Previous Article | Next Article 
Antimicrobial Agents and Chemotherapy, March 1998, p. 589-595, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Prevalence of Antimicrobial-Resistant Pathogens in
Middle Ear Fluid: Multinational Study of 917 Children with Acute
Otitis Media
Michael R.
Jacobs,1,*
Ron
Dagan,2
Peter C.
Appelbaum,3 and
Daniel
J.
Burch4
Department of Pathology (Clinical
Microbiology), Case Western Reserve University School of Medicine and
University Hospitals of Cleveland, Cleveland,
Ohio1;
Department of Pediatrics
(Pediatric Infectious Disease Unit), Ben-Gurion University of the Negev
and Soroka Medical Center, Beer-Sheva, Israel2;
and
Department of Pathology (Clinical Microbiology), Milton
S. Hershey Medical Center, Hershey,3 and
Department of Anti-Infectives, SmithKline Beecham
Pharmaceuticals, Collegeville,4 Pennsylvania
Received 30 June 1997/Returned for modification 10 December
1997/Accepted 17 December 1997
 |
ABSTRACT |
The management of acute otitis media is complicated by the
emergence of resistance to 
-lactam and other antibiotics among common pathogens. We conducted a large, international study of infants
and children with acute otitis media to identify pathogens and
susceptibility patterns. During the winter of 1994 to 1995, middle ear
fluid samples were collected from 917 patients with acute otitis media
in Bulgaria, the Czech Republic, Hungary, Romania, Slovakia, Israel,
and the United States. A single reference laboratory performed in vitro
susceptibility testing. Pathogens were isolated from 62% of the
patients. For Streptococcus pneumoniae (30% of the
patients), untypeable Haemophilus influenzae (17%), and
Moraxella catarrhalis (4%), there was significant
variation among geographic regions (P < 0.001). The
composite susceptibilities of these three organisms to amoxicillin
ranged from 62% in the United States to 89% in Eastern and Central
Europe; the corresponding susceptibilities to amoxicillin-clavulanate
ranged from 90% in Israel to 95% in Eastern and Central Europe.
-Lactamase was produced by 31 and 100% of the isolates of H. influenzae and M. catarrhalis, respectively. More
isolates of S. pneumoniae were susceptible to amoxicillin (90%) or amoxicillin-clavulanate (90%) than to penicillin (70%; P = 0.002). The prevalence of resistant S. pneumoniae was highest in patients less than 12 months of age.
S. pneumoniae, H. influenzae, and M. catarrhalis remain the most important bacterial pathogens in
patients with acute otitis media; however, their prevalence is variable
and resistance patterns are changing.
| |
INTRODUCTION |
Acute otitis media continues to be
an important public health problem around the world. The most common
bacterial pathogen, Streptococcus pneumoniae, has been
implicated as part of the current antibiotic resistance crisis
(33). The first cases of penicillin-resistant S. pneumoniae were reported in Australia and New Guinea in the early
1970s (21, 22). In less than a decade, highly resistant strains that exhibited resistance to multiple antibiotics were isolated
from patients with invasive infections, as well as from carriers, in
South Africa (3, 28). The prevalence of penicillin-resistant pneumococcal infections has escalated steadily. The increasing use of
day-care facilities provides a vector for transmission of resistant
pneumococci (10, 39). International spread of resistant
isolates has been documented (30, 32, 43), so that
penicillin-resistant pneumococcal infections have become a global
problem (1, 2).
The optimal management of acute otitis media is widely debated for many
reasons (6, 20, 38), beginning at the most basic level of
medical management, because there is no consensus regarding diagnostic
criteria (5). The selection of antibiotic therapy is usually
empiric because of the difficulty of obtaining cultures. Although
authorities usually agree that S. pneumoniae and untypeable
Haemophilus influenzae are the most common bacterial pathogens (5), the prevalence of resistance is not as well documented. Eradication of pathogens from middle ear fluid and clinical
outcome have been reported to be less favorable if pathogens with
reduced antimicrobial susceptibility are present (12, 19).
To help answer these questions, we conducted a large, prospective study
of bacterial isolates associated with acute otitis media. To minimize
the risk of overlooking any isolates, especially penicillin-resistant
S. pneumoniae, we evaluated a large number of patients in
several countries. Strict diagnostic criteria for otitis media were
used, including otoscopic findings of middle ear effusion or purulent
otorrhea and local indicators of acute inflammation. This report
summarizes the microbiological findings on pretherapy middle ear fluid
specimens obtained from 917 patients with acute otitis media as part of
a prospective, multinational clinical study.
(The clinical results reported here were published previously
[23], and the preliminary microbiologic results were
published as abstracts [26, 27].)
| |
MATERIALS AND METHODS |
Patients.
Infants and children up to 12 years of age who met
strict criteria for acute otitis media with effusion (23)
were eligible for enrollment. The lower age limits of eligibility were
3 months in the United States and Israel and, because of regulatory
issues, 9 months in Eastern and Central Europe. Acute otitis media was diagnosed on the basis of otoscopic findings of either middle ear
effusion or purulent otorrhea with a duration of less than 24 h.
Informed consent was obtained from parents or legal guardians. The
protocol was approved by institutional review boards at participating
institutions.
Microbiology.
