Background Ear infections are a common cause of illness during the first two years of life. New conjugate vaccines may be able to prevent a substantial portion of cases of acute otitis media caused by Streptococcus pneumoniae. Methods We enrolled 1662 infants in a randomized, double-blind efficacy trial of a heptavalent pneumococcal polysaccharide conjugate vaccine in which the carrier protein is the nontoxic diphtheria-toxin analogue CRM197. The children received either the study vaccine or a hepatitis B vaccine as a control at 2, 4, 6, and 12 months of age. The clinical diagnosis of acute otitis media was based on predefined criteria, and the bacteriologic diagnosis was based on a culture of middle-ear fluid obtained by myringotomy. Results Of the children who were enrolled, 95.1 percent completed the trial. With the pneumococcal vaccine, there were more local reactions than with the hepatitis B vaccine but fewer than with the combined whole-cell diphtheria–tetanus–pertussis and Haemophilus influenzae t...

Efficacy of a Pneumococcal Conjugate Vaccine against Acute Otitis Media

ContextPneumococcal polysaccharide vaccine is recommended for elderly persons
and adults with certain chronic illnesses. Additionally, a recently licensed
pneumococcal 7-valent conjugate vaccine has been recommended for use in young
children and could dramatically change the epidemiology of pneumococcal disease.ObjectivesTo assess pneumococcal disease burden in the United States, estimate
the potential impact of new vaccines, and identify gaps in vaccine recommendations.Design and SettingAnalysis of data from the Active Bacterial Core Surveillance (ABCs)/Emerging
Infections Program Network, an active, population-based system in 9 states.PatientsA total of 15 860 cases of invasive pneumococcal disease occurring
between January 1, 1995, and December 31, 1998.Main Outcome MeasuresAge- and race-specific pneumoccocal disease incidence rates per 100 000
persons, case-fatality rates, and vaccine preventability.ResultsIn 1998, overall incidence was 23.2 cases per 100 000, corresponding
to an estimated 62 840 cases in the United States. Incidence was highest
among children younger than 2 years (166.9) and adults aged 65 years or older
(59.7). Incidence among blacks was 2.6 times higher than among whites (95%
confidence interval [CI], 2.4-2.8). Overall, 28.6% of case-patients were at
least 65 years old and 85.9% of cases in this age group were due to serotypes
included in the 23-valent polysaccharide vaccine; 19.3% of case-patients were
younger than 2 years and 82.2% of cases in this age group were due to serotypes
included in the 7-valent conjugate vaccine. Among patients aged 2 to 64 years,
50.6% had a vaccine indication as defined by the Advisory Committee on Immunization
Practices (ACIP). The case-fatality rate among patients aged 18 to 64 years
with an ACIP indication was 12.1% compared with 5.4% for those without an
indication (relative risk, 2.2; 95% CI, 1.7-2.9).ConclusionsYoung children, elderly persons, and black persons of all ages are disproportionately
affected by invasive pneumococcal disease. Current ACIP recommendations do
not address a subset of persons aged 18 to 64 years but do include those at
highest risk for death from invasive pneumococcal disease.

https://jamanetwork.com/journals/jama/articlepdf/193707/joc01710.pdf

Epidemiology of Invasive Streptococcus pneumoniae Infections in the United States, 1995-1998: Opportunities for Prevention in the Conjugate Vaccine Era

Background. Timely information on the bacteriology of primary, noncomplicated acute otitis media (AOM) may today be needed more than ever, because of the increasing antimicrobial resistance of its major bacterial causes and because of the potential of new pneumococcal and other bacterial vaccines for prevention of AOM. Methods. The study followed 329 children from 2 to 24 months of age at scheduled healthy visits and sick visits at the study clinic. Whenever AOM was diagnosed during the follow-up, myringotomy was performed and middle ear fluid was aspirated for bacterial culture. Results. At least one middle ear fluid sample was available from 772 AOM events;Streptococcus pneumoniae (Pnc) was isolated in 201 (26%), Moraxella catarrhalis (Mc) in 177 (23%) and Haemophilus influenzae (Hi) in 174 events (23%). The incidence of Pnc AOM peaked at 12 months of age, whereas the incidence of Mc AOM showed the first peak at 6 months and Hi AOM at 20 months. Pnc AOM showed less prominent seasonality in occurrence than Mc and Hi AOM. Hi was a rare cause of the first 2 AOM episodes (13%) but became increasingly common from the third episode on (32% on average). Conclusions. Pnc, Mc and Hi were almost equally common findings in AOM. Pnc seems to be the most pathogenic of these three, the role of Mc is increasing and Hi is clearly associated with recurrent AOM.

