Share this article on:

Evolving Microbiology and Molecular Epidemiology of Acute Otitis Media in the Pneumococcal Conjugate Vaccine Era

Pichichero, Michael E. MD*; Casey, Janet R. MD

The Pediatric Infectious Disease Journal: October 2007 - Volume 26 - Issue 10 - p S12-S16
doi: 10.1097/INF.0b013e318154b25d

Abstract: The addition of the 7-valent pneumococcal conjugate vaccine (PCV7) to the routine immunization schedule in the United States for infants has produced a much more favorable impact on the incidence of acute otitis media (AOM) than anticipated. Because the serotypes included in PCV7 were those most frequently expressing antibiotic resistance in 2001, predictions were made that up to 98% of pneumococcal AOM episodes would be caused by penicillin susceptible strains. However, recent studies have shown that the benefits of PCV7 are becoming eroded. Replacement serotypes of pneumococci have emerged, expressing polysaccharide capsules different from those included in PCV7, with increasing frequency. These replacement strains are coming to dominate in the nasopharynx and in AOM isolates (and in invasive disease). Expansion in the isolation of serotypes 3, 7F, 15B/C/F, 19A, 22F, 33F, and 38 has been described in various surveillance systems. Pneumococcal strains expressing non-PCV7 capsular serotypes also appear to be rapidly acquiring resistance to penicillin and other antibiotics. Emergence of strains of pneumococci expressing non-PCV7 capsular serotypes is occurring by multiple mechanisms including capsular switching as suggested by molecular epidemiology studies. Expansion of the number of serotypes included in pneumococcal conjugate vaccines is needed to sustain a long-term benefit from immunization against these bacteria.

From the Departments of *Microbiology and Immunology; and †Pediatrics, University of Rochester, Rochester, New York.

Accepted for publication July 17, 2007.

The authors' studies on pneumococcal AOM epidemiology is supported by the Thrasher Research Foundation; and on pneumococcal AOM molecular epidemiology by Wyeth.

Michael E. Pichichero, MD has indicated that he has received grant/research support from Abbott, GlaxoSmithKline, MedImmune, Sanofi-Aventis, Sanofi-Pasteur; Honoraria from Abbott, GlaxoSmithKline, Sanofi-Aventis, Sanofi-Pastuer, and Wyeth.

Address for correspondence: Michael E. Pichichero, MD, Professor of Microbiology and Immunology, University of Rochester, 601 Elmwood Avenue, Box 672, Rochester, NY 14642. E-mail:

CME Overview

Accreditation and Certification

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Boston University School of Medicine and The Physicians Academy for Clinical and Management Excellence. Boston University School of Medicine is accredited by the ACCME to provide continuing medical education for physicians.

Boston University School of Medicine designates this educational activity for a maximum of 1.25 AMA PRA Category 1 Credits TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Statements of credit will be provided by mail within six weeks following activity participation and upon completion and return of evaluation form to Boston University School of Medicine at BUSM CME, E.PCV11PA07, 715 Albany St., A-305, Boston, MA 02118, Fax: 617-638-4905. For CME questions, please call BUSM CME at 617-638-4605.

Intended Audience

This activity has been designed for adult and pediatric clinical infectious disease specialists, microbiologists, and vaccinologists. It will provide material that is relevant to the concerns of clinicians and researchers who are interested in the treatment and management of infectious disease and how these strategies impact on patient outcomes.

Educational Needs Addressed

Acute otitis media (AOM) is one of the most common afflictions affecting children under the age of 5 years of age. In developed countries, nearly every child becomes a nasopharyngeal carrier of S. pneumoniae (SP) during the first year of life and the pathogen persists in the nasopharynx, which is significant as most cases of AOM result from a middle ear reflux from the nasopharynx. In developing countries, SP is one of the most notable bacterial pathogens for children under 6 months of age. Based upon available data, SP is estimated to kill one million children under five years of age worldwide. New vaccines are needed to provide the protective immunity necessary against the large number of SP serotypes that exist globally. The changing microbiology of SP disease, with a shift from SP to non-typeable H. influenzae (NTHi), likely based on the impact of currently available vaccine, demonstrates the even greater need for education on the use of existing and emergent conjugate vaccines in treating AOM. Success will also require expanded coverage against additional otopathogens, especially NTHi. A meaningful educational and action-oriented approach will enhance the global ability to prevent and treat AOM and its sequelae.

