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Pediatric Infectious Disease Journal:
doi: 10.1097/INF.0b013e318154b273
Article

Bacterial Biofilms in Otitis Media: Evidence and Relevance

Bakaletz, Lauren O. PhD

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Author Information

From the College of Medicine, The Ohio State University, Center for Microbial Pathogenesis, Columbus Children's Research Institute, Columbus, Ohio.

Accepted for publication July 17, 2007.

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 a commercial product.

Address for correspondence to: Lauren O. Bakaletz, PhD, The Ohio State University, College of Medicine, Director, Center for Microbial Pathogenesis, Columbus Children's Research Institute, 700 Children's Drive, Room 591, Columbus, Ohio. E-mail: BakaletL@pediatrics.ohio-state.edu.

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 CreditsTM. 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.

1. World Health Organization. World Development Report 1993: Investing in Health. Oxford: Oxford University Press; 1993:215-222.

2. Poehling KA, Lafleur BJ, Szilagyi PG, et al. Population-based impact of pneumococcal conjugate vaccine in young children. Pediatrics. 2004;114:755-761.

3. Acuin J. Chronic suppurative otitis media: burden of illness and management options. World Health Organization (WHO). 2006 update.

4. Belshe RB, Edwards KM, Vesikari T, et al. Live attenuated versus inactivated influenza vaccine in infants and young children. N Engl J Med. 2007;356:685-696.

Educational Objectives

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

1. Describe the global demographics and burden of Acute Otitis Media citing current available data.

2. Discuss the management of children with recurrent and relapsing respiratory tract disease, specifically Acute Otitis Media.

3. Outline the impact of Pneumococcal Conjugate Vaccine on Acute Otitis Media in the US and discuss the global implication of a vaccine targeting both pneumococcal and H. influenzae (NTHi) respiratory infections.

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

Faculty

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.

Disclosures

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 cme@bu.edu

Boston University Privacy Policy: http://www.bu.edu/cme/policies/privacy_policy.html

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Abstract

Abstract: A biofilm is a highly organized, multicellular network of bacteria encased in a matrix and found in close association with a surface. Substantial effort in understanding the biologic and biochemical nature of biofilms has resulted in evidence supporting their importance in otitis media (OM), both from the perspective how pathogens develop viable communities in the middle ear as well as how this structure impedes successful antibiotic therapy. This new understanding may explain the recurrent nature of OM, and the persistence of middle ear fluid after infection. This article looks closely at biofilms in OM and suggests that an improved understanding of the unique properties of bacteria resident within a biofilm and the proteins they express while part of this organized community has the potential to identify novel and perhaps biofilm-specific molecular targets for the design of vaccine candidates for the prevention of OM.

A biofilm is a highly organized, multicellular network ofbacteria encased in a matrix and found in close association with a surface. This is the normal state of bacterial growth in nature, and it is currently believed that most—if not all—bacteria are capable of biofilm growth. Bacteria resident within a biofilm (or sessile) possess a number of characteristics that are unique from those growing in suspension (or planktonic). These qualities include a reduced growth rate; a distinct pattern of gene expression; and increased resistance to the action of antibiotics as well as to effectors of innate and acquired immunity. The reduced efficacy of antibiotics against bacteria within a biofilm, once believed due to the limited ability of antibiotics to penetrate a biofilm matrix, has more recently been attributed to both a reduced metabolic rate of bacteria within the biofilm and limited availability of oxygen within a biofilm. Because of the varied and unique properties of bacteria resident within a biofilm community, illnesses that include a biofilm component intrinsic to the disease course [such as otitis media (OM)] require novel diagnostic, therapeutic, and prevention strategies.

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A PIVOTAL TURNING POINT IN OM RESEARCH

Biofilms have been long associated with complications of indwelling devices and growth on foreign substances; however, their association with OM evolved following a paradigm-shifting hypothesis originally put forth by Rayner, and colleagues in 1998.1 This hypothesis was developed to explain several commonly observed but unexplained characteristics of clinical conditions collectively termed OM. These perplexing characteristics included the absence of a response to antibiotics; the chronic and/or recurrent nature of OM; the observation that middle ear effusions were commonly “culture-negative” (or sterile); the finding that a large proportion of culture-negative otitis media with effusion (OME) were PCR-positive for bacterial DNA; and lastly, the demonstration that bacterial mRNA (suggesting the presence of replicating bacteria) was present in culture negative middle ear fluids. This latter observation was a pivotal turning point for the OM research community, providing evidence for bacterial life (rather than bacterial antigens) in the middle ear.