Middle ear fluid samples were collected by
tympanocentesis or myringotomy. If tympanostomy tubes were present or
the tympanic membrane had ruptured, samples were collected on swabs.
Initial isolation procedures were performed on blood and chocolate agar plates, by local microbiology laboratories, and all isolates recovered were forwarded to the reference laboratory of one of the investigators (M.R.J.) for confirmation of identification and in vitro susceptibility testing. Isolates received at the reference laboratory were identified by standard methods (34). Serotypes of penicillin-resistant S. pneumoniae isolates were determined by the Statens
Seruminstitut, Copenhagen, Denmark, courtesy of Helle Bossen Konradsen.
Susceptibility testing.
MICs of penicillin, amoxicillin,
amoxicillin-clavulanate, erythromycin, clindamycin,
trimethoprim-sulfamethoxazole, tetracycline, and chloramphenicol were
determined by the broth microdilution method of the National Committee
for Clinical Laboratory Standards with cation-adjusted Mueller-Hinton
broth (Difco Laboratories, Detroit, Mich.) supplemented with 5% lysed
horse blood for S. pneumoniae (35). MICs of
amoxicillin and amoxicillin-clavulanate were determined by using
Haemophilus test medium for Haemophilus species
and Moraxella (Branhamella)
catarrhalis (35). -Lactamase production was
determined for Haemophilus species and M. catarrhalis by the chromogenic cephalosporin method by using
nitrocefin as the substrate (34).
MICs were interpreted according to the National Committee for Clinical
Laboratory Standards M100-S6 informational supplement (36).
All -lactamase-producing H. influenzae and M. catarrhalis isolates were interpreted as resistant to amoxicillin,
regardless of the MICs.
Statistical design and analysis.
The target enrollment was
set at 1,000 assessable patients to obtain 30 to 50 patients with acute
otitis media due to S. pneumoniae isolates that were
intermediately or fully resistant to penicillin. Data from Eastern and
Central Europe were combined. Data analyses were performed with SAS
Institute statistical software (41). Log-linear techniques
were used to test for statistical independence of age (categorized),
region of origin, and pathogen prevalence for each age group. Where the
null hypotheses of independence were rejected, subsequent analyses were
conducted at the appropriate level of detail for comparisons between
age groups and regions. One-way analysis of variance or the
Kruskal-Wallis test compared means across regions. Chi-square tests
were used to test bivariate null hypotheses of independence.
P values were adjusted for multiple comparisons as
appropriate (16).
| |
RESULTS |
Patients.
Specimens of middle ear exudate were obtained from
917 assessable patients enrolled in the study during the winter of 1994 to 1995. Twenty-one investigators from Eastern and Central European countries enrolled 529 patients (58%). Four investigators from Israel
enrolled 107 patients (12%). Ten centers in the United States,
comprising six university-affiliated hospitals and four private
practices, enrolled 281 patients (31%).
Mean ages (± the standard deviation) were 4.6 ± 2.9 years in
Eastern and Central Europe, 1.4 ± 1.8 years in Israel, and
2.6
± 2.3 years in the United States (
P = 0.0001, between regions).
Because of differences in the lower age limits of
eligibility,
younger patients were enrolled in the <12-month age group
in the
United States (mean, 7.8 ± 2.3 months;
n = 63) and Israel (mean,
6.7 ± 2.7 months;
n = 52)
than in Eastern and Central Europe (9.2
± 1.9 months;
n = 25) (
P = 0.0001, between regions).
Microbiology results.
Specimens were obtained by
tympanocentesis (80%) or from the discharge from ruptured tympanic
membranes (18%) or tympanostomy tubes (2%) (Table
1). Pathogens were isolated from 569 patients (62%). The most frequently isolated pathogen was S. pneumoniae (30%), which was followed by untypeable H. influenzae (17%), S. pyogenes (7%), M. catarrhalis (4%), and mixtures of these pathogens (3%) (Fig.
1).
View larger version (28K):
[in this window]
[in a new window]
|
FIG. 1.
Culture results of middle ear aspirates obtained from
patients in Eastern and Central Europe, Israel, and the United
States.
|
|
There were differences in the geographic distribution of potentially
resistant pathogens (i.e., pathogens that have developed
antimicrobial
resistance, namely,
S. pneumoniae,
H. influenzae,
and
M. catarrhalis). Among the three geographic regions,
significant
differences (
P < 0.001) were found for the
following comparisons:
any versus no pathogen,
S. pneumoniae
versus no
S. pneumoniae,
S. pneumoniae versus
H. influenzae and
M. catarrhalis,
H. influenzae versus no
H. influenzae, and
H. influenzae versus
S. pneumoniae and
M. catarrhalis.
The likelihood of isolating a potentially resistant pathogen decreased
with increasing age. In Eastern and Central Europe,
the prevalence of
resistant pathogens fell from 73 to 40% as the
patients' ages rose
from <12 to >60 months (
P = 0.008) and from
57 to
44% as the ages rose from
35 to
36 months (
P = 0.006).
In the United States, the corresponding prevalence fell from 72
to 41% (
P = 0.005) and from 72 to 62%
(
P = 0.03). There were not
enough older patients in
Israel to analyze this trend. The likelihood
of isolating
S. pneumoniae (
P = 0.012) decreased in Eastern and
Central Europe as the ages rose from
35 to
36 months, but not
in
the other regions.
Susceptibility testing.
