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Figure 1.
Transmission electron microscopic findings. A, Middle ear epithelium (Epit) with infiltrating cells (bar = 2 μm); B, encapsulated bacterium (arrow) at the epithelial surface (bar = 1 μm); and C, epithelial cyst (asterisk) with villi (arrows) and cilia (bar = 0.2 μm) (uranyl acetate–lead citrate).

Transmission electron microscopic findings. A, Middle ear epithelium (Epit) with infiltrating cells (bar = 2 μm); B, encapsulated bacterium (arrow) at the epithelial surface (bar = 1 μm); and C, epithelial cyst (asterisk) with villi (arrows) and cilia (bar = 0.2 μm) (uranyl acetate–lead citrate).

Figure 2.
Scanning electron microscopic findings. A, Biofilm fragment and single, rod-shaped bacteria (arrowheads) (bar = 1 μm); B, ciliary epithelium with mucous remnants and disarrayed cilia (arrows) (bar = 10 μm); and C, ciliary epithelium with 1 encapsulated coccus (arrowhead) (bar = 1 μm).

Scanning electron microscopic findings. A, Biofilm fragment and single, rod-shaped bacteria (arrowheads) (bar = 1 μm); B, ciliary epithelium with mucous remnants and disarrayed cilia (arrows) (bar = 10 μm); and C, ciliary epithelium with 1 encapsulated coccus (arrowhead) (bar = 1 μm).

