|Acute Otitis Media: Treatment
in an Era of Increasing Antibiotic Resistance
Published in American Family Practice, 2000, Vol. 61, Pgs. 2410-2416
Michael E. Pichichero, MD
University of Rochester Medical Center
Elmwood Pediatric Group
Department of Microbiology/Immunology
601 Elmwood Avenue, Box 672
Rochester, NY 14642
Word count: 2,584
Empiric antibiotic treatment of acute otitis media (AOM) must
take into account risk factors for infection due to the rapidly
rising number of resistant pathogens such as penicillin resistant
S. pneumoniae and beta lactamase producing Haemophilus influenzae.
Recommendations have been offered by the Centers for Disease
Control for management of antibiotic resistant Streptococcus
pneumoniae AOM episodes. Amoxicillin remains the antibiotic
treatment of first choice, although a double dose (80-100
mg/kg//day to a maximum of 3 grams/day) may improve the likelihood
of eradication of resistant S. pneumoniae. Cefuroxime axetil,
Amoxicillin-clavulanate combined with amoxicillin and injections
of Ceftriaxone are suggested second line choices. These recommendations
should be considered in the context of varying anticipated
efficacy, safety, and compliance potential among these and
other drugs approved for use in AOM. Withholding antibiotics
as treatment for AOM has been proposed as an option, particularly
in children beyond 3 years of age. Shortening the standard
duration of antibiotics to 5 days results in similar outcomes
as 10 days therapy, in most patients, with less side effects
and cost. Selective use of tympanocentesis is now being advocated
to allow pathogen-specific antibiotic selection after treatment
Physicians often feel overwhelmed when it comes to understanding
the variable spectrum of activity of the many antibiotics with
an AOM indication (Table 1). The situation is getting more
complex due to changing and escalating resistance patterns
among the AOM pathogens (1-5). An evaluation of reported pathogens
and rates of resistance in AOM based on data obtained prior
to 1993 (6) almost certainly would not be reflective of the
current situation. Resistance rates vary geographically and
among patient groups. The primary explanation for the increasing
rates of antibiotic resistance is antibiotic selective pressure
followed by geographic migration of strains (7).
Reduced penicillin (and amoxicillin) susceptibility among
strains of S. pneumoniae now ranges between 30% and 60% in
the United States (2, 4, 5); trimethoprim-sulfamethoxazole
resistance generally exceeds 50% (5). Quinolone resistance
among S. pneumoniae strains is rising (8).
The proportion of beta lactamase-producing H. influenzae and
M. catarrhalis strains has nearly tripled from rates of 15-20%
in the 1980s to currently reported rates of up to 55% for H.
influenzae (1-3, 9); virtually 100% of M. catarrhalis strains
from AOM infected patients in the US produce beta lactamase
(1-3, 9). Resistance of H. influenzae to trimethoprim-sulfamethoxazole
is increasing (10, 11).
Antibiotic resistance occurs most frequently in a recently
treated AOM patient. Our group reported a 46% rate of penicillin-resistant
S. pneumoniae from patients recently treated (9); 33% of 93
S. pneumoniae strains were highly penicillin-resistant (9).
The incidence of resistant pathogens is higher in children
in day care, especially the winter time (12) and in children
below 4 years of age (13) (Table 2).
Much mis-information has been generated regarding the role
of Mycoplasma pneumoniae and Chlamydia pneumoniae in AOM. Klein
et al (14) noted in the 1970s that M. pneumoniae was recovered
from only one of 771 tympanocentesis samples. Block et al (15)
C. pneumoniae from 8 of 101 children with AOM; however it was
the sole microbe isolated in only two children. Viruses cause
AOM as the sole pathogen in < 10% of cases; viral upper
respiratory infections frequently precede AOM and viruses are
not uncommonly isolated along with the typical AOM bacterial
pathogens from middle ear effusions (16). Anaerobes may play
a role in chronic otitis media but not AOM.
Antibiotic Impact on Outcomes from AOM
In the past, physicians have been accustomed to optimistic
reports of high cure rates for most antibiotics used to treat
AOM. Then again, ten years ago, S. pneumoniae were almost universally
susceptible to amoxicillin and 20 years ago, H. influenzae
infrequently produced the beta lactamase enzyme and M. catarrhalis
was not pathogenic. Particularly, non-tympanocentesis clinical
trials almost always revealed successful clinical outcomes.
Explanations for such positive results included: 1) over-diagnosis
at study entry (patient never had AOM in the first place),
2) the lack of validated otoscopists as investigators conducting
the evaluations, 3) inclusion of only mild to moderate AOM
cases, 4) exclusion of difficult to treat patients, and 5)
use of overly broad criteria for satisfactory outcome assessments
(symptom resolution only).