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BIOFILMS AND THE MIDDLE EAR

Once the biofilm hypothesis was put forth for OM, early descriptive data of middle ear histopathology in support of the presence of biofilms appeared. Several laboratories began to investigate the capability of bacteria commonly associated with OM to develop biofilms in greater detail; they also better characterized the biochemical composition of the matrix formed by these microorganisms. Despite being a relatively young concept, substantial data have already been collected, illustrating that the 3 primary causative agents of OM, nontypeable Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis, readily form biofilms in vitro2–7 and in vivo.8–14 Data for the biofilming phenotype of H. influenzae is more extensive while that for S. pneumoniae and M catarrhalis are evolving. Briefly, in 2002, Ehrlich et al demonstrated that a clinical isolate of H. influenzae was able to form a well-developed biofilm in the middle ear of the chinchilla host within 5 days after direct challenge of the middle ear cavity. Work from several other groups illustrated that proteins (or epitopes) expressed by H. influenzae when growing in a biofilm are unique from those expressed when grown planktonically.10 Webster et al, using electron microscopy, showed that certain proteins, adhesins, bacterial enzymes and lipo-oligosaccharide(s) (LOS) occupied distinct compartments within the H. influenzae-formed biofilm.15

Bacterial biofilms have also been demonstrated in a rodent model and with human tissue. Bouchet et al8 demonstrated in an experimental chinchilla model of OM that sialylation of H. influenzae LOS is a major virulence factor; and Greiner et al,16 and later Jurcisek et al,13 demonstrated that sialylated LOS, or endotoxin, with sialic acid in a specific linkage position to galactose, is a key component of formed biofilms in vitro and in vivo. Swords et al elucidated that sialylation of the LOS expressed by H. influenzae promoted formation of a biofilm14; they also demonstrated that when the phosphorylcholine content of H. influenzae LOS increases within a biofilm, stimulation of the host inflammatory response decreases. H. influenzae may also be promoting persistence and residence in the human airway through enhanced resistance to host bacterial clearance.7,12 Using middle ear mucosal biopsy specimens recovered from the children with chronic or recurrent OM combined with fluorescent in situ hybridization (FISH) and confocal scanning laser microscopy (CSLM), Hall-Stoodley et al demonstrated that H. influenzae, as well as S. pneumoniae and M catarrhalis had formed biofilms in recovered middle ear mucosal samples.11 These biofilms were often of mixed microbial etiology, an observation with broad implications in terms of the standard medical practice of empirically prescribing antimicrobials for OM (as discussed below).

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INTERESTING ASPECTS OF OM-RELATED BIOFILMS

Images from the middle ear have revealed interesting aspects of OM-related biofilms: these communities of microbes are viable, they are well organized, and highly structured. In the middle ear of the chinchilla host, gross microscopic images reveal the presence of a creamy colored biomass of semisolid and uniform consistency anchored to the mucosal epithelium of the inferior bulla, the thin bone that surrounds the middle ear space of the chinchilla host (Fig. 1A). 13 When this biomass is snap frozen over liquid nitrogen and subjected to a vital fluorescent dye (live bacteria fluoresce green; dead bacteria fluoresce red), one can readily see the fingerlike projections of viable bacteria that extend from the mucosal surface into the middle ear space (Fig. 1B). These fingerlike projections are separated by dark areas that represent regularly spaced but bacteria-free water channels whose function is to bathe, feed, and detoxify the biofilm community.

Figure 1
Figure 1
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MIDDLE EAR MUCOSA FROM CHILDREN WITH CHRONIC OR RECURRENT DISEASE

Figure 2 shows an example of a CSLM image of mucosa recovered from a 2-year-old with OME that after staining with a live-dead fluorescent stain, demonstrated that despite the culture-negative status of the effusion, the specimen was heavily populated with viable bacteria.11 Given that this effusion was PCR-positive for H. influenzae, at least a portion of these bacteria are likely to be H. influenzae. Similarly, additional CSLM FISH images of middle ear mucosa recovered from children with culture-negative OME or recurrent OM (from the same report) clearly showed the presence of both S. pneumoniae and M. catarrhalis within the biofilms present on these tissue specimens.

Figure 2
Figure 2
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BIOFILMS IN AOM

It would seem short-sighted to exclude the possibility of a role for biofilms in AOM and OME. Biofilm formation is the preferred state of bacterial growth; it is observed in the laboratory within 48 hours when any of the 3 discussed otopathogens are placed on respiratory epithelial cells, and in the middle ear of an intact mammalian host within a few days of bacterial challenge. Thus, a role for biofilms in AOM should be strongly considered. Evidence supporting the existence of a biofilm component in OM is consistent with and provides a potential explanation for the antibiotic unresponsiveness and chronic nature of OM, and may offer a rationale for the commonality of treatment failures in AOM.

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CLINICAL RELEVANCE OF BIOFILMS

An understanding that the most common pediatric disease includes a biofilm component has important clinical relevance. The susceptibility profiles of sessile versus planktonically growing bacteria are reported to be very different.17 Selection of antimicrobials for treating OM has been based on testing on planktonically grown bacteria. Further evaluation of the difference(s) in antibiotic susceptibility between planktonic and sessile bacterial populations will be needed to more fully understand the implications of biofilm formation on therapeutic options. Knowledge that biofilms formed in the middle ears are possibly of mixed microbial etiology might help explain the high frequency of treatment failures among children where antibiotic choice has been largely empiric, and are likely to influence future guidelines for medical management of treatment-failures.