Educational Objectives

Upon completion of this educational activity participant should be better able to:

Release date   October 1, 2007   Expiration date   September 30, 2008

Estimated Time to Complete This Activity

1 hour and 15 minutes

Method of Participation

In order to successfully complete this activity, participants are required to read the entire supplement and complete and submit the test answer sheet by September 30, 2008. CME credit will be awarded provided a score of 70% or better is achieved. Statements of credit will be provided by mail within six weeks of receipt of the test answers to those who successfully complete the examination.

Course Director

Stephen I. Pelton, MD

Chief, Pediatric Infectious Disease

Boston Medical School

Professor of Pediatrics and Epidemiology

Boston University School of Medicine


Lauren O. Bakaletz, PhD

Professor of Pediatrics

The Ohio State University, College of Medicine

Director, Center for Microbial Pathogenesis

Columbus Children's Research Institute

Janet R. Casey, MD

Legacy Pediatrics, PLLC

University of Rochester, School of Medicine and Dentistry

Amanda J. Leach, PhD

Ear and Respiratory Health Unit

Tropical and Infectious Diseases Division

Menzies School of Health Research

Charles Darwin University

Eugene Leibovitz, MD

Pediatric Infectious Disease Unit

Soroka Medical Center and The Faculty of Health Sciences

Ben-Gurion University of the Negev

Peter S. Morris, MBBS, FRACP, PhD

Deputy Leader of Child Health Division

Menzies School of Health Research

Charles Darwin University

Associate Professor of Pediatrics

Flinders University

Michael E. Pichichero, MD

Professor of Microbiology and Immunology

Professor of Pediatrics and Professor of Medicine

University of Rochester, School of Medicine and Dentistry

Disclosure Policy

Boston University School of Medicine asks all individuals involved in the development and presentation of Continuing Medical Education (CME) activities to disclose all relationships with commercial interests. This information is disclosed to CME activity participants. Boston University School of Medicine has procedures to resolve apparent conflicts of interest. In addition, faculty members are asked to disclose when any discussion of unapproved use of pharmaceuticals and devices is being discussed.


Stephen I. Pelton, MD has indicated that he has received grant/research support from Sanofi-Aventis; serves as a consultant for GlaxoSmithKline and Wyeth; and has been on the Speakers Bureau for Sanofi-Aventis. Dr. Pelton does not plan to discuss off-label/investigational uses of commercial products.

Amanda J. Leach, PhD has no relevant financial relationships to disclose. Dr. Leach does not plan to discuss off-labeled/investigational uses of commercial products.

Peter S. Morris, PhD has no relevant financial relationships to disclose. Dr. Morris does not plan to discuss off-label/investigational uses of commercial products.

Eugene Leibovitz, MD has no relevant financial relationships to disclose. Dr. Leibovitz does not plan to discuss off-label/investigational uses of commercial products.

Michael E. Pichichero, MD has indicated that he has received grant/research support from Abbott, GlaxoSmithKline, MedImmune, Sanofi-Aventis, and Sanofi-Pasteur; Honoraria from Abbott, GlaxoSmithKline, Sanofi-Aventis, and Sanofi-Pastuer. Dr. Pichichero does not plan to discuss off-label/investigational uses of commercial products.

Janet R. Casey, MD has indicated that she has been a single-day consultant for Abbott, GlaxoSmithKline, Sanofi-Aventis, and Sanofi-Pasteur. Dr. Casey does not plan to discuss off-label/investigational uses of commercial products.

Lauren Bakaletz, PhD has indicated that she has received grant/research support from GlaxoSmithKline Biologicals. Dr. Bakaletz does not plan to discuss off-label/investigational uses of commercial products.

Planning Committee: Mary Deering, Barry A. Fiedel, PhD, Heidi J. Katz, RPh, Amy Klopfenstien, MS and Kelly McPherson of Physicians Academy, along with Julie White, MS, Elizabeth Gifford and Elizabeth D. Barnett, MD of Boston University School of Medicine have no relevant financial relationships to disclose.

