http://id.medscape.com/SCP/IIM/2001/v18.n05/m1805.02.leib/m1805.02.leib-01.html
From
Infections in
Medicine®
Eugene Leibovitz, MD, Ron Dagan, MD, Soroka
University Medical Center, Ben-Gurion University of the Negev, Beer-Sheva,
Israel
Acute otitis media (AOM) is the most common illness that
requires a visit to a physician in the developed world, and the number of cases
has increased substantially in the past 2 decades. This same period has been
marked by a significant increase in drug resistance among pathogens that cause
AOM. We provide an evaluation of the agents used to control infections with
these pathogens. Prophylactic modalities are also discussed. Advent of the Streptococcus
pneumoniae polysaccharide conjugate vaccine, coupled with more judicious
use of antibiotics, will improve management of AOM in the coming years. [Infect
Med 18(5):263-270, 2001. © 2001 Cliggott Publishing Co., Division of
SCP/Cliggott Communications, Inc.]
In Part 1 of this article (Infect Med.
2001;18:212-216), we presented an overview of drug resistance in acute otitis
media (AOM), described specific pathogens and the
pharmacokinetics/pharmacodynamics of specific antibiotic agents, and outlined
the correlation between antibiotic resistance and clinical/bacteriologic
outcome. In this second part of the article, we discuss nasopharyngeal
colonization in AOM, provide an in-depth analysis of drug resistance linked to
various anti-AOM agents, and describe current methods of chemoprophylaxis and
immunoprophylaxis.
Nasopharyngeal colonization with Streptococcus
pneumoniae, Haemophilus influenzae (nontypable strains), and Moraxella
catarrhalis increases significantly in temporal association with AOM.[1-3] S pneumoniae can be
isolated in 25% to 60% of nasopharyngeal cultures obtained from healthy
children.[4,5] Its main
reservoirs are infants and young children who become colonized with the
organism during their first 2 years of life. The pathogen is spread via close
contact, especially among children in day-care facilities.[6-8]
Significant changes in nasopharyngeal colonization with S pneumoniae
occur during antibiotic treatment. Generally, children who harbor
penicillin-susceptible strains will have a major decrease of S pneumoniae
in the nasopharyngeal carriage during the first weeks following the completion
of a ß-lactam therapeutic regimen.[9-13]
However, a rapid and early selection of nonsusceptible S pneumoniae
isolates in the nasopharynx is common during AOM therapy.[10,11] This phenomenon was particularly
and extensively observed when azithromycin and trimethoprim-sulfamethoxazole
(TMP-SMX) were used in the treatment of AOM.[10,11,14]
Although the overall carriage of S pneumoniae was reduced from 57% (on
day 1) to 29% (on days 4 and 5) during azithromycin therapy, all the remaining
strains were resistant to azithromycin.[10]
A 10-day regimen of TMP-SMX for AOM was shown to cause an early increase in the
carriage rate of both TMP-SMX-resistant and penicillin-resistant S
pneumoniae, which persisted for at least 1 month after therapy.[11]
Furthermore, we have recently shown that antibiotic therapy in AOM may
induce middle ear fluid (MEF) superinfection by acquisition of preexisting
nasopharyngeal antibiotic-resistant S pneumoniae.[12] Nasopharyngeal colonization with
penicillin-nonsusceptible S pneumoniae was found to be associated with
an increased incidence of nonresponsive AOM.[14,15]
Nasopharyngeal cultures have also been evaluated as predictors of the
presence of pathogens in the MEF of patients with AOM. A low positive
predictive value (22% to 45% for S pneumoniae) was uniformly reported
for the use of this method in the bacterial assessment of AOM.[15,16]
Physicians prescribe antibiotics for the majority of infants
and children with AOM because usually they are unable to determine by physical
examination which patients will have spontaneous resolution of their disease.
In general, antibiotics must be administered if AOM is diagnosed in infants and
young children who have recurrent AOM, in those who have structural or
immunologic abnormalities, and in those who are severely ill. Children aged 2
years and older, patients without fever, and those with minimal clinical signs
may be managed without antibiotics, but a follow-up evaluation is required 24
to 72 hours later.