Table. 
Characteristics of Biopsy Specimens
Characteristics of Biopsy Specimens
1.
Johnson  TALoeffler  KABurne  RAJolly  CNAntonelli  PJ Biofilm formation in cochlear implants with cochlear drug delivery channels in an in vitro model. Otolaryngol Head Neck Surg 2007;136 (4) 577- 582
PubMedArticle
2.
Loeffler  KAJohnson  TABurne  RAAntonelli  PJ Biofilm formation in an in vitro model of cochlear implants with removable magnets. Otolaryngol Head Neck Surg 2007;136 (4) 583- 588
PubMedArticle
3.
Cohen  NLRoland  JT  JrMarrinan  M Meningitis in cochlear implant recipients: the North American experience. Otol Neurotol 2004;25 (3) 275- 281
PubMedArticle
4.
Wei  BPShepherd  RKRobins-Browne  RMClark  GMO’Leary  SJ Pneumococcal meningitis: development of a new animal model. Otol Neurotol 2006;27 (6) 844- 854
PubMedArticle
5.
Wei  BPRobins-Browne  RMShepherd  RKAzzopardi  KClark  GMO’Leary  SJ Protective effects of local administration of ciprofloxacin on the risk of pneumococcal meningitis after cochlear implantation. Laryngoscope 2006;116 (12) 2138- 2144
PubMedArticle
6.
Cohen  NRamos  ARamsden  R  et al.  International consensus on meningitis and cochlear implants. Acta Otolaryngol 2005;125 (9) 916- 917
PubMedArticle
7.
Cunningham  CD  IIISlattery  WH  IIILuxford  WM Postoperative infection in cochlear implant patients. Otolaryngol Head Neck Surg 2004;131 (1) 109- 114
PubMedArticle
8.
Post  JC Direct evidence of bacterial biofilms in otitis media. Laryngoscope 2001;111 (12) 2083- 2094
PubMedArticle
9.
Post  JCStoodley  PHall-Stoodley  LEhrlich  GD The role of biofilms in otolaryngologic infections. Curr Opin Otolaryngol Head Neck Surg 2004;12 (3) 185- 190
PubMedArticle
10.
Hall-Stoodley  LHu  FZGieseke  A  et al.  Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media. JAMA 2006;296 (2) 202- 211
PubMedArticle
11.
Kuchma  SLO’Toole  GA Surface-induced and biofilm-induced changes in gene expression. Curr Opin Biotechnol 2000;11 (5) 429- 433
PubMedArticle
12.
Davey  MEO’Toole  GA Microbial biofilms: from ecology to molecular genetics. Microbiol Mol Biol Rev 2000;64 (4) 847- 867
PubMedArticle
13.
Hall-Stoodley  LStoodley  P Developmental regulation of microbial biofilms. Curr Opin Biotechnol 2002;13 (3) 228- 233
PubMedArticle
14.
Parsek  MRSingh  PK Bacterial biofilms: an emerging link to disease pathogenesis. Annu Rev Microbiol 2003;57677- 701
PubMedArticle
15.
Patel  JANguyen  DTRevai  KChonmaitree  T Role of respiratory syncytial virus in acute otitis media: implications for vaccine development. Vaccine 2007;25 (9) 1683- 1689
PubMedArticle
16.
Luntz  MTeszler  CBShpak  TFeiglin  HFarah-Sima’an  A Cochlear implantation in healthy and otitis-prone children: a prospective study. Laryngoscope 2001;111 (9) 1614- 1618
PubMedArticle
17.
Klein  JO Bacterial resistance and antimicrobial drug selection. Rosenfeld  RMBluestone  CDEvidence-Based Otitis Media. 2nd ed. Hamilton, ON BC Decker Inc2003;
18.
Lee  H-YAndalibi  AWebster  P  et al.  Antimicrobial activity of innate immune molecules against Streptococcus pneumoniae, Moraxella catarrhalis and nontypeable Haemophilus influenzae. BMC Infect Dis 2004;412
PubMedArticle
19.
Lim  DJChun  YMLee  HY  et al.  Cell biology of tubotympanum in relation to pathogenesis of otitis media—a review. Vaccine 2000;19 ((suppl.1)) S17- S25
PubMedArticle
20.
Leong  AS-Y Fixation and fixatives. Woods and Ellis 2000 Web site. http://www.adam.com.au/royellis/fix.htm. Accessed January 4, 2008
21.
Costerton  JWStewart  PSGreenberg  EP Bacterial biofilms: a common cause of persistent infections. Science 1999;284 (5418) 1318- 1322
PubMedArticle
22.
Dohar  JEHebda  PAVeeh  R  et al.  Mucosal biofilm formation on middle-ear mucosa in a nonhuman primate model of chronic suppurative otitis media. Laryngoscope 2005;115 (8) 1469- 1472
PubMedArticle
23.
Bogaert  DSluijter  MToom  NL  et al.  Dynamics of pneumococcal colonization in healthy Dutch children. Microbiology 2006;152 (pt 2) 377- 385
PubMedArticle
24.
Tonnaer  ELSanders  EACurfs  JH Bacterial otitis media: a new non-invasive rat model. Vaccine 2003;21 (31) 4539- 4544
PubMedArticle
25.
Tonnaer  ELRijkers  GTMeis  JF  et al.  Genetic relatedness between pneumococcal populations originating from the nasopharynx, adenoid, and tympanic cavity of children with otitis media. J Clin Microbiol 2005;43 (7) 3140- 3144
PubMedArticle
26.
Bernstein  JM Immunologic aspects of otitis media. Curr Allergy Asthma Rep 2002;2 (4) 309- 315
PubMedArticle
27.
Falk  B Negative middle ear pressure induced by sniffing: a tympanometric study in persons with healthy ears. J Otolaryngol 1981;10 (4) 299- 305
PubMed
28.
Brattmo  MTideholm  BCarlborg  B Middle ear pressure equillibration ability and spontaneous pressure changes in healthy ears with ventilation tubes. Acta Otolaryngol 2005;125 (7) 702- 706
PubMedArticle
29.
Winther  BGwaltney  JM  JrPhillips  CDHendley  JO Radiopaque contrast dye in nasopharynx reaches the middle ear during swallowing and/or yawning. Acta Otolaryngol 2005;125 (6) 625- 628
PubMedArticle
30.
Stenfors  L-E Non-specific and specific immunity to bacterial invasion of the middle ear cavity. Int J Pediatr Otorhinolaryngol 1999;49 ((suppl 1)) S223- S226
PubMedArticle
31.
Rao  VKKrasan  GPHendrixson  DRDawid  SSt Geme  JW  III Molecular determinants of the pathogenesis of disease due to non-typeable Haemophilus influenzae. FEMS Microbiol Rev 1999;23 (2) 99- 129
PubMedArticle
32.
Antonelli  PJLee  JCBurne  RA Bacterial biofilms may contribute to persistent cochlear implant infection. Otol Neurotol 2004;25 (6) 953- 957
PubMedArticle
33.
Pawlowski  KSWawro  DRoland  PS Bacterial biofilm formation on a human cochlear implant. Otol Neurotol 2005;26 (5) 972- 975
PubMedArticle
Original Article
March 2009

Detection of Bacteria in Healthy Middle Ears During Cochlear Implantation

Author Affiliations

Author Affiliations: Department of Otorhinolaryngology, Donders Institute for Brain, Cognition, and Behaviour, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.