These materials and all other materials provided in conjunction with continuing medical education activities are intended solely for purposes of supplementing continuing medical education programs for qualified health care professionals. Anyone using the materials assumes full responsibility and all risk for their appropriate use. Trustees of Boston University makes no warranties or representations whatsoever regarding the accuracy, completeness, currentness, noninfringements, merchantability or fitness for a particular purpose of the materials. In no event will Trustees of Boston University be liable to anyone for any decision made or action taken in reliance on the materials. In no event should the information in the materials be used as a substitute for professional care.

For questions regarding CME, please contact

Boston University Privacy Policy:

Back to Top | Article Outline


Eskola et al were the first to examine the efficacy of pneumococcal conjugate vaccine (PCV) 7 against acute otitis media (AOM).1 The Finnish investigators reported that the vaccine reduced the number of episodes of AOM from any cause by 6% (95% CI, −4% to 16%). The vaccine also reduced culture-confirmed pneumococcal AOM episodes by 34% (95% CI, 21%–45%) and the number of episodes due to the serotypes contained in the vaccine by 57% (95% CI, 44%–67%) (Table 1). The number of episodes that were attributed to serotypes that were cross-reactive with those in the PCV7 was reduced by 51% whereas the number of episodes due to all other serotypes increased by 33%.



The study by Fireman et al from the Kaiser Permanente Research Group in Oakland, California, was the second pivotal trial to examine the impact of PCV7 on the incidence of AOM including frequent AOM and tympanostomy tube procedures.2 The Kaiser group evaluated 37,868 children who had been randomized to receive PCV7 or control in a double-blind trial. Children given PCV7 had fewer otitis visits than control children in every age group, sex, race, and season examined. In children who completed the primary series, PCV7 reduced otitis media visits by 7.8% (95% CI, 5.4%–10.2%) and antibiotic prescriptions by 5.7% (95% CI, 4.2%–7.2%). Frequent otitis was reduced by amounts that increased with otitis frequency from a 10% reduction in the risk of 3 visits to a 20% reduction in the risk of 10 visits within a 6-month period. Tympanostomy tube placements were reduced by 24% (95% CI, 12%–35%) (Table 1). In the Finnish OM study, vaccine efficacy in preventing tympanostomy tube placement was only 4% (95% CI, −19% to 23%); however, subsequent follow-up after 24 months of age found that the rate of surgery was 3.5 per 100 person years in the PCV7-vaccinated and 5.7 per 100 person years in the control children, giving a vaccine efficacy for tympanostomy tube placement of 39% (95% CI, 4%–61%) (Table 1).3 The authors speculated that expanded access to tympanostomy tube placement during the first 24 months may have impacted on the early results.

Two prospective studies from the otitis media research centers in Rochester, New York and Bardstown, Kentucky, published in 2004, compared the predominant otopathogens among children undergoing tympanocentesis post-PCV7 introduction (2001–2003) compared with the pre-PCV introduction (1990s).4,5 The studies involved primarily children less than 2 years of age with AOM antibiotic treatment failure (AOMTF) and/or recurrent AOM undergoing tympanocentesis for clinical indications. AOMTF and recurrent AOM were observed to decrease by 24% after the introduction of PCV7, and the proportion of AOM caused by Streptococcus pneumoniae serotypes contained in the PCV7 vaccine declined by about 50% (Tables 1 and 2).4,5 In conjunction with the decline in pneumococcal AOMTF and recurrent pneumococcal AOM, Haemophilus influenzae became the predominant organism causing these infections.



Poehling et al presented a population-based study of the impact of PCV7 in young children by evaluating data from the Tennessee Medicaid database and the database of 3 commercial insurance plans in Rochester, New York.6 The investigators measured annual rates of medical visits for pneumococcal-related diseases including otitis media. There was a significant reduction in otitis media visits, declining by 118 and 430 per 1000 children in Tennessee and Rochester, New York, respectively. The authors concluded that the addition of PCV7 to the childhood immunization schedule was associated with a much greater reduction in otitis media than the previously reported reductions in clinical trials using culture-confirmed disease end points. Using the National Ambulatory Medical Care Survey (NAMCS), Grijalva et al also examined rates of ambulatory visits for otitis media comparing the timespan 1994–1999 (pre-PCV7) and 2002–2003 (post-PCV7).7 After the introduction of PCV7, otitis media visits declined by 20% in children aged less than 2 years. This decline represented 246 fewer otitis media visits per 1000 children aged less than 2 years, annually (Table 1).