Factors to be considered in choosing the appropriate antibiotic therapy for
AOM include activity of the drug against the main AOM pathogens, local
epidemiology, adverse events, tolerability, and cost. For example, marked
variations were shown in the acceptance of and compliance with oral antibiotic
suspensions prescribed for children. In a previous study performed in southern
Israel, 76% of the children who received cefaclor reported acceptance of the
drug without problems, while the respective figures for amoxicillin, TMP-SMX,
and cefuroxime axetil were 60%, 55%, and 20%, respectively.[17]
The most commonly used antibiotic drugs, their expected MEF levels, and
activity against the main pathogens that cause AOM are shown in Table 1. While most of
the drugs approved for the treatment of AOM may have relatively good in vitro
activity against the common AOM pathogens, there are many variations among
these drugs in terms of their in vitro activity and their penetration into the
MEF. Double-tympanocentesis studies discerned major differences in
bacteriologic efficacy, suggesting that the current armamentarium of
antibiotics used in the treatment of AOM should be limited to only those drugs
that have proven bacteriologic effectiveness.
Amoxicillin is the most commonly used oral antibiotic for
the treatment of AOM. At the standard dosages of 40 to 50 mg/kg/d, it is highly
effective against H influenzae that do not produce ß-lactamase and
against penicillin-susceptible and intermediately resistant S pneumoniae.
It achieves its effectiveness by reaching MEF concentrations of 1 to 6 µg/mL.[18,19] However, these concentrations may
not be high enough to eradicate penicillin-fully resistant S pneumoniae
with minimum inhibitory concentrations (MICs) greater than 2 µg/mL. Higher
dosages of amoxicillin (70 to 90 mg/kg/d) are recommended in those situations
in which the presence of these pneumococci is suspected or proved.[20-22]
The MICs of amoxicillin are generally about equal to or 2 to 4 times less
than the MIC of benzyl penicillin, and high-level resistance to penicillin has
been previously associated with low-level resistance to amoxicillin.[23] Recently, S pneumoniae with
high-level resistance to amoxicillin (MICs of 4 µg/mL or greater) has emerged
in France, most probably under the strong selective pressure caused by the
extensive use of high doses of this drug and other ß-lactams.[24] In addition, amoxicillin is not
effective against ß-lactamase-producing H influenzae.
At present, amoxicillin in a dosage of 40 to 50 mg/kg/d is recommended for
the empiric treatment of the first episode of AOM in children of all ages when
antibiotic therapy is indicated. In areas with a low prevalence of
antibiotic-resistant S pneumoniae, amoxicillin (40 to 50
mg/kg/d) and amoxicillin/clavulanate (depending on the prevalence of
ß-lactamase-producing H influenzae) represent the drugs of choice for
the empiric treatment of uncomplicated AOM.
The higher dosage (70 to 90 mg/kg/d) of amoxicillin is advised for the
empiric treatment of AOM in infants and children younger than 2 years in areas
with a high rate of recovery of antibiotic-resistant S pneumoniae. It
is also recommended for the therapy of culture-proven AOM caused by penicillin-intermediate
and fully resistant S pneumoniae.