Bacteriology of acute otitis media in a cohort of Finnish children followed for the first two years of life

Conjugation of pneumococcal polysaccharide antigens to a protein carrier may improve protective immunity after vaccination of young children, an age group with high incidence of Streptococcus pneumoniae infection and poor immune responses to polysaccharide vaccines. To identify serotypes most commonly associated with infection in young children, pneumococcal isolates were serotyped from 3884 children < 6 years old (including 3007 < 2 years old) with pneumococcal bacteremia (n = 3169), meningitis (n = 401), or otitis media (n = 314). The isolates were submitted as part of a national surveillance during 1978-1994. Seven serotypes (14, 6B, 19F, 18C, 23F, 4, and 9V) accounted for 3045 isolates (78%). A conjugate pneumococcal vaccine protecting against these seven serotypes and serologically cross-reactive serotypes could potentially prevent 86% of bacteremia and 83% of meningitis but only 65% of otitis media cases. The proportion of isolates covered by such a vaccine increased from 78% to 87% during 1978-1994. Surveillance for pneumococcal serotypes causing infection is needed to detect shifts in serotype distribution over time.

Serotype Distribution of Streptococcus pneumoniae Infections among Preschool Children in the United States, 1978–1994: Implications for Development of a Conjugate Vaccine

Objectives/Hypothesis Bacteriologic studies of otitis media with effusion (OME) using highly sensitive techniques of molecular biology such as the polymerase chain reaction have demonstrated that traditional culturing methods are inadequate to detect many viable bacteria present in OME. The presence of pathogens attached to the middle-ear mucosa as a bacterial biofilm, rather than as free-floating organisms in a middle-ear effusion, has previously been suggested to explain these observations. The suggestion has been speculative, however, because no visual evidence of such biofilms on middle-ear mucosa has heretofore been collected. The hypotheses motivating the current study were: 1) biofilms of nontypable Hemophilus influenzae will form on the middle-ear mucosa of chinchillas in an experimental model of OME, 2) these biofilms will exhibit changes in density or structure over time, and 3) biofilms are also present on tympanostomy tubes in children with refractory post-tympanostomy otorrhea. The objective of this study was to collect visual evidence of the formation of bacterial biofilms in these situations.



Study Design Laboratory study of bacteriology in an animal model and on medical devices removed from pediatric patients.



Methods Experimental otitis media was induced in chinchillas by transbullar injection of nontypable H. influenzae. Animals were killed in a time series and the surface of the middle-ear mucosa was examined by scanning electron microscopy (SEM) for the presence of bacterial biofilms. Adult and fetal chinchilla uninfected controls were similarly examined for comparison. In addition, tympanostomy tubes that had been placed in children's ears to treat OME and removed after onset of refractory otorrhea or other problems were examined by SEM and by confocal scanning laser microscopy for bacterial biofilms, and compared with unused control tubes.



Results Bacterial biofilms were visually detected by SEM on the middle-ear mucosa of multiple chinchillas in which H. influenzae otitis media had been induced. Qualitative evaluation indicated that the density and thickness of the biofilm might increase until at least 96 hours after injection. The appearance of the middle-ear mucosa of experimental animals contrasted with that of uninjected control animals. Robust bacterial biofilms were also visually detected on tympanostomy tubes removed from children's ears for clinical reasons, in contrast with unused control tubes.



Conclusions Bacterial biofilms form on the middle-ear mucosa of chinchillas in experimentally induced H. influenzae otitis media and can form on tympanostomy tubes placed in children's ears. Such biofilms can be directly observed by microscopy. These results reinforce the hypothesis that the bacterial aggregates called biofilms, resistant to treatment by antibiotics and to detection by standard culture techniques, may play a major etiologic role in OME and in one of its frequent complications, post-tympanostomy otorrhea.

Candidate's Thesis: Direct Evidence of Bacterial Biofilms in Otitis Media

Data collected from 1980 to 1989 by investigators at the Pittsburgh Otitis Media Research Center were examined to detect changes over time in the prevalence of bacteria isolated from middle ear effusions in patients with otitis media. The organisms isolated most commonly from the 7396 effusions cultured at the center were Streptococcus pneumoniae and Haemophilus influenzae. S. pneumoniae predominated in the subgroup of patients with acute otitis media, whereas H. influenzae was isolated most frequently from patients with otitis media with effusion. The most notable changes to occur during the 10-year period were a statistically significant increase in the prevalence of S. pneumoniae in patients with acute otitis media and a progressive rise in the percentage of beta-lactamase-producing strains of H. influenzae and Moraxella (Branhamella) catarrhalis. The latter finding suggests the need for therapeutic alternatives to amoxicillin, which is not active against beta-lactamase-producing organisms, when these organisms are suspected or cultured from the middle ear.

Lillian M. Martin

Papers

Ten-year review of otitis media pathogens.