Back to Top | Article Outline


In 2001 Jolaba et al examined the antimicrobial susceptibility of PCV7 serotypes of S. pneumoniae isolated from children with AOM.8 Of the 418 isolates studied, 84% belonged to PCV7-related serogroups, whereas 16% belonged to nonvaccine-related serogroups (Table 2). Serotype 3 was observed to account for 59% of the nonvaccine-related serogroups. In addition, 93% of the isolates from children aged ≤3 years belonged to serotypes that were included in or related to PCV7 vaccine. Most of the isolates (98%–100%) recovered from middle ear fluid of children with AOM that were resistant to the antimicrobial agents tested were included in the PCV7 vaccine. The authors concluded that PCV7 could, therefore, potentially provide protection against all but 1 (serotype 3) of the common AOM-associated pneumococcal serogroup infections as well as against 98% of the antibiotic-resistant isolates. In 2003, Finkelstein et al evaluated children who were aged less than 7 years residing in the greater Boston area during the time frame of 2001.9 Of the pneumococcal isolates from the nasopharynx (NP), nonsusceptibility to penicillin was more common in the PCV7 strains (45%) and potentially cross-reactive strains (51%) than in the non-PCV7 serotype (8%) (Table 2). In another Boston multicommunity study, pneumococcal antibiotic resistance was common and was most frequently found in PCV7-included serotypes and PCV7 serogroup strains isolated from the NP, leading the authors to conclude that the long-term impact of PCV7 immunization on antibiotic-resistant pneumococcal infections could be profound.10

Back to Top | Article Outline


As a consequence of the apparent favorable impact of PCV7 on AOM incidence and microbiology and antibiotic resistance among remaining strains, the topic of AOM management in an era of PCV vaccination was addressed in reviews in 2002 and 2003 by Pelton and Harrison.11,12 Both authors suggested that the potential effect of a fully implemented PCV vaccine schedule on AOM infections would be remarkable; clinical success rates of various antimicrobials used the in the treatment of AOM in children fully vaccinated would increase. Both raised the question of potential serotype substitution in children with AOM and the possibility of an increased incidence of infection with H. influenzae in children immunized with PCV7.

Back to Top | Article Outline


In a study of Alaska children, the proportion of children who were up to date for age with respect to PCV7 vaccination increased from 0% in 2000 to 55% in 2002.13 Carriage of PCV7-type pneumococci decreased by 43%. Risk of carriage of PCV7-type pneumococci was lower in each year of study. Introduction of PCV7 into routine infant immunization in the Alaskan community that had a high prevalence of microbial-resistant pneumococci seemed to reduce transmission of PCV7 vaccine serotypes and related pneumococci, but had no impact on the overall carriage of pneumococci or carriage of penicillin nonsusceptible S. pneumoniae (PNSP) (Table 3). Pelton et al sought to identify changes in NP colonization and in antimicrobial susceptibility among S. pneumoniae organisms after introduction of PCV7. During the 3-year post-PCV7 introduction study period (October 2000–September 2003), NP colonization with vaccine serotypes declined from 22% to 2%, but nonvaccine serotypes increased from 7% to 16% (Table 3). The marked declines in vaccine serotype NP carriage of PCV7 serotypes among young children was encouraging; but the coincident rise of nonvaccine serotypes raised concerns for the future. Importantly, however, shifts in antimicrobial susceptibility were not observed. Rates of antibiotic resistance of S. pneumoniae isolates to penicillin, amoxicillin, azithromycin, and trimethoprim-sulfamethoxazole were 29.3%, 2.2%, 26.5%, and 28.1% respectively.



In a subsequent study of the 2001–2004 NP specimens from Massachusetts children of a similar population, Huang et al reported that PCV7 serotypes decreased from 36% to 14% and non-PCV7 serotypes increased from 34% to 55% (Table 3).10 Overall carriage of pneumococci did not change, nor did carriage of potentially cross-reactive serotypes. The most common non-PCV7 serotypes isolated from NP samples were serotypes 11, 15, and 29. A new finding of the study was a substantial increase in penicillin nonsusceptibility from 8% to 25% in non-PCV7 serotypes; 35% of strains were highly resistant to penicillin. At the same time, penicillin nonsusceptibility increased slightly from 45% to 56% among PCV7 serotypes while remaining stable among PCV7 potentially cross-reactive strains. The shift towards increased carriage of nonvaccine serotypes raised concern and led the authors to suggest vigilance in monitoring changes in the epidemiology of pneumococcal disease.