Amoxicillin/clavulanate is a combination antibiotic
containing amoxicillin and clavulanate potassium, a ß-lactamase inhibitor that
extends the spectrum of amoxicillin against ß-lactamase-producing bacteria. A
twice-daily regimen (45 mg/kg/d of amoxicillin, 6.4 mg/kg/d of clavulanate in 2
divided doses for 10 days) was recently proved to be as effective as the
previously used 3-times-daily regimen (40 mg/kg/d of amoxicillin, 10 mg/kg/d of
clavulanate in 3 divided doses). In addition, the twice-daily preparation was
associated with a decrease in adverse effects (particularly diarrhea and
abdominal upset) and increased patient compliance.[25,26]
Recently, a multicenter study evaluated the bacteriologic efficacy of this
twice-daily regimen and reported an overall eradication rate of AOM pathogens
of 83% (87% forH influenzae and 90% for S pneumoniae).[27] In this study, the bacteriologic
success rates were consistently high for both H influenzae and S
pneumoniae and the amoxicillin/clavulanate MICs were within the
susceptible range for the great majority of these pathogens. The clinical
efficacy rate with this regimen, measured at the end of therapy and on days 22
to 28, paralleled the bacteriologic efficacy rate.[27]
The possible additional benefits of a higher dosage of
amoxicillin/clavulanate (90 mg/kg/d of amoxicillin, 6.4 mg/kg/d of clavulanate
in 2 divided doses for 10 days) are presently being evaluated in a prospective,
multicenter double-tympanocentesis study. Preliminary results of this study,
summarized for the first 521 children enrolled, showed that all
penicillin-susceptible and -intermediate S pneumoniae and 97% of
penicillin-resistant strains were eradicated by this regimen. In addition, 95%
and 100% of H influenzae and M catarrhalis organisms,
respectively, were also eradicated.[28]
Among oral cephalosporins, cefuroxime axetil is the only one
that reaches MEF levels above the MIC values for both S pneumoniae and
H influenzae for about 40% of the dosing interval.[29] The bacteriologic and clinical
efficacy of cefuroxime axetil has been recently proved in a
double-tympanocentesis study.[30-32]
Cefaclor, cefixime, loracarbef, and ceftibuten are less active in vitro against
S pneumoniae, particularly against penicillin-intermediate and
-resistant strains.[31-33]
Cefpodoxime has good in vitro activity against H influenzae, M
catarrhalis, and antibiotic-resistant S pneumoniae,[34] but its bacteriologic efficacy has
not yet been evaluated in prospective, comparative, double-tympanocentesis
studies. Cefprozil has a good in vitro sensitivity profile against AOM
pathogens, but the limited data available suggest a poor eradication rate of H
influenzae from the MEF.[35]
MEF concentrations of ceftriaxone exceed the MICs for AOM pathogens for
about 56 hours after a single 50 mg/kg intramuscular injection.[36] However, with ceftriaxone MICs for
penicillin- and ceftriaxone-resistant S pneumoniae higher than 2 µg/mL
and 1 µg/mL, respectively, MEF concentrations of the drug may decline below
therapeutic values and therefore failures may be expected.
While a single 50 mg/kg dose of ceftriaxone was approved by the FDA for the
treatment of AOM, we consider that there is no place today for ceftriaxone
therapy in the management of simple, uncomplicated AOM, with the exception of
cases of persistent vomiting and lack of compliance with oral drugs. The use of
ceftriaxone should be limited to second- and even third-line therapy for
nonresponsive AOM.[37,38]
Recently, a 3-day 50 mg/kg/d ceftriaxone regimen was shown to be
significantly superior clinically and bacteriologically to a 1-day regimen in
the treatment of nonresponsive AOM, and this difference was found to be mainly
caused by the superior eradication rate of penicillin-resistant S
pneumoniae by the 3-day regimen.[39]
It is important to mention, however, that the eradication rate of H
influenzae and penicillin-susceptible S pneumoniae was 100% in
the 1-day ceftriaxone-treated patients, and therefore such a regimen is
appropriate for nonresponsive AOM caused by these pathogens.[39]
Erythromycin. The resistance of S
pneumoniae to erythromycin has increased substantially in every area of
the world, and considerable cross-resistance exists between this drug and
ß-lactams.[40-43] Moreover,
this agent shows lack of activity against H influenzae. Therefore,
erythromycin currently has no place in the empiric treatment of AOM, as either
a first- or a second-line therapy.
Azithromycin. This newer azalide is closely related to the
macrolide class, with good in vitro activity against macrolide-susceptible S
pneumoniae, M catarrhalis and, to a lesser extent, H influenzae.