Also, AOM has a favorable natural history.
By the fifth day after symptom onset, about 89% of M. catarrhalis
50% of H. influenzae infections and 20% S. pneumoniae infections
have been eradicated by the body's natural host defenses (17).
A meta-analysis of studies conducted from 1966 to 1992 (18)
concluded that the overall spontaneous resolution rate of AOM
was 81% (95% confidence interval 69% to 94%). The benefit of
antibiotics on AOM was 13.7% (95% confidence interval, 8.2%
to 19.2%) over placebo. Examined another way, antibiotics were
assessed to offer approximately 2 days of faster resolution
of pain compared to non-treatment or treatment with analgesics
(19). These "marginal" benefits has led to a proposed
non-treatment paradigm (20) or a delay in treatment of about
2 days to see if symptoms resolve on their own. In my view,
these recommendations are flawed because the data upon which
they are based come from a different era of bacterial resistance.
Bacterial Resistance After Antibiotic Therapy Failures
During the 1980s, H. influenzae accounted for the majority
(46%-62%) of pathogens recovered from bacteriologic failures
in AOM (21). Currently, it appears that S. pneumoniae, and
in particular resistant strains, may account for the majority
of pathogens recovered from antibiotic
failures (9, 22, 23). The highest risk for penicillin-resistant
S. pneumoniae occurs in those who have been recently treated
(particularly within the preceding month) or are failing antibiotics
(9, 22 23).
When treating persistent and recurrent AOM, practitioners
should expect success rates in the range of 60%-70% even when
the most efficacious broad spectrum oral antibiotics are chosen
(1, 22). Currently, minimal data are available regarding the
treatment of AOM caused by fully penicillin-resistant S. pneumoniae.
Thus far only five antibiotics (amoxicillin, amoxicillin-clavulanate,
cefuroxime, cefprozil, ceftriaxone) have demonstrated (9, 23-25).
Studies with other broad spectrum agents are currently underway.
CDC Recommendations for AOM Management
CDC report from the drug-resistant S. pneumoniae therapeutic
working group, which included representatives
of the American
Academy of Family Physicians, gave specific recommendations
for treatment of AOM (Table 3) (26). The CDC working group
distinguished initial treatment options based on recent antibiotic
exposure because recent exposure clearly increases the risk
of resistant pathogens, as previously discussed. A switch in
empiric therapy was recommended on day 3 of therapy and/or
10-28 days after initial diagnosis in cases of clinically defined
treatment failure. Agents selected for alternative therapy
met two criteria according to the report. The antibiotics were
effective against (1) S. pneumoniae, including most drug-resistant
strains, and (2) H. influenzae and M. catarrhalis, including
beta lactamase resistant strains. For empiric therapy after
amoxicillin treatment failure three agents were selected: high
dose amoxicillin-clavulanate (AMX-CLV), cefuoxime axetil and
intramuscular ceftriaxone. With currently available U.S. formulations,
the AMX-CLV regimen would require two prescriptions: amoxicillin
(dosed at 40 mg/kg/day) and for AMX-CLV (also dosed at 40 mg/kg/day
of amoxicillin). Different from the approved use of ceftriaxone
in uncomplicated AOM where a single injection is acceptable,
treatment with ceftriaxone when resistant bacteria are suspected
was said to require three injections over three days. Two other
antibiotics were strongly considered as empiric candidates-cefprozil
and cefpodoxime-but were not included among the preferred choices
because more data were needed. Cefdinir, the newest approved
antibiotic for AOM was not licensed at the time of the CDC
review. Tympanocentesis was recommended as an option at both
time points of clinically defined treatment failure (day three
on treatment and day 10-28 after completion of treatment).
Tympanocentesis was viewed as "particularly important
if a child has recently received several courses of antimicrobial
therapy and if therefore more likely to harbor a multiply resistant
strain" (26). In this context, the working group stated, "In
an era of increasing antimicrobial resistance, clinicians treating
children with AOM should consider developing the capacity to
perform tympanocentesis themselves or establish ready referral
mechanisms to a clinician with this capacity" (26). If
tympanocentesis is performed and S. pneumoniae are isolated
then clindamycin becomes a treatment option (Table 3).
Interpreting Empiric Antibiotic Selection Recommendations
the CDC Working Group
Higher doses of amoxicillin were recommended by the CDC as
one strategy to address the issue of penicillin resistant pneumococci
(26). By increasing the dose, higher levels of antibiotic have
been demonstrated in middle ear fluid (27). Beta lactam antibiotics
follow first order kinetics. Thus, the strategy favored by
the CDC to achieve a longer time above the MIC was to give
a higher dose; the decline in drug concentration according
to half-life should result in a longer time above the MIC.
