standard of care:
Medical-legal issues
Delays symptomatic relief
Days 2-7 pain decreased by 41% (Del Mar, BMJ, 1997)

May place young children at added risk for serious

sequelae
We should treat real infections with antibiotics and focus
our antibiotic reductions in areas that we know wont help
21% prescription rate for common cold, 46% for bronchiolitis ( El
Sayed, Eur J Ped, 2009)
44% - common colds, 75% bronchiolitis ( Nyquist, JAMA, 1998)

Follow-up and Communication

You SHOULDNT use this option unless
Caregiver understands the risks and benefits of
this treatment specifically the need to contact
PMD with progressive course
Caregiver has reliable means of communicating
with PMD and vice-versa
Follow-up can be assured in the next 2-3 days

Antibiotics DO have a role in the

management of AOM
Observation is more work!

Individual Patient Data Meta-Analysis

RCTs on AOM and Antibiotics
Country

year

Burke
Appelman

UK
NL

1991
1991

232
121

Damoiseaux
Little
Le Saux
McCormick

NL
UK
Canada
USA

2000
2001
2005
2005

240
315
512
223

Rovers et al. Lancet 2006

Results for Pain and/or Fever at 37 days Subgroups

Rate Difference (95% CI)

NNT

< 2 years + bilateral AOM

< 2 years + unilateral AOM
2 years + bilateral AOM
2 years + unilateral AOM

25% (20 - 30)

5% (2 - 8)
12% (7 - 17)
4% (2 - 6)

4
20
9
25

Otorrhea
yes
no

36% (27 - 45)

14% (11 - 17)

3
8

Rovers et al. Lancet 2006

Impact of AOM Guidelines

Coco A, et al Pediatrics 2010;125: 214-220.
30 month period before and after guideline publication using
ambulatory medical care survey
Antibiotics
Has made a negligible impact on the overall amount of antibiotics
prescribed for AOM = 11%-16% not treated
Mild infections are being Rxd less commonly
Absence of pain or fever

Pain
71% increase in the use of analgesics for AOM
Increased further in patients managed with observation option

Risk Factor (RF) Reduction

Modifiable
Tobacco exposure
Breast feeding
Vaccines
Influenza Benefit unclear (Hoberman A, JAMA, 2003)
Pneumococcal Clear but small benefit

Child care arrangements

Bottle/pacifier use
?? Early onset first infection
GERD
Allergy

Risk Factor (RF) Reduction

Not Modifiable
Anatomic considerations
Syndromic
Craniofacial
Down

Gender
Socioeconomic status
Family History
Race Indigenous
Immune deficiency

Only 2nd large scale

study looking at
caregiver knowledge
regarding OM RF
Significant
opportunities to educate
caregivers
Significant willingness
to modify behaviors to
lessen OM risk

Viruses
Increased interest due to potential for
vaccines
Major players
RSV
Influenza
Parainfluenza
Adenovirus
Rhinovirus

Viral Otitis Media

Sole causative agent
30%

Mixed Infections
Significant precursor to bacterial infections
RSV identified in 53% of MEE by PCR
(Okamoto, J Infect Dis, 1993)

Viral Effects
Eustachian Tube Dysfunction
Cytokine mediated inflammation

Immunosuppression
Increase in bacterial colonization and
adherence

Severity of Mixed Infections

Mucosal damage
Immune changes with potential for poor
bacterial clearance
Changes in antibiotic pharmacokinetics
Viruses decrease amoxicillin concentration
in MEE (Canafax, infect Dis J, 1998)

Changes in cytokine mediators

Vaccines
Viral
Influenza A
Clinically available
Reduction in AOM by 36% in daycare setting
during influenza season

(Heikkinen, Am J Dis child, 1991)

RSV
Most commonly associated with OM
Invades ME readily

Vaccines
Pneumococcal conjugate (7-valent)
Efficacy
Finland (2001) - 6% reduction in OM (CI -4 - 16)
California (2000) - 7% reduction in OM (CI 4-10)

Meta-analysis not possible on multiple studies

Follow-up
6% reduction (Fireman, 2003)
Diagnosis and definitions are important

Replacement with non-covered serotypes

Overall Impact for Otitis Media Modest
Cost not really very cost effective for OM