In addition, it has the advantages of single daily dosing, short duration of
therapy (3 to 5 days), and a low rate of adverse events.
Clinical efficacy studies performed during the last 10 years demonstrated a
beneficial effect of this drug in AOM,[44-46]
but many of the patients enrolled in these studies were older than 2 years and
had a milder form of disease. Double-tympanocentesis studies demonstrated the
lack of bacteriologic efficacy of azithromycin in AOM caused by H
influenzae and macrolide-resistant S pneumoniae.[33,47,48]
These bacteriologic efficacy results were in fact very close to the results
obtained with placebo. In addition to low bacteriologic efficacy, a recent
study also demonstrated an inferior clinical efficacy for azithromycin (on days
12 to 14 of therapy) when compared with amoxicillin/clavulanate.[27] The poor results in these studies
are probably related to the specific pharmacokinetic and pharmacodynamic
properties of azithromycin, which may allow the achievement of higher drug
concentrations in polymorphonuclear cells and much lower concentrations in the
extracellular compartment of the MEF, where the pathogens that cause AOM
concentrate.[47-49]
Clindamycin. This antimicrobial agent has good activity
against most penicillin-nonsusceptible S pneumoniae and may be used to
treat pneumococcal AOM that is unresponsive to ß-lactam antibiotics. The drug
has no activity against H influenzae and M catarrhalis.
Prospective, controlled studies of the bacteriologic and clinical efficacy of
clindamycin in the treatment of AOM are missing. Before deciding to use this
drug, the physician should be certain via MEF culture that the AOM episode was
caused by S pneumoniae -- which is unfeasible in most common
practices.
TMP-SMX has been used extensively in the past as a first-
and second-line agent in the treatment of AOM and also as a prophylactic agent.
However, given the high resistance rate of S pneumoniae to TMP-SMX
(greater than 50% in many areas of the world), there is no place today for its
use in the empiric treatment of AOM as either a first- or a second-line agent.
A recently completed double-tympanocentesis study performed in patients with
AOM who were treated with TMP-SMX showed a 56% and 15% overall bacteriologic
failure rate for S pneumoniae and H influenzae, respectively.[14]
In patients with AOM caused by TMP-SMX-resistant organisms, the
bacteriologic failure rates were much higher: 79% and 46% for S pneumoniae
and H influenzae, respectively, similar to the failure rates
encountered when placebo was administered.[14,50]
An analysis of 27 clinical trials involving 3766 patients
with AOM who received various antibiotic drugs for a shortened period (fewer
than 10 days) concluded that the prospects for a successful outcome seem quite
high for most uncomplicated cases of AOM.[51]
However, most of these studies had major design flaws, such as lack of
bacteriologic efficacy data and the under-representation of children younger
than 2 years. In addition, many of these studies were performed before the
emergence of antibiotic-resistant S pneumoniae as the major challenge
in the treatment of AOM.
Further studies evaluating shortened antibiotic regimens for AOM will have
to be performed in children younger than 2 years and patients with
nonresponsive AOM; these studies will need to investigate the bacteriologic
outcome of these shortened antibiotic regimens in addition to their clinical
efficacy. Until the results of these studies are available, we cannot recommend
shortened antibiotic regimens in the routine management of AOM or in the
treatment of AOM in the following groups:
The efficacy of different antibiotic regimens for the
prevention of AOM -- such as amoxicillin or sulfisoxazole at half the
therapeutic daily doses -- has been evaluated in many previous controlled
clinical trials. A meta-analysis study found a significant reduction of new and
symptomatic episodes of AOM in the treated groups.[54-59] The major concern related to the extensive use of
chemoprophylaxis for AOM is the risk of emergence of resistant organisms.
At present, we must consider the tremendous increase in the resistance to
antibiotics of the main pathogens that cause AOM ( particularly S
pneumoniae) and the high rate of nasopharyngeal colonization with these
pathogens in infants and toddlers, as well as the potential of prolonged
antibiotic administration to considerably increase the resistance of these
organisms. As a result, the decision to start antibiotic prophylaxis in a
patient who has AOM must be made on an extremely selective basis.