In vitro susceptibility testing was
performed on 454 potentially resistant pathogens that were received in
viable condition by the reference laboratory. The composite
susceptibility to amoxicillin for S. pneumoniae, H. influenzae, and M. catarrhalis was 76%, ranging from
62% in the United States to 89% in Eastern and Central Europe (Table
2). The corresponding susceptibility to
amoxicillin-clavulanate was 94% overall, ranging from 90% in Israel
to 95% in Eastern and Central Europe.
Of 147 isolates of
H. influenzae, 31% produced
-lactamase, including 13% of 52 from Eastern and Central Europe,
26% of 31
from Israel, and 47% of 64 from the United States. Of 36 isolates
of
M. catarrhalis, all produced
-lactamase.
Of 271 isolates of
S. pneumoniae, 30% were intermediately
or fully resistant to penicillin, including 31% in Central and Eastern
Europe, 52% in Israel, and 21% in the United States
(
P = 0.012).
The prevalence of intermediately or fully
penicillin-resistant
S. pneumoniae isolates was variable
among Central and Eastern
European countries, ranging from 4% in the
Czech Republic to 41%
in Romania (Table
3).
More isolates of
S. pneumoniae were susceptible to
amoxicillin (90%) or amoxicillin-clavulanate (90%) than to penicillin
(70%;
P = 0.002; Table
4). Figure
2 illustrates the distribution of
MICs of
penicillin and amoxicillin; MICs of amoxicillin-clavulanate
were nearly
identical to those for amoxicillin (data not shown).
The three
-lactam antibiotics had identical MICs at which 50%
of the isolates
were inhibited (MIC
50s (0.015 µg/ml) and
MIC
90s
(1 µg/ml). However, while almost all fully and
intermediately
penicillin-susceptible strains were susceptible to
amoxicillin
and amoxicillin-clavulanate, penicillin-resistant strains
were
all intermediately or fully resistant to these agents (Table
5).
Susceptibilities to non-
-lactam
antimicrobials ranged from 59%
for trimethoprim-sulfamethoxazole to
90% for chloramphenicol.
When susceptibilities to other antimicrobials
were stratified
by penicillin susceptibility (Table
5), intermediately
or fully
penicillin-resistant isolates were more likely to be resistant
to trimethoprim-sulfamethoxazole (82 versus 23%;
P = 0.001) and
erythromycin (39 versus 4%;
P = 0.001) than
were penicillin-susceptible
isolates.
View this table:
[in this window]
[in a new window]
|
TABLE 5.
Susceptibility of 271 isolates of S. pneumoniae to various antimicrobials with respect to
penicillin susceptibility
|
|
The prevalence of resistant
S. pneumoniae was highest in the
youngest age groups (Fig.
3). Values for
intermediately or fully
penicillin-resistant isolates were higher in
the <12-month age
group than in the
12-month age group in all
regions (48 versus
26%;
P = 0.001) and in the United
States (47 versus 13%;
P = 0.001);
the corresponding
differences were not statistically significant
in Eastern and Central
Europe (47 versus 30%) or in Israel (50
versus 13%).
Amoxicillin-resistant
S. pneumoniae was isolated
from 10%
of all patients, and its prevalence was highest in the
<12-month age
group in the United States (37% of 19 patients)
and in the 12- to
23-month age group in Israel (60% of 5 patients)
and Eastern and
Central Europe (12% of 42 patients); however,
these differences were
not significant. Analogous findings were
obtained for
amoxicillin-clavulanate-resistant isolates of
S. pneumoniae.
Erythromycin and trimethoprim-sulfamethoxazole resistance
was highest
in the youngest and oldest children, but these differences
were not
significant.
Resistance patterns and serotypes were determined for 82 isolates of
S. pneumoniae that were intermediately or fully resistant
to
penicillin (Table
6). The most common
serotypes were 6A (24%)
and 23F (21%). The most common pattern was
resistance to penicillin
and trimethoprim-sulfamethoxazole (38% of
intermediately or fully
resistant isolates), found in eight serotypes,
followed by resistance
to penicillin, trimethoprim-sulfamethoxazole,
tetracycline, erythromycin,
and clindamycin (22%), found predominantly
in serotype 6A, and
resistance to penicillin (13%), found in six
serotypes. Thirty-nine
isolates (48%) exhibited resistance to three or
more antimicrobials.
View this table:
[in this window]
[in a new window]
|
TABLE 6.
Antibiotic resistance patterns and serotypes of 23 fully
penicillin-resistant isolates and 59 intermediately
penicillin-resistant isolates of S. pneumoniae
|
|
| |
DISCUSSION |
To our knowledge, this is the largest multinational, single-season
microbiologic study of infants and children with acute otitis media.
Bacterial pathogens were cultured from 62% of the patients who had
acute otitis media as defined by strict diagnostic criteria. As
expected, S. pneumoniae and H. influenzae
predominated, but the prevalence, age distribution, and antibiotic
susceptibility of these species varied among geographic regions.
S. pneumoniae was more likely to be isolated from patients
in Eastern and Central Europe (35% of patients) than from those in
Israel (21%) or the United States (26%). In contrast, the prevalence
of H. influenzae was higher in Israel (27%) and the United
States (26%) than in Eastern and Central Europe (11%). Finally, the
prevalence of M. catarrhalis was highest in the United
States (12%), while the prevalence of S. pyogenes was
highest in Eastern and Central Europe (10%).