NTHI likely around the corner

Holy grail There will be the need for antibiotics and surgeons in
the future

http://pediatrics.aappublications.org/
cgi/reprint/113/5/1412

OME - Children at Risk

At risk for speech, language , learning
difficulties
Need early assessment of hearing
levels, speech and language
progression and need early intervention
Just finished work on recommendations
for OME of short duration

Children at Risk
Underlying hearing loss not associated with
OME
Congenital
Anatomic unilateral microtia

Suspected or diagnosed language delay

Cleft palate
Visual impairment
Syndromes or craniofacial disorders with
cognitive, speech or language delays
Autism and other pervasive developmental
disorders

Watchful Waiting
3 months from date of onset/diagnosis
Most OME is self-limited
80% of effusions with AOM resolve by 3 months

Need to consider
Hearing levels
Recurrent infections
Development

Not mutually exclusive from RecOM

54% of patients referred for OME
Pediatrician screening device

Medications
Antihistamines
Decongestants
Corticosteroids
Antimicrobials
No evidence of benefit with OME

Hearing and Language

Hearing testing
Minimum intervention after 3 months OME
Sooner with speech or other
developmental delay
Primary care screening
4 years and older
4 frequency testing (500, 1000, 2000, 4000 Hz)

Formal audiological testing

Children younger than 4
Older children with a failed screen

Language Testing
Assessed in all children with persisting
hearing loss
Language Development Survey (caregiver
only)
Early Language Milestone Scale
Denver Development Screening Test II

Surveillance
Most Controversial Point
When to place
tympanostomy tubes (TT)?
Follow-up every 3 months
until:
Fluid resolves
Significant hearing loss
develops
Structural abnormalities of
the ear are suspected
Tympanostomy tubes are
generally mandated if
patient develops
Retraction pocket
Adhesive atelectasis
Ossicular erosion

Significant Hearing Loss

HL > 40dB = Moderate hearing loss
Tympanostomy tubes
Clear evidence of negative impact on speech
language and academic performance

HL of 21 to 39dB = Mild hearing loss

Still significant
Evidence of negative impact on speech, language
and school performance in children with
permanent SNHL
Need to optimize listening and learning
environment

Optimizing Hearing and Listening

TABLE 4. Strategies for Optimizing the Listening-Learning
Environment for Children With OME and Hearing Loss*
Get within 3 feet of the child before speaking.
Turn off competing audio signals such as unnecessary music and
television in the background.
Face the child and speak clearly, using visual clues (hands, pictures) in
addition to speech.
Slow the rate, raise the level, and enunciate speech directed at the child.
Read to or with the child, explaining pictures and asking questions.
Repeat words, phrases, and questions when misunderstood.
Assign preferential seating in the classroom near the teacher.
Use a frequency-modulated personal- or sound-field-amplification
system in the classroom.
*

Modified with permission from Roberts et al.

Significant Hearing Loss

<20 dB hearing = Normal hearing
Assess unilaterality even in younger
children
Assess speech and language
Assess additive or risk factors
Caregiver environment
Socioeconomic environment

Assess behavioral issues

Attention
Balance
Otalgia

OME/Language Studies
Some studies have questioned the impact of
OME on speech/language (Paradise JL, et al. NEJM,
2007)

Significant methodolical errors

Intense screening process
Not equivalent to real world
Impact of TT is greatest on patients who are symptomatic
(hearing, balance) and seek treatment

Very mild disease in treatment group

Most kids had unilateral disease

Eliminated patients most likely to benefit

Patients with speech delay, ADHD, developmental delay,
other chronic illnesses, poor socioeconomic factors

OME
Cochrane review 2010
Looked for randomized trials
Primary outcome was hearing level

Many of the studies had mild disease

3 studies with persistent bilateral OME- more
severe
Difference at 3 months = 12 dB
Difference at 6-9 months = 4dB

Short acting tubes

Leaving out children with development issues

Surgery
Tympanostomy tubes for initial surgery
Consideration of adenoidectomy for
secondary procedures
National Institute for Health and Clinical
Excellence

National
Institute for
Health and
Clinical
Excellence-2008
www.nice.org.uk

Surgery based
on
Hearing
Development
Education

Different
pathways
Downs
Cleft

Ear Tube Otorrhea

Post tympanostomy tube placement
Ototopical drops only required if middle
ear fluid is present at time of tube
placement
Decreases post-operative otorrhea and
tube plugging
Poetker DM, et al. Ofloxacin otic drops
versus neomycin/polymyxin b otic
drops as prophylaxis against posttympanostomy tube otorrhea. Archives
of Otolaryngology Head and Neck
Surgery 2006;131(6):1294-1298.