This prophylactic approach should be limited to only those few patients who
have entered the vicious circle in which they spend weeks and months almost
continuously taking antibiotic treatment for recurrent AOM. The present
recommendations reserve antimicrobial prophylaxis for children with recurrent
AOM defined by having 3 or more documented episodes in 6 months or 4 or more
episodes in 12 months.[59]
The concern for increased antibiotic resistance has led various
investigators to examine the role of oligosaccharides and xylitol in the
prevention of AOM episodes.[60-63]
Children who used daily xylitol chewing gum or suspension were found to have
significantly fewer AOM episodes than children who used sucrose chewing gum or
suspension.[63,64]
Prevention of pneumococcal invasive diseases and also of AOM
caused by pneumococci represents a tremendous challenge, especially in this era
of antibiotic-resistant organisms. The excellent results obtained with the
large-scale use of H influenzae type b conjugate vaccine have paved
the way for the development of multivalent pneumococcal conjugate vaccines to
be used for the prevention of pneumococcal invasive diseases and AOM.
Immunogenicity studies have indicated that infants respond to each conjugate
polysaccharide type with concentrations of antibodies believed to be
protective.[64] In addition,
the use of conjugate vaccines in infants and toddlers has been shown to
decrease the nasopharyngeal carriage of many pneumococcal serotypes, especially
the resistant strains included in the vaccine.[65-68]
Three recent studies have demonstrated the clinical benefit of the
conjugated vaccines in the prevention of AOM caused by S pneumoniae.
Two of them, performed in California[69]
and Finland,[70,71] showed a
reduction in pneumococcal AOM after the administration of a 7-valent
pneumococcal conjugate vaccine in infants. The third study, from Israel,[72] showed a reduction in respiratory
infections, including AOM, and a reduction in antibiotic use in toddlers
attending day-care centers following the administration of a 9-valent
pneumococcal CRM197 vaccine.
Future studies require more complete answers to additional questions related
to the reduction in the carriage of resistant strains, the possible replacement
of vaccine strains by nonvaccine strains, the overall impact on the prevalence
of multidrug-resistant strains, and the serum and local antibody levels
required to confer protection against AOM.
Management Recommendations
Clinicians involved in the treatment of children should be
aware of the major increase in the proportion of resistant organisms that
cause AOM and of the direct relationship between this increase and antibiotic
use. It is well known that in some Western European countries, the treatment
policy for AOM is to withhold antimicrobial drugs in patients with AOM, using
antibiotics only after a 1- to 3-day observation period during which the
patient remains ill.[73]
However, no evidence-based data exist to support the withholding of
antibiotic therapy in children younger than 2 years with AOM, patients with
complicated AOM, or children attending day-care centers. Therefore, the
policy of observation alone may be recommended only in children older than 2
years who are mildly symptomatic.[43]
Table 2 summarizes
recommendations for first- and second-line therapy for AOM. The
Drug-resistant Streptococcus pneumoniae Therapeutic Working Group of
the CDC has recently published new guidelines for the antibiotic treatment of
AOM in the present era of pneumococcal resistance.[43] According to these guidelines,
amoxicillin (40 to 50 mg/kg/d or the higher dosage of 70 to 90 mg/kg/d)
represents the first-line treatment of choice for AOM. High-dose amoxicillin
or amoxicillin/clavulanate or cefuroxime axetil is recommended as first-line
treatment of AOM in those patients who have received antimicrobial therapy
during the month preceding the AOM episode. In cases of clinical failure after 3 full days of therapy, we recommend
the performance of a diagnostic (and in many situations therapeutic)
tympanocentesis, particularly in areas with a high prevalence of
antibiotic-resistant S pneumoniae. The 3 second-line antibiotic drugs recommended for clinical failures are:
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Drs Leibovitz and Dagan are with the
pediatric infectious disease unit, Soroka University Medical Center, and the Faculty
of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel.
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