While the identity of the organisms is not surprising, our findings, in
agreement with those of other investigators, suggest that resistance
patterns are changing. The proportions of fully or intermediately
penicillin-resistant S. pneumoniae isolates are high,
ranging from 30 to 50% in recent studies (7, 12, 15, 17, 19, 31,
40), each involving 61 to 155 isolates of S. pneumoniae from middle ear fluid. Intermediately
penicillin-resistant isolates predominate in some regions, such as
southern Israel, where Dagan et al. (15) reported that 38%
of S. pneumoniae isolates were intermediately resistant and
only 4% were fully resistant. In contrast, fully resistant isolates
predominate in Paris, where Gehanno et al. (19) reported
that 38% of isolates were fully resistant and only 12% were
intermediately resistant. Numbers of intermediately or fully
penicillin-resistant S. pneumoniae isolates from middle ear
fluid were similar to (15, 24, 40) or higher than (8,
9, 17, 29, 44) those associated with invasive pneumococcal
infections. Of 271 isolates of S. pneumoniae tested in our
study, 30% were intermediately or fully resistant to penicillin and
8% were fully resistant. Interestingly, the prevalence of
intermediately and fully penicillin-resistant S. pneumoniae
isolates from Central and Eastern Europe in our study matched the
prevalence of fully resistant nasopharyngeal isolates from children in
the same countries (4). Finally, 48% of intermediately and
fully penicillin-resistant isolates were resistant to multiple antimicrobial classes in our study.
Only 10% of the isolates of S. pneumoniae were resistant to
amoxicillin or amoxicillin-clavulanate in our study, with no difference in activity between the latter two agents against this species. Doern
et al. (17) reported that many isolates of
penicillin-resistant S. pneumoniae were susceptible to
amoxicillin or amoxicillin-clavulanate; amoxicillin and
amoxicillin-clavulanate were more active against penicillin-resistant
S. pneumoniae isolates than was cefuroxime and nearly as
active as cefotaxime and ceftriaxone (17). Furthermore, Craig and Andes (11) evaluated the ability of currently
approved dosage regimens, including -lactam agents, macrolides, and
trimethoprim-sulfamethoxazole, to provide concentrations above the
MIC90 for at least 40% of the dosing interval.
Amoxicillin-clavulanate and ceftriaxone were considered the best
available antibiotics for covering the bacterial pathogens associated
with otitis media, including intermediately and fully
penicillin-resistant S. pneumoniae (11).
The most frequently isolated pneumococcal serotypes in our study were
6A (24%) and 23F (21%), while serotypes 9V, 14, and 19F collectively
accounted for 37%. These serotypes also predominated in other studies
of intermediately or fully penicillin-resistant S. pneumoniae isolated from middle ear fluid (7, 15, 40), other sites (8, 9, 17, 24, 29, 42, 44), and nasopharyngeal carriers (4, 13, 14).
Resistance to amoxicillin was common among nonpneumococcal organisms.
Thirty-one percent of the isolates of H. influenzae produced
-lactamase, including 47% of those from the United States. Similarly, 51% of the H. influenzae isolates produced
-lactamase in a recent multicenter study of middle ear isolates from
the United States (31). All isolates of M. catarrhalis produced -lactamase in our study and, similarly, in
a study of patients from rural Kentucky (7).
Young age appears to be an important risk factor for isolation of a
bacterial pathogen from middle ear fluid and for antibiotic resistance.
In our study, bacterial isolation was highest for the youngest patients
and declined progressively with increasing age. In addition, the
penicillin resistance of S. pneumoniae was higher in younger
patients and occurred in nearly half of those in the <12-month age
category. In contrast, isolates of S. pyogenes were found
primarily in older children. Although we are not aware of previous
reports of an association between age and the likelihood of isolation
of a bacterial pathogen, others have described an association between
young age and penicillin resistance of S. pneumoniae
isolated from middle ear fluid (7, 40) or from other sites
(8, 9). Hypoimmunogenic serogroups, mainly groups 6, 9, 14, 19, and 23, are most often carried by infants and young children
(4, 14, 18, 25), whereas other serogroups are usually
carried by older patients. Because infants and young children are more
frequently treated with antibiotics, the corresponding serogroups are
more likely to be exposed to antibiotics and therefore may be more
likely to develop resistance than other serogroups.
Our microbiologic findings may have clinical implications because the
selection of antibiotic therapy for intermediately or fully
penicillin-resistant S. pneumoniae infections depends on patient factors, such as site of infection, and on antibiotic factors,
such as route of administration. While serious pneumococcal infections
such as meningitis require treatment with high-dose parenteral
cefotaxime, ceftriaxone, vancomycin, or possibly a carbapenem (18,
25), the need for these antibiotics is not clear in the case of
nonmeningeal infections. In a recent study of patients with
pneumococcal pneumonia from Barcelona (37), parenteral
penicillin therapy produced comparable outcomes and similarly low
mortality, regardless of whether the infection was caused by
penicillin-resistant or -susceptible isolates. The need for parenteral
agents in patients with acute otitis media is especially doubtful
because of the low morbidity, high frequency of spontaneous recovery,
and frequent resolution of clinical signs and symptoms, despite the
persistence of bacteria in middle ear fluid (5, 6, 18).