Ototopical Therapy
Character of otorrhea
Drop administration
Microbiology of infection
NEED CULTURE!!
Fungal infections
Lotrimin drops
Diflucan
Martin TJ, Kerschner JE, Flanary VA. IJPO
2005;69:1503-1508.

Eustachian Tube
Eustachian Tube Dysfunction Model of Otitis
Viral infection edema poor opening negative pressure
transudate when tube does open sucks in bacteria from
nasopharynx

A key component in OM
Developmentally immature
It is important to describe the growth and development of the
tube to understand why infants and young children have more
middle-ear infections than older children and adults.
Convincing evidence
Bluestone CD, Klein JO. Otitis media and eustachian tube dysfunction. In:
Bluestone CD, Stool SE, eds. Pediatric Otolaryngology, Philadelphia, PA:
Saunders; 2003:497.

Commonly referenced as cause and solution to difficulties with

OM in children

Eustachian Tube
Eustachian Tube Dysfunction Model of Otitis
Viral infection edema poor opening negative pressure
transudate when tube does open sucks in bacteria from
nasopharynx

A key component in OM
Developmentally immature
It is important to describe the growth and development of the
tube to understand why infants and young children have more
middle-ear infections than older children and adults.
Convincing evidence
Bluestone CD, Klein JO. Otitis media and eustachian tube dysfunction. In:
Bluestone CD, Stool SE, eds. Pediatric Otolaryngology, Philadelphia, PA:
Saunders; 2003:497.

Commonly referenced as cause and solution to difficulties with

OM in children

What Is The Evidence?

Eustachian Tube Dysfunction
Anatomic - ET does change from infancy
Length
50% as long as adult (~40mm)
Age 7 reaches adult length
Too short to protect from nasopharyngeal secretions

Width
Cartilage, lumen and levator veli palatini (TVP) m. increase in overall
cross-sectional area and volume
Very little actual change in width of lumen itself

Orientation
10 angle to the horizon in infants
45% in adults
TVP angle to cartilage is larger in children
Tube wont open increasing incidence of OM

Cartilage composition
Infants with increased cartilage cell density but less elastin
Too floppy or compliant impairing protection from nasopharynx
and decreasing ability to open
Cartilage does not provide adequate support during attempts at
opening and may buckle

What Is The Evidence?

Muscular attachments
Passively closed at rest with active muscular
opening and cartilage recoil to close again
TVP attributed as primary ET muscle
2 distinct bundles lie mediolateral to the tube
TVP more lateral
Dilator tubae cartilagenous insertion

Internal pterygoid help with closure

Especially for abnormal populations

Tensor tympani interacts with the TVP

Levator veli palatini close proximity but no
consensus as to ability to affect ET

Functions Pressure Regulation

Adults clear pressure changes more
efficiently
Negative pressure chamber
35% children could not clear verses 5% adults
Bylander A, et al. Acta Otolaryngol 1983;96:255.

Increased incidence of normal children

with negative pressure on tympanogram

Experimental Evidence?
TVP muscle inactivation
Muscular destruction or inactivation (botulinum)
Produces middle ear effusions (MEE) - reversible
Casselbrant ML, et al, Acta Otolaryngol 1988;106:178185.

Infectious implications ?