Arch Otolaryngol Head Neck Surg. 2009;135(3):232-237. doi:10.1001/archoto.2008.556
Abstract

Objective  To assess whether free-living and/or biofilm bacteria are present in the putative sterile middle ear cavity before insertion of the electrode array during cochlear implantation.

Design  Prospective study.

Setting  Tertiary academic hospital.

Patients  The study included 45 healthy children (with or without a history of otitis media) undergoing cochlear implantation.

Interventions  Transmission electron microscopy or scanning electron microscopy was used to detect the presence of bacteria.

Main Outcome Measure  Presence of both free-living bacteria and biofilm bacteria on the epithelial surface of biopsy specimens of middle ear mucosa.

Results  A majority of all mucosal specimens from clinically healthy tympanic cavities displayed inflammatory areas as well as dispersed, nonmatrix-enclosed bacteria. Also, rarely, fragments of biofilms were found.

Conclusions  The presence of bacteria in the tympanic cavity, which is generally assumed to be sterile in healthy individuals, may provide an explanation for infectious complications after cochlear implantation. However, the possibility that the electrode array of a cochlear implant will actually become contaminated during insertion is unlikely because of the small amounts and dispersed presence of bacteria, which may account for the relatively low incidence of infectious complications after cochlear implantation.

The development of infectious complications after cochlear implantation is rare, with an incidence of 1% to 4%.1 However, when infections do occur they may be intractable and difficult to eradicate with antibiotics.2 Sometimes, they may even be fatal.3 Cochlear implants (CIs) may be exposed to bacteria not only at surgery but also thereafter via the route from middle ear to inner ear or by hematogenic dissemination. Both routes of infection have been investigated in animal studies.4,5 Therefore, infectious disorders (including acute otitis media [OM], chronic OM, and wound infections) combined with inefficient sealing of the cochleostomy after implantation6 theoretically carry a risk of meningitis because of the possibility of intracranial spread along the intracochlear electrode toward the meninges.7 Because OM is the most common bacterial infection during childhood, children are especially at risk. Most common microorganisms in post-CI meningitis are Streptococcus pneumoniae and Haemophilus influenzae.3 These bacteria are also the most prominent in OM. Because it is known that OM may be a biofilm disease,810 special care should be taken to prevent perioperative infection.

Biofilm formation represents a protected mode of growth that allows microbes to survive in a hostile environment. Biofilms can be characterized as complex communities of sessile microorganisms embedded in a self-produced matrix, adhered to a foreign body, eg, a mucosal surface. They are difficult to eradicate owing to their resistance to immunologic defense mechanisms and antibiotics, resulting in persistent infections. They may also act as a nidus for recurrrent infections through the release of planktonic bacteria. Direct evidence for the hypothesis that OM may be a biofilm disease was provided by the demonstration of characteristic matrix-enclosed adherent clusters of bacteria on the middle ear mucosa of children with chronic OM who had not responded to multiple courses of antibiotics.10 When bacteria gain access to the tympanic cavity via the eustachian tube and adhere to the mucosal lining, a cascade of events will be initiated, finally leading to a biofilm.1113

In the middle ear cavity, there may be several areas with biofilm,8 without provoking any symptoms, as a biofilm itself is not necessarily highly pathogenic. However, if biofilms are present at cochlear implantation, it is conceivable that bacteria may inadvertently be introduced into the cochlea through insertion of the electrode array. Also, they may enter the cochlea after surgery through an inefficiently sealed cochleostomy, leading to infectious complications.

This study was initiated to determine whether free-living bacteria and/or biofilm bacteria are present in the middle ear cavity at the site of the cochleostomy before insertion of the electrode array. Healthy children (with or without a history of OM) receiving a CI device were selected for participation.

METHODS
PATIENTS

For this study, institutional approval was obtained from the Committee on Research Involving Human Subjects of Nijmegen, the Netherlands. Specimens of the middle ear mucosa were obtained from 45 children who were undergoing cochlear implantation. The mixed population included children without a history of OM as well as those with a history of ventilation tubes, OM with effusion, or 1 or more episodes of acute OM before referral. It should be emphasized, however, that a cochlear device was implanted in the children only when no clinical signs of OM were present; ie, when the tympanic cavity was aerated and the tympanic membrane was thin and translucent.