However, Gehanno et al. (19) and Dagan et al.
(12) reported an increased risk of clinical and
microbiologic failure when oral -lactam antibiotics with reduced
activity against penicillin-resistant S. pneumoniae (i.e.,
cefaclor or cefuroxime axetil) were administered. On the other hand,
the clinical response to amoxicillin-clavulanate therapy was
independent of penicillin susceptibility in children with pneumococcal
otitis media in the clinical analysis (23) of our study. In
addition, our finding of a 23% improvement in the composite
susceptibility of potentially resistant pathogens after addition of
clavulanate to amoxicillin suggests that this combination may be
appropriate for acute otitis media, particularly in the United States,
where -lactamase-producing organisms were most prevalent.
Our findings underscore the need for additional studies to assess the
clinical relevance of our findings. In the meantime, practitioners
should familiarize themselves with local microbiologic surveillance
data. Our findings also underscore the need for vaccines to prevent
colonization with otitis media pathogens, as has been achieved with
H. influenzae type b conjugate vaccines in preventing bacteremia and meningitis due to this organism. While the current pneumococcal polysaccharide vaccines are poorly immunogenic in children
under 3 years of age, conjugate pneumococcal vaccines, which should
include serotypes associated with resistance, should greatly reduce the
spread of these organisms (13) and the occurrence of disease
in infants and young children. Development of vaccines against
untypeable H. influenzae and M. catarrhalis could
have similar efficacy against these species, but this approach has not
been addressed.
| |
ACKNOWLEDGMENTS |
This work was supported by a grant from SmithKline Beecham
Pharmaceuticals, Collegeville, Pa.
We thank the following investigators for enrolling their patients: Drs.
Ashkenazi, Barzilai, Dagan, and Somekh of Israel; Drs. Fekete, Pataki,
Reti, and Votisky of Hungary; Drs. Kovatchev, Manasieva, Pazardjikliev,
Todorov, Ulevinov, and Wrantchewa of Bulgaria; Drs. Antolikova, Hacko,
Hupkova, and Kisska of Slovakia; Drs. Kominek, Navratil, and Slapak of
the Czech Republic; Drs. Balanescu, Florescu, Iorgu, and Mitrea of
Romania; and Drs. Aronovitz, Blatter, Block, Blumer, Fiddes, Giebink,
Harrison, Hoberman, Johnson, and Schwartz of the United States. We also
thank Jim Poupard, SmithKline Beecham Pharmaceuticals, for study
design; Pierre Geslin, Service de Microbiologie, Centre Hospitalier
Intercommunal, Creteil, France, for coordinating transport of isolates
from Europe and Israel; Saralee Bajaksouzian, Department of Pathology,
Case Western Reserve University, Cleveland, Ohio, for technical
assistance with identification and susceptibility testing of bacterial
isolates; Sara M. Debanne and Grace W. Wu, Department of Epidemiology
and Biostatistics, Case Western Reserve University, for statistical analysis; and Cindy W. Hamilton, Virginia Beach, Va., for editorial assistance.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Department of
Pathology, University Hospitals of Cleveland, 11100 Euclid Avenue,
Cleveland, OH 44106. Phone: (216) 844-3484. Fax: (216) 844-5601.
| |
REFERENCES |
| 1.
| Appelbaum, P. C. 1994. Antibiotic-resistant pneumococci facts and fiction. J. Chemother.
6(Suppl. 4):7-15.
|
| 2.
|
Appelbaum, P. C.
1992.
Antimicrobial resistance in Streptococcus pneumoniae: an overview.
Clin. Infect. Dis.
15:77-83[Medline].
|
| 3.
|
Appelbaum, P. C.,
A. Bhamjee,
J. N. Scragg,
A. F. Hallett,
A. J. Bowen, and R. C. Cooper.
1977.
Streptococcus pneumoniae resistant to penicillin and chloramphenicol.
Lancet
ii:995-997.
|
| 4.
|
Appelbaum, P. C.,
C. Gladkova,
W. Hryniewicz,
B. Kojouharov,
D. Kotulova,
F. Mihalcu,
J. Schindler,
L. Setchanova,
N. Semina,
J. Trupl,
S. Tyski,
P. Urbaskova, and M. R. Jacobs.
1996.
Carriage of antibiotic-resistant Streptococcus pneumoniae by children in Eastern and Central Europea multicenter study with use of standardized methods.
Clin. Infect. Dis.
23:712-717[Medline].
|
| 5.
|
Berman, S.
1995.
Otitis media in children.
N. Engl. J. Med.
332:1560-1565[Free Full Text].
|
| 6.
|
Bernstein, J. M.
1995.
Otitis media with effusion: to treat or not to treat?
J. Respir. Dis.
16:88-99.
|
| 7.
|
Block, S. L.,
C. J. Harrison,
J. A. Hedrick,
R. D. Tyler,
R. A. Smith,
E. Keegan, and S. A. Chartrand.
1995.
Penicillin-resistant Streptococcus pneumoniae in acute otitis media: risk factors, susceptibility patterns and antimicrobial management.
Pediatr. Infect. Dis. J.
14:751-759[Medline].
|
| 8.
|
Breiman, R. F.,
J. C. Butler,
F. C. Tenover,
J. A. Elliott, and R. R. Facklam.
1994.
