Chronic Middle Ear Infections Linked To Resistant Biofilm Bacteria

Biofilms are antibiotic resistant colonizations of bacteria that attach to surfaces and form a slime-like barrier that acts as a formidable defense mechanism, protecting the bacteria from eradication.

The discovery of biofilms in the setting of chronic otitis media represents a landmark evolution in the medical community's understanding about a disease that afflicts millions of children world-wide each year and further endorses the emerging biofilm paradigm of chronic infectious disease, said Garth Ehrlich, Ph.D., principal investigator and executive director of the ASRI Center for Genomic Sciences.

Over the past ten years, Dr. Ehrlich and J. Christopher Post, M.D., Ph.D., FACS, an Allegheny General Hospital pediatric ear specialist and medical director of the Center for Genomic Sciences, have pioneered the biofilm theory to explain the persistence of chronic ear infections. In 2002, the team published in JAMA (Apr 2002; 287: 1710 – 1715) the first animal evidence of biofilms in the middle ear, setting the stage for the current clinical investigation.

According to co-investigator Joseph E. Kerschner M.D., "Today's study completely alters the concept about how physicians should approach the treatment of children with otitis media. This historic finding sheds new light on the decreasing efficacy of antibiotics in treating kids with ear infections and has serious implications about the future direction of therapeutic research." Dr. Kerschner is associate professor of otolaryngology at the Medical College and chief of pediatric otolaryngology at the College and Children's Hospital of Wisconsin, a major teaching affiliate of the College.

"Nearly all of the children in our study who suffered from chronic otitis media tested positive for biofilms in the middle ear, even those who were asymptomatic.

It appears that in many cases recurrent disease stems not from re-infection as was previously thought and which forms the basis for conventional treatment, but from a persistent biofilm," Ehrlich said.

"Given that bacteria living in biofilms are metabolically resistant to antibiotics, this study makes a definitive, scientifically-based statement against the use of these drugs to treat children with chronic ear infections. It simply does not help the child and increases the risk of breeding more resistant strains of bacteria," he said.

Characterized as either an acute or chronic disease, otitis media (OM) is the most common illness for which children visit a physician, receive antibiotics or undergo surgery in the United States. There are two subtypes of chronic OM: recurrent OM (ROM) is diagnosed when children suffer repeated infections over a span of time and during which clinical evidence of the disease resolves between episodes, and chronic OM with effusion is diagnosed when children have persistent fluid in the ears that lasts for months in the absence of any other symptoms except conductive hearing loss.

Though antibiotics have proven to be effective for children with acute OM where biofilms have not yet formed, those with chronic disease typically benefit little from the drugs and more so from myringotomy, a surgical procedure in which small tubes are placed in the eardrum to continuously drain infectious fluid (called effusion).

Working with Dr. Kerschner, Drs. Ehrlich and Post obtained middle ear muscosa – or membrane tissue - biopsies from children undergoing myringotomy for OM with effusion (OME) and ROM. The team gathered uninfected mucosa biopsies from children and adults undergoing cochlear implantation as a control.

Using advanced confocal laser scanning microscopy, three dimensional images were obtained of the biopsies and evaluated for biofilm morphology using generic stains and species-specific probes for Haemophilus influenzae, Streptococcus pneumoniae and Moraxella catarrhalis by Luanne Hall Stoodley, Ph.D. and her ASRI colleagues. Effusions, when present, were also evaluated for evidence of pathogen specific nucleic acid sequences (indicating presence of live bacteria).

The study found mucosal biofilms in the middle ears of 46/50 children (92%) with OME and ROM. Biofilms were not observed in eight control middle ear mucosa specimens obtained from cochlear implant patients.

"Our findings demonstrate what we have suspected for years, that children with chronic otitis media have biofilms in their middle ears. Healthy children do not. The idea of treating recurrent disease with antibiotics therefore is not supported by the scientific evidence," Dr. Post said. "Chronic middle ear infection is not the result of a sterile inflammatory process, but an indolent bacterial disease. Understanding that, we can now begin to explore more effective treatments for it."

Dr. Post said future therapies may be medical, technological or biological in nature, including the use of probiotics – an approach in which children are deliberately populated – but not infected – with good bacteria that prevent the formation of biofilms. In an ongoing study at the University of Florida, researchers are inoculating children against cavities using a bacteria that sets up house in their teeth where plaque biofilms usually grow.

"The idea with chronic middle ear infections would be to engineer a bacteria that could occupy the nasopharynx but not cause recurring infection," Dr. Post said.

"Until something new comes along, however, placement of ear tubes to provide children with symptomatic relief will still be necessary and recommended. Antibiotics should also continue to be prescribed for acute otitis media to help prevent potentially serious complications, such as mastoiditis and meningitis," Dr. Kerschner said.

This research was supported by the AGH Allegheny Singer Research Institute, the Medical College of Wisconsin and grants from the National Institute on Deafness and other Communication Disorders and the Health Resources and Services Administration of the U.S. Department of Health and Human Services.