ACQUISITION AND PREPARATION OF SPECIMENS

One of the procedures to detect biofilm infections is the direct examination of tissue in search of bacteria in matrix-enclosed clusters attached to a surface.14 However, because inspection of the middle ear mucosa in vivo is impossible, 1 mucosal biopsy specimen per patient was obtained from the site of the cochleostomy during surgery. Tissue samples of middle ear mucosa (approximately 1 mm2) were obtained from the promontory, just anterior to the round window niche, with sterile, not yet used instruments and directly transferred to Karnovsky fixative (a mix of 2% paraformaldehyde and 2.5% glutaraldehyde in 0.1M phosphate buffer). Postfixation was performed with osmium tetroxide (1%) in phosphate buffer (pH, 7.3).

SCANNING ELECTRON MICROSCOPY AND TRANSMISSION ELECTRON MICROSCOPY

Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) were used as imaging tools to detect the presence of free-living bacteria and/or biofilm bacteria in the biopsy specimens. At random, the specimens were either used for TEM or for SEM. For TEM, dehydrated specimens were embedded in epoxy resin and then sectioned. Ultrathin sections were stained with uranyl acetate and lead citrate and examined with a transmission electron microscope (Jeol 1010; Jeol Ltd, Akishima, Japan). Samples for SEM were dehydrated in a series of upgrading ethanol concentrations, up to 100%. After critical-point drying in carbon dioxide, the specimens were mounted on stubs and sputter coated with gold before examination with a scanning electron microscope (Jeol 6310) operating at 15 kV. Multiple areas of each mucosal sample were checked thoroughly for the presence of biofilm and/or free-living bacteria. Examination of the specimens was performed blinded; ie, the observer did not know the clinical background (whether or not otitis prone) of the patients.

RESULTS
CLINICAL DATA

Twenty-seven patients (60%) appeared to be free of infectious middle ear diseases (Table). Negative middle ear pressures had previously been documented in 8 of the 27 patients, while infectious middle ear problems appeared to be absent. Three months before surgery, a deviant tympanic membrane was observed at otoscopy in 2 of these patients. Also, 6 patients had a flat tympanogram. Despite these deviations, an association with a history of OM with effusion or acute OM could not be demonstrated. A history of OM with effusion or acute OM was recorded in the medical files of 18 patients (40%) (with or without ventilation tubes).

SURGICAL DATA

Although cochlear implantation was performed only when no clinical signs of OM were present, several middle ear mucosae (24%) appeared to be “inflamed” at the time of surgery, as they were found to be erythematous and/or edematous. In the rest of the patients, the middle ear mucosa appeared to be clinically normal.

TRANSMISSION ELECTRON MICROSCOPY

The unaltered epithelial areas of the middle ear mucosa were composed of both ciliated and nonciliated, cuboidal or columnar, and secretory cells. However, in addition to a normal epithelial lining, 18 specimens (40%) also displayed inflammatory mucosal areas characterized by edematous epithelium and/or the presence of infiltrating leukocytes (Figure 1A) and/or increased vascularization. Moreover, some epithelial cells showed clustering or clumping of cilia, while epithelial cysts (Figure 1C) were also observed in a few biopsy specimens. Ciliated areas of almost all TEM specimens were devoid of mucus. Only sparse mucous fragments were detected. Single bacteria (Figure 1B) were evident on the mucosal epithelial surface in many specimens; however, none of the specimens showed ultrastructural evidence of a biofilm.

SCANNING ELECTRON MICROSCOPY

Some tissue samples that were used for SEM were completely covered by a layer of mucus, preventing assessment of bacterial presence on the mucosa. These tissue blocks were not included in the Table. Parts of all biopsyspecimens showed denuded ciliated cells (ie, they had no layer of mucus). Simple columnar or cuboidal epithelium with cilia and microvilli was observed. Areas of cuboidal epithelium with a “cobblestone” appearance were also sometimes visible owing to widened intercellular spaces as well as to different shapes and sizes of the apical surfaces. Ciliated cells demonstrated normal intact cilia, and there were some cells with disarrayed cilia (Figure 2B). Areas with flat, squamous epithelium were also evident.