Emergence of drug-resistant pneumococcal infections in the United States.
JAMA
271:1831-1835[Abstract/Free Full Text].
|
| 9.
|
Butler, J. C.,
J. Hofmann,
M. S. Cetron,
J. A. Elliott,
R. R. Facklam,
R. F. Brieman, and The Pneumococcal Sentinel Surveillance Working Group.
1996.
The continued emergence of drug-resistant Streptococcus pneumoniae in the United States: an update from the Centers for Disease Control and Prevention's Pneumococcal Sentinel Surveillance System.
J. Infect. Dis.
174:986-993[Medline].
|
| 10.
|
Centers for Disease Control.
1994.
Drug-resistant Streptococcus pneumoniaeKentucky and Tennessee, 1993.
Morbid. Mortal. Weekly Rep.
43:23-25[Medline], 31.
|
| 11.
|
Craig, W. A., and D. Andes.
1996.
Pharmacokinetics and pharmacodynamics of antibiotics in otitis media.
Pediatr. Infect. Dis. J.
15:255-259[Medline].
|
| 12.
|
Dagan, R.,
O. Abramson,
E. Leibovitz,
R. Lang,
S. Goshen,
D. Greenberg,
P. Yagupsky,
A. Leiberman, and D. M. Fliss.
1996.
Impaired bacteriologic response to oral cephalosporins in acute otitis media caused by pneumococci with intermediate resistance to penicillin.
Pediatr. Infect. Dis. J.
15:980-985[Medline].
|
| 13.
|
Dagan, R.,
R. Melamed,
M. Muallem,
L. Piglansky,
D. Greenberg,
O. Abramson,
P. M. Mendelman,
N. Bohidar, and P. Yagupsky.
1996.
Reduction of nasopharyngeal carriage of pneumococci during the second year of life by a heptavalent conjugate pneumococcal vaccine.
J. Infect. Dis.
174:1271-1278[Medline].
|
| 14.
|
Dagan, R.,
R. Melamed,
M. Muallem,
L. Piglansky, and P. Yagupsky.
1996.
Nasopharyngeal colonization in southern Israel with antibiotic-resistant pneumococci during the first 2 years of life: relation to serotypes likely to be included in pneumococcal conjugate vaccines.
J. Infect. Dis.
174:1352-1355[Medline].
|
| 15.
|
Dagan, R.,
P. Yagupsky,
A. Goldbart,
A. Wasas, and K. Klugman.
1994.
Increasing prevalence of penicillin-resistant pneumococcal infections in children in southern Israel: implications for future immunization policies.
Pediatr. Infect. Dis. J.
13:782-786[Medline].
|
| 16.
|
Debanne, S. M., and D. Y. Rowland.
1983.
The conservative chi-square test for sparse data, p. 705-708.
In
Proceedings of the Business and Economics Section. American Statistical Association, Washington, D.C.
|
| 17.
|
Doern, G. V.,
A. Bruggemann,
H. P. Holley, Jr., and A. M. Rauch.
1996.
Antimicrobial resistance of Streptococcus pneumoniae recovered from outpatients in the United States during the winter months of 1994 to 1995: results of a 30-center national surveillance study.
Antimicrob. Agents Chemother.
40:1208-1213[Abstract].
|
| 18.
|
Friedland, I. R., and G. H. McCracken, Jr.
1994.
Management of infections caused by antibiotic-resistant Streptococcus pneumoniae.
N. Engl. J. Med.
331:377-382[Free Full Text].
|
| 19.
|
Gehanno, P.,
G. Lenoir, and P. Berche.
1995.
In vivo correlates for Streptococcus pneumoniae penicillin resistance in acute otitis media.
Antimicrob. Agents Chemother.
39:271-272[Abstract].
|
| 20.
|
Giebink, G. S.
1992.
Otitis media update: pathogenesis and treatment.
Ann. Otol. Rhinol. Laryngol.
101:21-23.
|
| 21.
|
Hansman, D.,
L. Devitt,
H. Miles, and I. Riley.
1974.
Pneumococci relatively insensitive to penicillin in Australia and New Guinea.
Med. J. Aust.
2:353-356[Medline].
|
| 22.
|
Hansman, D.,
H. Glasgow,
J. Sturt,
L. Devitt, and R. Douglas.
1971.
Increased resistance to penicillin of pneumococci isolated from man.
N. Engl. J. Med.
284:175-177.
|
| 23.
|
Hoberman, A.,
J. L. Paradise,
S. Block,
D. J. Burch,
M. R. Jacobs, and M. I. Balanescu.
1996.
Efficacy of amoxicillin/clavulanate potassium for acute otitis media: relation to Streptococcus pneumoniae susceptibility.
Pediatr. Infect. Dis. J.
15:955-962[Medline].
|
| 24.
|
Hofmann, J.,
M. S. Cetron,
M. M. Farley,
W. S. Baughman,
R. R. Facklam,
J. A. Elliott,
K. A. Deaver, and R. F. Breiman.
1995.
The prevalence of drug-resistant Streptococcus pneumoniae in Atlanta.
N. Engl. J. Med.
333:481-486[Abstract/Free Full Text].
|
| 25.
|
Jacobs, M. R.
1992.
Treatment and diagnosis of infections caused by drug-resistant Streptococcus pneumoniae.
Clin. Infect. Dis.