Back to Top | Article Outline


The Centers for Disease Control and Prevention published an update in 2006 on their monitoring of serotypes and clonal associations among pneumococci that were occurring as an adaptation to the selective pressures exerted by PCV7.15 The incidence of invasive disease due to non-PCV7 serogroups together with serotype 19A increased significantly. Among the non-PCV7 serogroups, newly emerging clones were uncommon but a significant expansion of already established clones occurred for serotypes 3, 7F, 15B/C and F, 19A, 22F, 33F, and 38. S. pneumoniae are able to switch their serotypes through serotype capsular transformation. Pneumococci that have switched capsular serotypes can be found by various molecular subtyping techniques, including multi-locus serotyping (MLST) and pulsed-field gel electrophoresis (PFGE). Using PFGE, MLST, and penicillin binding protein 2B amplicon restriction profiles, pneumococcal isolates recovered from children with AOM during the timeframe from 1999 through 2001 were studied by McEllistrem et al.17 The proportion of nonvaccine serotypes was observed to increase from 14.8% to 36.5% (P < 0.01). Among children who received at least 2 doses of the PCV7 vaccine, 46.7% of the isolates had nonvaccine serogroups compared with 20.8% of the isolates from the children who did not get PCV7 vaccine (P = 0.05). Overall the serogroups involved in capsular switching were 6 and 19; 6, 14, and 35; 15 and 19; and 19 with 23F. In 1999 and 2001, 30.8% and 26.1% of the nonvaccine serogroups were implicated in capsular switching.

Back to Top | Article Outline


Using antibiotic susceptibility patterns and molecular typing by PFGE, Porat et al studied 46 NP and middle ear fluid (MEF) isolates expressing serotype 11A, 45 MEF isolates expressing serotype 15B/C, and 57 MEF isolates expressing serotype 19F.18 Most of these isolates were nonsusceptible to penicillin. Penicillin-nonsusceptible pneumococcal clones of serotypes not related to those included in the PCV7 vaccine seemed to be derived from capsular switching of vaccine-related serotypes. Of particular concern in this study was detection of a serotype 11A variant that had successfully acquired a capsular type from the International Spanish 9V clone that is multiresistant to antibiotics. These observations, made in a setting where PCV7 was not in use, demonstrated that selective pressure from the vaccine is only 1 potential precipitant for these events.

Hanage et al examined the diversity in antibiotic resistance among nonvaccine serotypes of S. pneumoniae NP carriage isolates in the post-PCV era.19 In response to the selective pressure of PCV7, increased asymptomatic carriage of antibiotic nonsusceptible nonvaccine types was observed. Possible mechanisms evaluated included de novo acquisition of resistance, serotype switching, introduction of new clones, and/or expansion of existing clones. The investigators found no evidence of penicillin resistance due to either serotype switching or de novo acquisition. Nonetheless, resistance increased through the expansion of previously recognized clones of non-PCV7 types; particularly the serotypes 19A, 15A, and 35B. The authors concluded that the decreased prevalence of antibiotic resistance that followed the introduction of PCV7 would likely be partially eroded over time as vaccine-included serotypes were replaced by resistant clones of nonvaccine types. The authors questioned the clinical significance of the finding as this would depend on the pathogenic potential of replacing clones to cause local disease, ie, AOM or invasive disease.

Because cases of invasive pneumococcal disease due to serotype 19A among children less than 5 years of age were identified in ABC surveillance system between January 2003 and June 2004, Pai et al20 characterized these strains by serotyping antibiotic susceptibility and PFGE. The rate of serotype 19A-invasive pneumococcal disease in children aged less than 5 years increased significantly from 2.6 cases per 100,000 population pre-PCV7 to 6.5 cases per 100,000 population post-PCV7. This was accompanied by significant increases in penicillin nonsusceptibility and multidrug resistance among serotype 19A isolates. As was observed during the pre-PCV7 era, clonal complex MLST199 predominated within serotype 19A, representing about 70% of invasive serotype 19A isolates from children aged less than 5 years during 2003–2004. New serotype 19A genotypes were observed during 2003–2004, including 6 new clonal complexes that were not found among pneumococcal serotype 19A isolates pre-PCV7.