There is a great deal of interest in developing methods to disrupt an existing biofilm, including those present in the middle ear cleft. Developing these methods will benefit from efforts to detail both the mechanisms of biofilm development, including perhaps quorem sensing (used by bacteria to determine both their own relative density and the presence of other bacterial species), and the biochemical composition of the biofilm matrix.

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CONCLUDING COMMENTS

Understanding the nature of a biofilm component in OM may have meaningful influence on strategies for preventing OM. The design and derivation of vaccine candidates for OM that currently focus on preventing colonization are predicated on the fact that by reducing the burden of bacteria present in the pediatric nasopharynx, one could reduce or eliminate the likelihood of retrograde ascension of the Eustachian tube by bacteria from the nasopharynx to the middle ear. If effective, this strategy could prevent biofilms from forming in the middle ear. Alternatively, an improved understanding of the unique properties of bacteria resident within a biofilm and the proteins they express while growing as part of this organized community has the potential to identify novel and perhaps biofilm-specific molecular targets for the design of vaccine candidates for the prevention of OM.

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REFERENCES

1.Rayner MG, Zhang Y, Gorry CM, et al. Evidence of bacterial metabolic activity in culture-negative otitis media with effusion. JAMA. 1998;279:296–299.

2.Allegrucci M, Hu FZ, Shen K, et al. Phenotypic characterization of Streptococcus pneumoniae biofilm development. J Bacteriol. 2006;188:2325–2335.

3.Murphy TF, Kirkham C. Biofilm formation by nontypeable Haemophilus influenzae: strain variability, outer membrane antigen expression and role of pili. BMC Microbiol. 2002;2:7.

4.Gallaher TK, Wu S, Webster P, et al. Identification of biofilm proteins in non-typeable Haemophilus influenzae. BMC Microbiol. 2006;6:65.

5.Pearson MM, Laurence CA, Guinn SE, et al. Biofilm formation by Moraxella catarrhalis in vitro: roles of the UspA1 adhesin and the Hag hemagglutinin. Infect Immun. 2006;74:1588–1596.

6.Starner TD, Zhang NZ, Kim G, et al. Haemophilus influenzae forms biofilms on airway epithelia: implications in cystic fibrosis. Am J Respir Crit Care Med. 2006;174:213–220.

7.West-Barnette S, Rockel A, Swords WE. Biofilm growth increases phosphorylcholine content and decreases potency of nontypeable Haemophilus influenzae endotoxins. Infect Immun. 2006;74:1828–1836.

8.Bouchet V, Hood DW, Li J, et al. Host-derived sialic acid is incorporated into Haemophilus influenzae lipopolysaccharide and is a major virulence factor in experimental otitis media. Proc Natl Acad Sci USA. 2003;100:8898–8803.

9.Daines DA, Bothwell M, Furrer J, et al. Haemophilus influenzae luxS mutants form a biofilm and have increased virulence. Microb Pathog. 2005;39:87–96.

10.Ehrlich GD, Veeh R, Wang X, et al. Mucosal biofilm formation on middle-ear mucosa in the chinchilla model of otitis media. JAMA. 2002;287:1710–1715.

11.Hall-Stoodley L, Hu FZ, Gieseke A, et al. Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media. JAMA. 2006;296:202–211.

12.Hong W, Mason K, Jurcisek J, et al. Phosphorylcholine decreases early inflammation and promotes the establishment of stable biofilm communities of nontypeable Haemophilus influenzae strain 86-028NP in a chinchilla model of otitis media. Infect Immun. 2007;75:958–965.

13.Jurcisek J, Greiner L, Watanabe H, et al. Role of sialic acid and complex carbohydrate biosynthesis in biofilm formation by nontypeable Haemophilus influenzae in the chinchilla middle ear. Infect Immun. 2005;73:3210–3218.

14.Swords WE, Moore ML, Godzicki L, et al. Sialylation of lipooligosaccharides promotes biofilm formation by nontypeable Haemophilus influenzae. Infect Immun. 2004;72:106–113.

15.Webster P, Wu S, Gomez G, et al. Distribution of bacterial proteins in biofilms formed by non-typeable Haemophilus influenzae. J Histochem Cytochem. 2006;54:829–842.

16.Greiner LL, Watanabe H, Phillips NJ, et al. Nontypeable Haemophilus influenzae strain 2019 produces a biofilm containing N-acetylneuraminic acid that may mimic sialylated O-linked glycans. Infect Immun. 2004;72:4249–4260.

17.Slinger R, Chan F, Ferris W, et al. Multiple combination antibiotic susceptibility testing of nontypeable Haemophilus influenzae biofilms. Diagn Microbiol Infect Dis. 2006;56:247–253.

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Keywords:

otitis media; biofilm

© 2007 Lippincott Williams & Wilkins, Inc.

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