15:119-127[Medline].
|
| 26.
|
Jacobs, M. R.,
S. Bajaksouzian,
D. J. Burch,
J. Poupard, and P. C. Appelbaum.
1995.
Antimicrobial susceptibility of Streptococcus pneumoniae isolated from patients with acute otitis media in Eastern Europe, Israel and U.S., poster E29.
In
Abstracts of the 35th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 27.
|
Jacobs, M. R.,
D. Burch,
J. Poupard,
G. Moonsammy,
S. Debanne,
P. Appelbaum, and The International Otitis Media Study Group.
1996.
Microbiology of acute otitis mediaresults of an international study of 917 patients, abstr. K26, p. 254.
In
Abstracts of the 36th Interscience Conference on Antimicrobial Agents and Chemotherapy. American Society for Microbiology, Washington, D.C.
|
| 28.
|
Jacobs, M. R.,
H. J. Koornhof,
R. M. Robins-Browne,
C. M. Stevenson,
Z. A. Vermaak,
I. Freiman,
G. B. Miller,
M. A. Witcomb,
M. Isaäcson,
J. I. Ward, and R. Austrian.
1978.
Emergence of multiply resistant pneumococci.
N. Engl. J. Med.
299:735-740[Abstract].
|
| 29.
|
Kaplan, S. L., and The U.S. Pediatric Multicenter Pneumococcal Surveillance Group.
1995.
One-year surveillance of systemic pneumococcal infections in children.
Pediatr. Res.
37:179A.
|
| 30.
|
Kristinsson, K. G.,
M. A. Hjalmarsdottir, and O. Steingrimsson.
1992.
Increasing penicillin resistance in pneumococci in Iceland.
Lancet
339:1606-1607[Medline]. (Letter.)
|
| 31.
|
McLinn, S., and D. Williams.
1996.
Incidence of antibiotic-resistant Streptococcus pneumoniae and beta-lactamase-positive Haemophilus influenzae in clinical isolates from patients with otitis media.
Pediatr. Infect. Dis. J.
15:S3-S9[Medline].
|
| 32.
|
Munoz, R.,
T. J. Coffey,
M. Daniels,
C. G. Dowson,
G. Laible,
J. Casal,
R. Hakenbeck,
M. Jacobs,
J. M. Musser,
B. G. Spratt, et al.
1991.
Intercontinental spread of a multiresistant clone of serotype 23F Streptococcus pneumoniae.
J. Infect. Dis.
164:302-306[Medline].
|
| 33.
|
Murray, B. E.
1994.
Can antibiotic resistance be controlled?
N. Engl. J. Med.
330:1229-1230[Free Full Text].
|
| 34.
|
Murray, P. R.,
E. J. Barron,
M. A. Pfaller,
F. C. Tenover, and R. H. Yolken (ed.).
1995.
Manual of clinical microbiology, 6th ed.
ASM Press, Washington, D.C.
|
| 35.
|
National Committee for Clinical Laboratory Standards.
1993.
Methods for dilution antimicrobial susceptibility tests for bacteria that grow aerobically, 3rd ed. Approved standard M7-A3.
National Committee for Clinical Laboratory Standards, Villanova, Pa.
|
| 36.
|
National Committee for Clinical Laboratory Standards.
1995.
Performance standards for antimicrobial susceptibility tests, sixth informational supplement (M 100-S6).
National Committee for Clinical Laboratory Standards, Villanova, Pa.
|
| 37.
|
Pallares, R.,
J. Liñares,
M. Vadillo,
C. Cabellos,
F. Manresa,
P. F. Viladrich,
R. Martin, and F. Gudiol.
1995.
Resistance to penicillin and cephalosporin and mortality from severe pneumococcal pneumonia in Barcelona, Spain.
N. Engl. J. Med.
333:474-480[Abstract/Free Full Text].
|
| 38.
|
Paradise, J. L.
1995.
Treatment guidelines for otitis media: the need for breadth and flexibility.
Pediatr. Infect. Dis. J.
14:429-435[Medline].
|
| 39.
|
Reichler, M. R.,
A. A. Allphin,
R. F. Breiman,
J. R. Schreiber,
J. E. Arnold,
L. K. McDougal,
R. R. Facklam,
B. Boxerbaum,
D. May,
R. O. Walton, and M. R. Jacobs.
1992.
The spread of multiply resistant Streptococcus pneumoniae at a day care center in Ohio.
J. Infect. Dis.
166:1346-1353[Medline].
|
| 40.
|
Reichler, M. R.,
J. Rakovsky,
A. Sobotová,
M. Slá iková,
B. Hlaváová,
B. Hill,
L. Krajíková,
P. Tarina,
R. R. Facklam, and R. F. Breiman.
1995.
Multiple antimicrobial resistance of pneumococci in children with otitis media, bacteremia, and meningitis in Slovakia.
J. Infect. Dis.
171:1491-1496[Medline].
|
| 41.
|
SAS Institute, Inc.
1989.
SAS/STAT users' guide, version 6, 4th ed.
SAS Institute, Inc., Cary, N.C.
|
| 42.
|
Scott, J. A. G.,
A. J. Hall,
R. Dagan,
J. M. S. Dixon,
S. J. Eykyn,
A. Fenoll,
M. Hortal,
L. P. Jetté,
J. H. Jorgensen,
F. Lamothe,
C. Latorre,
J. T. Macfarlane,
D. M. Shlaes,
L. E. Smart, and A. Taunay.
1996.