In 2007, Farrell et al reported the serotype distribution, PCV7 coverage and antimicrobial susceptibility among S. pneumoniae isolates collected from children 0 to 14 years of age in 2000–2001 (N = 2033 isolates), from 2002–2003 (N = 1740 isolates), and from 2003–2004 (N = 1591).21 The proportion of isolates covered by PCV7 vaccine serotypes decreased from 2000–2001 (65.5%) to 2002–2003 (34.7%) and to 2003–2004 (27.0%) (P < 0.0001). The most common serotypes in 2004 were nonvaccine types 19A, 6A, 3, 15, and 35B as well as vaccine serotype 19F. Antimicrobial resistance rates comparing 2000–2001 to 2003–2004 among the nonvaccine serotypes from respiratory tract sites increased for penicillin-resistant (PRSP) from 12.7% to 16.1%, for penicillin intermediate-resistance S. pneumoniae (PISP) from 20.1% to 31.5%, for erythromycin from 21.2% to 31.6%, for amoxicillin/clavulanate from 1.4% to 5.8%, and for multidrug resistance from 24.6% to 31.6%.

At the Otitis Media Research Center in Rochester, New York, our group has continued to monitor the evolving microbiology and molecular epidemiology of pneumococcal AOM in the PCV7 era. Since our publications of data for the timespan 1998–2003, we have observed a trend for increasing isolation of S. pneumoniae between 2004 and 2006, although H. influenzae remains the predominant organism.4 An increasing percentage of AOM with cases caused by pneumococci are due to organisms not included among the PCV7 serotypes. The non-PCV7 serotypes isolated in 2005–2006 were predominantly PRSP and some strains were multiresistant. The most frequent isolate was a multiresistant serotype 19A. As in our previous study, these isolates were obtained by tympanocentesis, mostly from children aged less than 2 years, PCV7 vaccinated, with AOMTF or persistent AOM.4

Back to Top | Article Outline


Temime et al using mathematical modeling predicted that the PCV7 vaccine would induce a decrease in carriage of vaccine-type pneumococci to very low levels, but that because of serotype replacement, the effects of PCV7 vaccination would not be sustained in the long term; and, almost simultaneously, nonvaccine type pneumococci would spread in the community.22 Thus, their model predicted that there would be a short-term decrease in the overall carriage rate of pneumococci followed by, after a few years, a renewed, although limited, increase. Their model predicted that vaccination with PCV7 would not affect the extent to which antibiotic resistance was selected. The authors concluded that because of serotype replacement the effects of PCV7 vaccination would not be sustained in the long term.

The benefits of PCV7 with respect to reducing invasive pneumococcal disease (IPD) and pneumococcal AOM are clear. However the initial reduction in PNSP that occurred among IPD and AOM isolates seems to be eroding over time. Studies of NP carriage and AOM have recently demonstrated an increase in the proportion of PNSP. Molecular epidemiologic studies have provided evidence that the emergence of non-PCV7 serotypes as important pathogens has begun to occur and these non-PCV7 serotypes are appearing as a consequence of several mechanisms, including capsular switching.