Nasal viral challenges human

Influenza A
ETD negative pressure
Small percentage developed MEE
Buchman CA, et al, J Infect Dis 1995;171:1348

Special Populations
Cleft palate and Down Syndrome
Shorter tubes
Decreased TVP musculature insertion into
cartilagenous tube
Greater cartilage cell density
Increased TVP angle with ET

Daycare populations
? Role of ET

Hypothesis
ET dysfunction or obstruction may result during the events of
OM but ETD is not the primary underlying cause of OM and
development of the ET is not the major event responsible for
resolution of OM as children get older.
Immunology, Inflammation and Genetics - Not Anatomy
Children with early first infection
Children in daycare
Genetics/family history
Polymorphisms
Mucins

Biofilms
GERD

Biofilms
Bacterial biofilms
Complex organization of bacteria
Anchored to a surface
Surrounded by exopolysaccharide Matrix
secreted by bacteria
Low metabolic rate
Escape host immune surveillance

Opposed to planktonic concept of bacteria

Biofilms
Bacteria growing as biofilms display a different phenotype
than free-living, planktonic, bacteria
Reduced metabolic rates that render them resistant to
antimicrobial treatment
Exopolysaccharide matrix that provides protection from
phagocytosis and other host defense mechanisms due to a lack
of accessibility by immunoglobulin and complement
Reliance on complex intracellular communication system that
provides for organized growth characteristics, quorum sensing
Resistant to standard culture techniques because of altered
metabolism
Altered genetic expression and ability to rapidly share genetic
information

Background
Many chronic infectious processes in humans have been
demonstrated to be dependent upon the development of
biofilm formation
Dental
Chronic bacterial prostatitis
Cystic fibrosis
Medical Implants
Orthopedic implants
Heart valves
Catheters

Native valve endocarditis (NVE)

Biofilms form on cardiac valves
streptococci (including pneumococci)
staphylococci g
gram-negative bacteria
fungi (Candida and Aspergillus spp.)

Interactive biofilm model: www.erc.montana.edu

OM as a Biofilm Disease?
Chronic infectious process
Difficulties with culturing effusions
Recalcitrant to antibiotic therapy

Indirect Evidence of Bacterial Biofilm

in Otitis Media with Effusion
Evidence suggesting that otitis media with effusion is not a
sterile inflammatory effusion, but rather a vibrant, active
bacterial process
Bacterial DNA is present in pediatric culturally sterile effusion
Purified bacterial DNA are cleared within hours while DNA from
live infectious bacterial DNA persist in sterile effusion for up to 4
weeks
Bacterial mRNA is present in culturally sterile, DNA-positive
middle ear effusions in children indicating that the bacteria are
intact and metabolically active.
Bacteria-synthesized proteins are present in sterile effusions
Rayner MG, et al. JAMA. 1998;279:296-9.

Direct Evidence of Bacterial Biofilms in

Otitis Media
Experimental chinchilla model of OM
H. influenzae injected via transbullar approach
bilaterally
Confocal and electron microscopic evidence of
biofilm formation

Ehrlich GD, et al, JAMA 2002;287:1710

Biofilms
JAMA 2006;296(2):202-211.

Hypotheses
Otitis media in humans is biofilm mediated
Otitis media with effusion (OME)
Recurrent otitis media (ROM)

Direct evidence of Streptococcus

pneumoniae (SP) and Haemophilus
influenzae (HI) biofilms is available in
children undergoing tympanostomy tube
(TT) placement for OM

Mucin
Laryngoscope
2007;117(9):1666-1676.

Mucin
20 human mucin genes
5 previously well-studied in the middle ear
Mucins can be membrane bound MUC 1
Mucins can be secretory (gel forming) MUC 2, MUC 4, MUC 5AC, MUC 5B
Additional 10 identified in middle ear in our laboratory and undergoing further
characterization

Variation in quantity and quality of mucin is important in the pathophysiology of

OM
Mucin determines the viscosity of middle ear fluid and mucociliary clearance
Mucin responsible for hearing loss in COME

Mucins perform important host-defense functions

Mechanical protection
Affect pathogen adherence and clearance

Biofilm interactions

Mucin

Data demonstrating a strong

correlation between increased
MUC2, MUC5AC and MUC5B
expression and poorer hearing
(higher dB levels).

Summary
Diagnosis of patients with OM is still one of
the most important aspects of OM
It is a very prevalent and expensive disease
to manage
This is unlikely to change in the near future
Basic and clinical research continues to hone
who benefits most from which interventions
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