Serogroup-specific epidemiology of Streptococcus pneumoniae: associations with age, sex, and geography in 7,000 episodes of invasive disease.
Clin. Infect. Dis.
22:973-981[Medline].
|
| 43.
|
Stephenson, J.
1996.
Icelandic researchers are showing the way to bring down rates of antibiotic-resistant bacteria.
JAMA
275:175[Abstract/Free Full Text].
|
| 44.
|
Welby, P. L.,
D. S. Keller,
J. L. Cromien,
P. Tebas, and G. A. Storch.
1994.
Resistance to penicillin and non-beta-lactam antibiotics of Streptococcus pneumoniae at a children's hospital.
Pediatr. Infect. Dis. J.
13:281-287[Medline].
|
Antimicrobial Agents and Chemotherapy, March 1998, p. 589-595, Vol. 42, No. 3
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
This article has been cited by other articles:
-
Hallstrom, T., Zipfel, P. F., Blom, A. M., Lauer, N., Forsgren, A., Riesbeck, K.
(2008). Haemophilus influenzae Interacts with the Human Complement Inhibitor Factor H. J. Immunol.
181: 537-545
[Abstract]
[Full Text]
-
Stone, K. C., Dagan, R., Arguedas, A., Leibovitz, E., Wang, E., Echols, R. M., Janjic, N., Critchley, I. A.
(2007). Activity of Faropenem against Middle Ear Fluid Pathogens from Children with Acute Otitis Media in Costa Rica and Israel. Antimicrob. Agents Chemother.
51: 2230-2235
[Abstract]
[Full Text]
-
Liu, D.-F., McMichael, J. C., Baker, S. M.
(2007). Moraxella catarrhalis Outer Membrane Protein CD Elicits Antibodies That Inhibit CD Binding to Human Mucin and Enhance Pulmonary Clearance of M. catarrhalis in a Mouse Model. Infect. Immun.
75: 2818-2825
[Abstract]
[Full Text]
-
Samuelsson, M., Hallstrom, T., Forsgren, A., Riesbeck, K.
(2007). Characterization of the IgD Binding Site of Encapsulated Haemophilus influenzae Serotype b. J. Immunol.
178: 6316-6319
[Abstract]
[Full Text]
-
Hallstrom, T., Trajkovska, E., Forsgren, A., Riesbeck, K.
(2006). Haemophilus influenzae Surface Fibrils Contribute to Serum Resistance by Interacting with Vitronectin. J. Immunol.
177: 430-436
[Abstract]
[Full Text]
-
Bauchner, H., Marchant, C. D., Bisbee, A., Heeren, T., Wang, B., McCabe, M., Pelton, S., Boston-Based Pediatric Research Group,
(2006). Effectiveness of Centers for Disease Control and Prevention Recommendations for Outcomes of Acute Otitis Media. Pediatrics
117: 1009-1017
[Abstract]
[Full Text]
-
Westman, E., Lundin, S., Hermansson, A., Melhus, A.
(2004). {beta}-Lactamase-Producing Nontypeable Haemophilus influenzae Fails To Protect Streptococcus pneumoniae from Amoxicillin during Experimental Acute Otitis Media. Antimicrob. Agents Chemother.
48: 3536-3542
[Abstract]
[Full Text]
-
Blasi, F.
(2004). Atypical pathogens and respiratory tract infections. Eur Respir J
24: 171-182
[Abstract]
[Full Text]
-
Dagan, R., Garau, J.
(2004). Appropriate Use of Antibiotics: Focus on Acute Otitis Media. CLIN PEDIATR
43: 313-321
-
Low, D. E., Pichichero, M. E., Schaad, U. B.
(2004). Optimizing Antibacterial Therapy for Community-Acquired Respiratory Tract Infections in Children in an Era of Bacterial Resistance. CLIN PEDIATR
43: 135-151
[Abstract]
-
Zhang, Q., Choo, S., Finn, A.
(2002). Immune Responses to Novel Pneumococcal Proteins Pneumolysin, PspA, PsaA, and CbpA in Adenoidal B Cells from Children. Infect. Immun.
70: 5363-5369
[Abstract]
[Full Text]
-
Giebink, G. S.
(2001). The Prevention of Pneumococcal Disease in Children. NEJM
345: 1177-1183
[Full Text]
-
Choo, S, Finn, A
(2001). Current topic: New pneumococcal vaccines for children. Arch. Dis. Child.
84: 289-294
[Full Text]
-
Thrane, N., Olesen, C., Sorensen, H. T., Schonheyder, H. C.
(2001). Individual use of antibiotics and prevalence of {beta}-lactamase production among bacterial pathogens from middle ear fluid. J Antimicrob Chemother
47: 211-214
[Abstract]
[Full Text]
-
Gehanno, P., Nguyen, L., Barry, B., Derriennic, M., Pichon, F., Goehrs, J. M., Berche, P.
(1999). Eradication by Ceftriaxone of Streptococcus pneumoniae Isolates with Increased Resistance to Penicillin in Cases of Acute Otitis Media. Antimicrob. Agents Chemother.
43: 16-20
[Abstract]
[Full Text]
Top
Abstract
Introduction