Back to Top | Article Outline


1.Eskola J, Kilpi T, Palmu A, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Eng J Med. 2001;344:403–409.
2.Fireman B, Black S, Shinefield HR, et al. Impact of the pneumococcal conjugate vaccine on otitis media. Pediatr Infect Dis J. 2003;22:10–16.
3.Palmu A, Verho J, Jokinen J, et al. The seven-valent pneumococcal conjugate vaccine reduces tympanostomy tube placement in children. Pediatr Infect Dis J. 2004;23:732–738.
4.Casey JR, Pichichero ME. Changes in frequency and pathogens causing acute otitis media in 1995–2003. Pediatr Infect Dis J. 2004;23:824–828.
5.Block SL, Hedrick J, Harrison CJ, et al. Community-wide vaccination with the heptavalent pneumococcal conjugate significantly alters the microbiology of acute otitis media. Pediatr Infect Dis J. 2004;23:829–833.
6.Poehling KA, Lafleur BJ, Szilagyi PG, et al. Population-based impact of pneumococcal conjugate vaccine in young children. Pediatrics. 2004;114:755–761.
7.Grijalva CG, Poehling KA, Nuorti JP, et al. National impact of universal childhood immunization with pneumococcal conjugate vaccine on outpatient medical care visits in the United States. Pediatrics. 2006;118:865–873.
8.Joloba ML, Windau A, Bajasouzian S, et al. Pneumococcal conjugate vaccine serotypes of Streptococcus pneumoniae isolates and the antimicrobial susceptibility of such isolates in children with otitis media. Clin Infect Dis. 2001;33:1489–1494.
9.Finkelstein JA, Huang SS, Daniel J, et al. Antibiotic-resistant Streptococcus pneumoniae in the heptavalent pneumococcal conjugate vaccine era: predictors of carriage in a multicommunity sample. Pediatrics. 2003;112:862–869.
10.Huang SS, Platt R, Rifas-Shiman SL, et al. Post-PCV7 changes in colonizing pneumococcal serotypes in 16 Massachusetts communities, 2001 and 2004. Pediatrics. 2005;116:e408–e413.
11.Pelton SI. Acute otitis media in an era of increasing antimicrobial resistance and universal administration of pneumococcal conjugate vaccine. Pediatr Infect Dis J. 2002;21:599–604.
12.Harrison CJ. Changes in treatment strategies for acute otitis media after full implementation of the pneumococcal seven valent conjugate vaccine. Pediatr Infect Dis J. 2003;22:S120–S130.
13.Moore M, Hyde TB, Hennessey TW, et al. Impact of a conjugate vaccine on community-wide carriage of nonsusceptible Streptococcus pneumoniae in Alaska. J Infect Dis. 2004;190:2031–2038.
14.Pelton SI, Loughlin AM, Marchant CD. Seven valent pneumococcal conjugate vaccine immunization in two Boston communities: changes in serotypes and antimicrobial susceptibility among Streptococcus pneumoniae isolates. Pediatr Infect Dis J. 2004;23:1015–1022.
15.Millar EV, O'Brien KL, Watt JP, et al. Effect of community-wide conjugate pneumococcal vaccine use in infancy on nasopharyngeal carriage through 3 years of age: a cross-sectional study in a high-risk population. Clin Infect Dis. 2006;43:8–15.
16.Beall B, McEllistrem MC, Gertz RE Jr, et al. Pre- and Postvaccination clonal compositions of invasive pneumococcal serotypes for isolates collected in the United States in 1999, 2001, and 2002. J Clin Microbiol. 2006;44:999–1017.
17.McEllistrem MC, Adams J, Mason EO, et al. Epidemiology of acute otitis media caused by Streptococcus pneumoniae before and after licensure of the 7-valent pneumococcal protein conjugate vaccine. J Infect Dis. 2003;188:1679–1684.
18.Porat N, Arguedas A, Spratt BG, et al. Emergence of penicillin-nonsusceptible Streptococcus pneumoniae clones expressing serotypes not present in the antipneumococcal conjugate vaccine. J Infect Dis. 2004;190:2154–2161.
19.Hanage WP, Huang SS, Lipsitch M, et al. Diversity and antibiotic resistance among nonvaccine serotypes of Streptococcus pneumoniae carriage isolates in the post-heptavalent conjugate vaccine era. J Infect Dis. 2007;95:347–352.
20.Pai R, Moore MR, Pilishvili T, et al. Postvaccine genetic structure of Streptococcus pneumoniae serotype 19A from children in the United States. J Infect Dis. 2005;192:1988–1995.
21.Farrell DJ, Klugman KP, Pichichero ME. Increased antimicrobial resistance among nonvaccine serotypes of Streptococcus pneumoniae in the pediatric population after the introduction of 7-valent pneumococcal vaccine in the United States. Pediatr Infect Dis J. 2007;26:123–128.
22.Temime L, Guillemot D, Boelle PY. Short- and long-term effects of pneumococcal conjugate vaccination of children on penicillin resistance. Antimicrob Agents Chemother. 2004;48:2206–2213.

epidemiology; invasive pneumococcal disease; nasopharyngeal carriage; pneumococcal conjugate vaccine; serotypes

© 2007 Lippincott Williams & Wilkins, Inc.