Regardless of the dose, amoxicillin will not eradicate beta
lactamase producing H. influenzae or M. catarrhalis. For this
reason, alternatives to amoxicillin should have stability against
The pharmacodynamics model (28, 29)-whereby
achievable antibiotic levels at the site of infection and
the MIC of pathogens for
particular drugs are used as predictors of successful bacteriologic
killing-heavily influenced the CDC recommendations. It seems
reasonable to presume that an effective antibiotic must have
in vitro killing activity against a specific pathogen in order
to offer benefit to the patient. In turn, the minimum concentration
of antibiotic to kill the bacteria must be achievable in vivo
(in the patient) at the specific site of infection (middle
ear mucosa and effusion space). Nevertheless, this model has
shortcomings: 1) Bacteriologic eradication is correlated with
a successful clinical outcome in > 90% of cases. However,
even when bacteriologic eradication is not achieved, clinical
success occurs in > 90% of patients. Much of this depends
on the endpoint one considers most important. Eventually almost
everyone gets better. Is the endpoint faster resolution of
pain and fever, or prevention of suppurative extension of infection,
e.g., mastoiditis, or faster resolution of middle ear effusion,
as a cause of temporary hearing loss or prevention of permanent
deafness? 2) Validation of the pharmacodynamic model relies
on double tap studies (wherein tympanocentesis cultures allow
identification of the causative bacteria and then a second
ear tap is done about 5 days later to determine if the antibiotic
given has killed the bacteria) and measurements of antibiotic
levels in the middle ear fluid (from acute and chronically
infected AOM patients). Some antibiotics such as azithromycin
and clarithromycin concentrate intracellularly and/or are bacteriostatic
for some AOM pathogens. The model may not accurately assess
the likelihood of bacteriologic or clinical success for these
agents 3) The MIC breakpoints used by the CDC were based on
NCCLS standards and these changed six months after the CDC
The CDC recommendations put a strong emphasis on tympanocentesis.
Yet very few family physicians have ever performed the procedure
or they performed it several decades ago. Otolaryngologists
infrequently are available to accommodate a same day referral
for the procedure and fewer still have done it without the
benefit of general anesthesia. Until 1999, only about 100 pediatricians
had performed an office-based tympanocentesis and fewer than
30 did so regularly. While family physicians and pediatricians
are now receiving CME-accredited training (Outcomes Management
Educational Workshops: 1-877-EAR-OMEW or www.omew.com) it will
take years before this skill becomes generally acquired. Thus,
while it appears that an ear tap will increasingly come back
into the purview of the family physician (as bacterial resistance
rises), for now it is somewhat impractical in most cases.
Empiric Antibiotic Selection Without Tympanocentesis
In the absence of bacteriologic data provided by tympanocentesis,
empiric selection of antibiotics is guided by each drug's spectrum
of activity (1, 17, 23, 26). The major considerations in empiric
antibiotic selection for AOM include comparative drug efficacy,
safety, compliance potential and cost (1, 17). Sources of antibiotic
information are often confusing and conflicting. Pharmaceutical
representatives produce brochures touting their drug as effective,
at least as good in clinical outcome as their main competitor
and perhaps better in some other way (diarrhea rate, taste,
dosing frequency, need for refrigeration of suspension, or
a few dollars lower in cost that day at the local pharmacy).
In my opinion, comparative efficacy assessments must take into
account the intrinsic antibacterial activity of the antibiotic
(in vitro susceptibility), clinical outcomes from patient trials,
the resistance patterns of bacterial pathogens present in a
particular community, and the pharmacologic properties of drugs
There is very little to distinguish one antibiotic from another
in terms of safety profiles. All of the antibiotics used for
AOM generally are quite safe. Compliance, duration of therapy
and cost are important issues. The main determinants of compliance
appear to be frequency of dosing, palatability of the agent,
and duration of therapy. In this regard, less frequent dosing
is desirable (once or twice a day) as opposed to more frequent
dosing which interferes with daily routines. In many instances,
palatability ultimately determines compliance in the pediatric
patient because if a parent must struggle with a child to force
oral ingestion then the child may prevail in the struggle and
no antibiotic will be consumed. Patients prefer a shorter course
of therapy (5 days or less) in contrast with traditional 10-14
day treatment courses employed in the United States. Besides,
many patients and parents only continue antibiotic therapy
until they become asymptomatic and then perhaps for one or
two additional days (30). The remainder of the prescription
is usually saved for future use when similar symptoms arise
(30). Antibiotic cost is an interesting component in the treatment
paradigm. Three office visits and three injections of intramuscular
ceftrixone will escalate the cost of treating AOM. Most patients
and health insurers look at the acquisition cost of antibiotics
rather than the total direct costs of care. Failed therapies
which result in loss of parent work or child attendance at
school/day care and second visits for more effective therapy
should also be considered important factors when a comprehensive
assessment of antibiotic cost is made.