On rare occasions (8.9%), fragments of a biofilm (Figure 2A), characterized by bacteria in matrix-enclosed adherent clusters, were evident; however, in most of the specimens from children without OM, nonmatrix-enclosed bacteria were observed, either singly (Figure 2C) or in small clusters, scattered over the middle ear epithelium. Twenty- four biopsy specimens (53%) (SEM and TEM) were found to be contaminated by single bacteria. Predominantly cocci, and only occasionally single, rod-shaped microbes, were seen. These bacteria were assumed to be H influenzae, S pneumoniae, or Moraxella catarrhalis, as these are the major pathogens of the middle ear.15 However, exact identification of bacterial strains by SEM was impossible because all of the strains involved encapsulated cocci of overlapping diameter. Bacterial typing using other techniques was not applicable as the biopsy specimens were too small.

COMMENT

Our findings demonstrate that biofilm fragments may sometimes be present in the middle ear cavity at the site of the cochleostomy in children with or without a history of OM. Also, in both groups, nonmatrix-enclosed single bacteria were observed at the epithelial surface of the mucosal lining in this location. Overall, 28 biopsy specimens (62%) were contaminated with either single bacteria or biofilm fragments. Also, “inflamed” mucosae were found at surgery not only in children with a history of OM (in whom OM had completely clinically resolved) but also in children without a history of OM. These findings are in agreement with those of Luntz et al.16

Our study provides evidence for the presence of both free-living bacteria and biofilm bacteria in the tympanic cavity of clinically healthy individuals. These findings, which do not agree with the general premise that a normal middle ear cavity is always sterile,17,18 are remarkable, especially because even more bacteria may have been present in the tympanic cavity but may have remained undetected because they were located at unscreened sections elsewhere in the middle ear cavity. After all, only 1 very small biopsy specimen of the lining of the promontory was screened in each case, while the major part of the middle ear was not studied. Also, it should be noted that partial loss of the mucous layer was observed in almost all specimens, which differs from the in vivo situation.19 Loss of mucous substances, including potentially present biofilm structures, may occur during tissue preparation, as both middle ear mucus and the slimelike matrix of a biofilm are primarily composed of polysaccharides for which no optimal fixative is available as yet, to our knowledge.20 As a result of suboptimal tissue fixation, a significant fraction of mucous layer and/or biofilm may be washed away in the subsequent liquid steps.21

Our findings in normal human middle ears seem to be unique, as evidence of cocci adhering to normal middle ear mucosa was previously only established by Dohar et al.22 Their observations in monkeys are in line with the results of our human study. Although, to our knowledge, such findings have not been reported before, it nevertheless seems unlikely that the presence of bacteria in the tympanic cavity of clinically healthy individuals is an exceptional phenomenon, as this region is connected to the nasopharynx, which is colonized by bacteria in individuals with OM as well as in healthy persons.23 Under certain circumstances, eg, subsequent to negative middle ear pressure, these nasopharyngeal bacteria can enter the tympanic cavity via the eustachian tube.24,25 Negative middle ear pressures often develop after blockage of the eustachian tube as a result not only of allergies, pollutants, and viruses, for example,26 but also of sniffing.27 Equilibration of the pressure differences between the middle ear and the nasopharynx is achieved when the eustachian tube reopens. Because air flows toward the middle ear on opening, colonizing nasopharyngeal pathogens may be insufflated into the tympanic cavity.24 Because negative middle ear pressures may occur in normal individuals as well as in persons with (developing) OM,28 it seems likely that almost all individuals will occasionally have to deal with transitory periods of negative middle ear pressure and subsequent pressure equilibrations. Therefore, transfer of bacteria from the nasopharynx to the tympanic cavity will occur not only in persons with middle ear diseases but also in healthy individuals. Furthermore, a preliminary study by Winther et al29 showed that radiopaque contrast medium introduced into the nasopharynx of healthy adults was displaced from the nasopharynx into the middle ear cavity during yawning and/or swallowing. These observations suggest that displacement of bacteria (present in nasopharyngeal secretions) to the middle ear may be a more frequent occurrence than anticipated from earlier reports. Apparently, in healthy individuals, this displacement does not provoke clinical symptoms because the middle ear is protected against invaders by the mucociliary system, by antimicrobial molecules of the innate immunity, and by the adaptive immune system.19,30 Despite these defense systems, attachment of bacteria on the middle ear mucosa can occur, implying that under certain conditions microorganisms are able to evade the mucociliary system and overcome local immune mechanisms (eg, secretory IgA and antimicrobial molecules). To gain access to the mucosal surface, several microbial strategies, such as paralysis of ciliary movement and inactivation of IgA, have evolved. Furthermore, bacteria deploy an array of adhesive molecules that recognize mucosal host cell receptors and facilitate the interaction with, and adhesion to, the epithelial surface.31 In fact, surface determinants of both bacterium and host are involved in adherence, which may be followed by colonization and/or biofilm formation.