Pathogen-Directed Antibiotic Selection
The microbiologic cause of AOM can be documented on the basis
of results of appropriate cultures of middle ear effusions
that have been obtained by tympanocentesis. A bacterial pathogen
is generally isolated from middle ear fluid of approximately
two-thirds of children with acute AOM (17) and 50% of children
with persistent and recurrent AOM following antibiotic treatment
(22). Even though the otoscopic examination demonstrates evidence
of middle ear inflammation, the AOM episode may be sterile
by the time the patient seeks care. The immune response and/or
prior antibiotic therapy may have eradicated the bacteria or
the pathogen was a virus for which antibiotics would be of
no value. Patients with no bacteria isolated require no antibiotic
treatment. If a tympanocentesis is performed, management options
include: (1) waiting for culture results before selecting an
antibiotic, or (2) providing the patient with 2 days of samples
while waiting for cultures and changing the prescription if
needed or discontinuing treatment if cultures are negative.
With tympanocentesis, the physician can identify the patients
for whom the infection is more likely to self-resolve by a
gram stain ($3-5) and possibly culture ($15-38) of middle ear
fluid. Withholding antibiotics from a child with M. catarrhalis
would make more sense than a child with S. pneumoniae. S. pneumoniae
isolates can be subjected to susceptibility testing (by E test
or broth dilution ($ 42-60), to determine whether the strains
are penicillin-susceptible, relatively or fully resistant.
With that specific information in hand, one can assess the
various antibiotics available with a more compelling mandate
for specific selections (Figure 1) (2, 4, 5, 23, 28, 31). Gram
negative organisms (H. influenzae and M. catarrhalis) can be
tested to identify whether the specific strain is beta lactamase
producing. For beta lactamase producing strains, the stability
and corresponding activity against these gram negative bacteria
differs substantially among the various agents available (Figure
2) (2, 31).
Many children with AOM do not benefit from antimicrobial agents
because the etiology is non-bacterial or the bacterial otitis
media resolves without use of a drug. At present, however,
we do not have clinical criteria by which to distinguish the
two groups of children. We need to implement education programs
for patients as well as physicians to discourage inappropriate
antibiotic use and to shift the emphasis from empiric to pathogen-directed
antibiotic therapy. Even with our best effort, antimicrobial
resistance of AOM pathogens is likely to continue to escalate
and therefore the development of effective new antibiotics
will be needed. Clinical trials are now ongoing with new families
of drugs for AOM to include new oral quinolones, oxazolidinones,
streptogramins, and ketolides. Also, conjugate pneumococcal
vaccines are in clinical trials which we hope will prove efficacious
in prevention of about half the cases of AOM caused by S. pneumoniae.
- Block SL. Causative pathogens, antibiotic resistance
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- Jacobs MR, Dagan R, Appelbaum PC, Burch DJ. Prevalence
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Antibiotics Labeled for the Treatment of AOM
Influence of Patient Age on Incidence of Isolation of
Resistant Pathogens in Acute and Recurrent Otitis Media
(n = 57)
(n = 168)
(n = 542)
SL et al. Presented at the 36th Interscience Conference
on Antimicrobial Agents and Chemotherapy; September 15018,
1996; New Orleans, LA. (13)
Acute otitis media treatment recommendations* for children who have not or have
received antimicrobial therapy during the prior month
DefinedTreatment Failure on Day 3
Defined Treatment Failure on Days 10-28
usual dose amoxicillin
dose amoxicillin-clavulanate; cefuroxime axetil; im ceftriaxone† im
ceftriaxone‡; clindamycins§ or tympanocentesis
as Day 3
dose amoxicillin; high dose amoxicillin-clavulanate;
dose amoxicillin-clavulanate; cefuroxime axetil; im ceftrixone‡ or
drugs are those for which strong evidence of efficacy
exits. Other drugs also may prove efficacious.
† High dose amoxicillin, 80 to 90 mg/kg/day. High dose amoxicillin-clavulanate,
80 to 90 mg/kg/day of the amoxicillin component, with 6.4 mg/kg/day of clavulanate
(require newer formulations, or combination with amoxicillin.
‡ Documented efficacy in AOM treatment failures if three daily doses are used.
§ Clindamycin is not effective against Haemophilus influenzae or Moroxella
Dowell et al. Pediatr Infect Dis J 1999;18:1-9. (26)
Comparative In Vitro Activity of Antibiotics
Against Streptococcus pneumoniae
Drugs listed alphabetically in each cluster
Comparative In Vitro Activity of Antibiotics
Against Haemophilus influenzae beta lactamase positive
Drugs listed alphabetically in each cluster