Although it is assumed that the bacteria that were found on tympanic epithelia in the present study originated from the nasopharynx, in theory their origin may also have been the skin flora (eg, corynebacteria), as bacteria from the skin flora may have been introduced into the middle ear inadvertently during opening of the mastoid bone during surgery. However, the latter route of infection seems most unlikely because sterilized instruments are used in a disinfected surgical area.

In conclusion, the detection of free-living bacteria as well as biofilm bacteria (although infrequently) in the middle ear cavity in the majority of healthy children was the most important observation of our study. The presence of bacteria in the tympanic cavity before cochlear implantation may provide an explanation for the development of infectious complications such as postimplantation meningitis and persistent CI infection.32,33 On the other hand, the presence of small amounts of microbes in the tympanic cavity does not unequivocally result in inflammatory complications, as the middle ears of healthy persons are protected against middle ear invaders by the mucociliary system as well as by the innate and adaptive immune system. However, immaturity (young children) and aging (elderly) of the immune system or dysfunction of either of the defense mechanisms may be a risk factor for the development of infectious complications.

At present, the exact incidence of biofilms in the middle ear cavity in clinically healthy children is unknown. It will be difficult to assess this incidence, especially because biofilm formation may arise from different locations on the mucosal lining,21 implying that the presence of 1 or more small biofilm fragments in the tympanic cavity may easily be overlooked. However, a noncontinuous biofilm may also be advantageous because the chance that a CI actually will become contaminated by one of these fragments during insertion of the electrode array is very small, thus accounting for the relatively low incidence of infectious complications after implantation.1

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Article Information

Correspondence: Edith L. Tonnaer, PhD, Department of Otorhinolaryngology, Donders Centre for Neuroscience, Radboud University Nijmegen Medical Center, Philips van Leydenlaan 15, PO Box 9101, 6500HB Nijmegen, the Netherlands (e.tonnaer@kno.umcn.nl).

Submitted for Publication: March 26, 2008; final revision received June 17, 2008; accepted July 9, 2008.

Author Contributions: Dr Tonnaer had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Tonnaer and Mylanus. Acquisition of data: Tonnaer and Mulder. Analysis and interpretation of data: Tonnaer and Curfs. Drafting of the manuscript: Tonnaer. Critical revision of the manuscript for important intellectual content: Tonnaer, Mylanus, Mulder, and Curfs. Obtained funding: Mylanus. Administrative, technical, and material support: Tonnaer, Mylanus, and Mulder. Study supervision: Mylanus, Mulder, and Curfs.

Financial Disclosure: None reported.

References
1.
Johnson  TALoeffler  KABurne  RAJolly  CNAntonelli  PJ Biofilm formation in cochlear implants with cochlear drug delivery channels in an in vitro model. Otolaryngol Head Neck Surg 2007;136 (4) 577- 582
PubMedArticle
2.
Loeffler  KAJohnson  TABurne  RAAntonelli  PJ Biofilm formation in an in vitro model of cochlear implants with removable magnets. Otolaryngol Head Neck Surg 2007;136 (4) 583- 588
PubMedArticle
3.
Cohen  NLRoland  JT  JrMarrinan  M Meningitis in cochlear implant recipients: the North American experience. Otol Neurotol 2004;25 (3) 275- 281
PubMedArticle
4.
Wei  BPShepherd  RKRobins-Browne  RMClark  GMO’Leary  SJ Pneumococcal meningitis: development of a new animal model. Otol Neurotol 2006;27 (6) 844- 854
PubMedArticle
5.
Wei  BPRobins-Browne  RMShepherd  RKAzzopardi  KClark  GMO’Leary  SJ Protective effects of local administration of ciprofloxacin on the risk of pneumococcal meningitis after cochlear implantation. Laryngoscope 2006;116 (12) 2138- 2144
PubMedArticle
6.
Cohen  NRamos  ARamsden  R  et al.  International consensus on meningitis and cochlear implants. Acta Otolaryngol 2005;125 (9) 916- 917
PubMedArticle
7.
Cunningham  CD  IIISlattery  WH  IIILuxford  WM Postoperative infection in cochlear implant patients. Otolaryngol Head Neck Surg 2004;131 (1) 109- 114
PubMedArticle
8.
Post  JC Direct evidence of bacterial biofilms in otitis media. Laryngoscope 2001;111 (12) 2083- 2094
PubMedArticle
9.
Post  JCStoodley  PHall-Stoodley  LEhrlich  GD The role of biofilms in otolaryngologic infections. Curr Opin Otolaryngol Head Neck Surg 2004;12 (3) 185- 190
PubMedArticle
10.
Hall-Stoodley  LHu  FZGieseke  A  et al.  Direct detection of bacterial biofilms on the middle-ear mucosa of children with chronic otitis media. JAMA 2006;296 (2) 202- 211
PubMedArticle
11.
Kuchma  SLO’Toole  GA Surface-induced and biofilm-induced changes in gene expression. Curr Opin Biotechnol 2000;11 (5) 429- 433
PubMedArticle
12.
Davey  MEO’Toole  GA Microbial biofilms: from ecology to molecular genetics. Microbiol Mol Biol Rev 2000;64 (4) 847- 867
PubMedArticle
13.
Hall-Stoodley  LStoodley  P Developmental regulation of microbial biofilms. Curr Opin Biotechnol 2002;13 (3) 228- 233
PubMedArticle
14.
Parsek  MRSingh  PK Bacterial biofilms: an emerging link to disease pathogenesis. Annu Rev Microbiol 2003;57677- 701
PubMedArticle
15.
Patel  JANguyen  DTRevai  KChonmaitree  T Role of respiratory syncytial virus in acute otitis media: implications for vaccine development. Vaccine 2007;25 (9) 1683- 1689
PubMedArticle
16.
Luntz  MTeszler  CBShpak  TFeiglin  HFarah-Sima’an  A Cochlear implantation in healthy and otitis-prone children: a prospective study. Laryngoscope 2001;111 (9) 1614- 1618
PubMedArticle
17.
Klein  JO Bacterial resistance and antimicrobial drug selection. Rosenfeld  RMBluestone  CDEvidence-Based Otitis Media. 2nd ed. Hamilton, ON BC Decker Inc2003;
18.
Lee  H-YAndalibi  AWebster  P  et al.  Antimicrobial activity of innate immune molecules against Streptococcus pneumoniae, Moraxella catarrhalis and nontypeable Haemophilus influenzae. BMC Infect Dis 2004;412
PubMedArticle
19.
Lim  DJChun  YMLee  HY  et al.  Cell biology of tubotympanum in relation to pathogenesis of otitis media—a review. Vaccine 2000;19 ((suppl.1)) S17- S25
PubMedArticle
20.
Leong  AS-Y Fixation and fixatives. Woods and Ellis 2000 Web site. http://www.adam.com.au/royellis/fix.htm. Accessed January 4, 2008
21.
Costerton  JWStewart  PSGreenberg  EP Bacterial biofilms: a common cause of persistent infections. Science 1999;284 (5418) 1318- 1322
PubMedArticle
22.
Dohar  JEHebda  PAVeeh  R  et al.  Mucosal biofilm formation on middle-ear mucosa in a nonhuman primate model of chronic suppurative otitis media. Laryngoscope 2005;115 (8) 1469- 1472
PubMedArticle
23.
Bogaert  DSluijter  MToom  NL  et al.  Dynamics of pneumococcal colonization in healthy Dutch children. Microbiology 2006;152 (pt 2) 377- 385
PubMedArticle
24.
Tonnaer  ELSanders  EACurfs  JH Bacterial otitis media: a new non-invasive rat model. Vaccine 2003;21 (31) 4539- 4544
PubMedArticle
25.
Tonnaer  ELRijkers  GTMeis  JF  et al.  Genetic relatedness between pneumococcal populations originating from the nasopharynx, adenoid, and tympanic cavity of children with otitis media. J Clin Microbiol 2005;43 (7) 3140- 3144
PubMedArticle
26.
Bernstein  JM Immunologic aspects of otitis media. Curr Allergy Asthma Rep 2002;2 (4) 309- 315
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