Otitis media (middle ear infection) is the second most common infectious disease in children after the common cold. Although the body’s own natural defenses would cure most cases of otitis media after about 72 hours, the pain and suffering children feel often drives parents and pediatricians to alleviate the problem with a course of antibiotic treatment. However, physicians are beginning to observe an alarming increase in cases of otitis media that are caused by bacteria with a resistance to antibiotics.
Antibiotic resistance can arise in multiple ways. For starters, bacteria are diehards with interesting defense mechanisms that allow them to minimize their exposure to antibiotics, as well as to our body’s own defense system (e.g., antibodies, antimicrobial molecules and immune cells). These stealth survival tactics can enable bacteria to stay alive and resurge even after a course of antibiotic treatment. Regardless of bacteria’s evasive maneuvers, their ability to resist antibiotics is always associated with increased antibiotic use. Indeed, the over-prescription of antibiotics for the treatment of middle ear infections appears to be the major contributing factor to the emergence of antibiotic-resistant middle ear infections. Of course, other factors, such as failure to complete a course of treatment and indiscriminate antibiotic use (such as in the farming industry), are also important.
Besides leading to the creation of super-bugs, frequent use of antibiotics can have other complications in young children. In addition to causing nausea, diarrhea or allergic reactions, recent studies have shown that there may be a link between extensive exposure to antibiotics at a young age and the occurrence of asthma later on. Avoiding antibiotic treatment unless absolutely necessary can thus be beneficial for many reasons.
When Good Bacteria Go Bad
The bacteria that cause otitis media are normal inhabitants of our nose and throat. The three most common otitis media pathogens are Streptococcus pneumoniae, nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis. We believe that these “peaceful” (non-pathogenic) inhabitants of the throat and nose turn sinister as they undergo a pathogenic transformation, either before they invade the middle ear or in the region where the nose and throat meet.
The middle ear is the cavity behind the eardrum that contains the three small bones (ossicles) responsible for transmitting sound from the eardrum to the inner ear (cochlea). The middle ear is connected to the junction of the nose and throat, a region called the nasopharynx, through the Eustachian tube. This tube normally prevents the access of bacteria to the middle ear cavity while at the same time equalizing pressure between the middle ear and outside air that is breathed in through the nose and mouth. Under certain conditions, however, bacteria make their way up the Eustachian tube and get into the middle ear. Once inside the middle ear, the bacteria multiply and attach to the cells lining the cavity causing the middle ear cells to secrete many molecules, including mucus. In some cases the amount of mucus produced can be quite high. Fluid in the middle ear can potentially lead to conductive hearing loss which, left untreated, can impede cognitive development during critical learning periods.
The reasons why harmless bacteria journey to the middle ear and then “join the dark side” are currently being studied. One possible cause could be that the Eustachian tube cells lose the tiny hairs on their surface. These tiny hairs, called “cilia,” help move mucus covering the cells back down the Eustachian tube. The mucus, containing bacteria and other trapped particles, is then swallowed. It is also possible that middle ears become more susceptible to bacterial colonization during, or just after, an infection by an upper respiratory virus (e.g., influenzae virus).
Mysteries of the Dark Side
Between 40 and 60 percent of patients with chronic otitis media with effusion (an infection where the only symptoms are fluid in the middle ear) have an absence of culturable bacteria in their middle ear fluid. However, these “sterile” fluids contain DNA, proteins and other cell components from otitis media bacteria, indicating that bacteria are present in the middle ear. The presence of phantom bacteria may be pointing to otitis media as a biofilm disease.
Biofilms are communities of bacteria glued together in sticky material that they secrete. These biofilms are important structures for the bacteria because they help attach the bacteria to cells and other surfaces. The biofilms act as a shield to protect bacteria from antibiotic and antibody attack and from being eaten by specialized immune cells called macrophages.
Bacteria that grow in biofilms are able to survive high doses of antibiotic treatment that could otherwise kill free-floating, non-biofilm bacteria. There is some evidence to suggest that antibiotics can even promote biofilm formation in some bacteria. Recent evidence strongly suggests that bacteria adhering to the middle ear cells can form biofilms. In current research funded by the Deafness Research Foundation, we are examining the ways that otitis media bacteria construct and maintain biofilms. Knowing how the bacteria can form biofilms will help us understand ways to interfere with the biofilm-forming process.
Innate Immune Molecules: The Force Is Within You
The health of the nose, throat, Eustachian tube and the middle ear is maintained in part by anti-microbial proteins and peptides whose function is to defend these tissues against microbial invasion. Some antimicrobial peptides are always on hand like peacekeeping forces; others are induced in response to crises – infection or inflammation.
Due to the rapid rise in antibiotic resistance among otitis media pathogens, the American Academy of Pediatrics in 2004 has recommended that doctors and parents of children with middle ear infection adopt a “watchful waiting” regimen, where antibiotics are given only if the infection does not resolve within 72 hours. The fact of the matter is that the antimicrobial proteins and peptides in the middle ear can clear an infection without resorting to antibiotics in the majority of cases. These powerful molecules can inhibit biofilm formation and kill the bacteria in the middle ear.
Otitis Media Vaccines
The good tidings of the body’s innate ability to heal itself do nothing to calm the cries of a child in pain. While waiting for those excruciating 72 hours to pass, many parents are probably wondering why middle ear infection cannot be readily prevented. One possibility for preventing the disease is to develop a vaccine that will simply stop otitis media from occurring. Renewed interest in vaccine development has resulted in several pneumococcal vaccines (against Streptococcus pneumoniae) that are effective against otitis media. Vaccines against the two other bacteria primarily responsible for otitis media, NTHi and Moraxella catarrhalis, are also in development.
The pneumococcal-CRM197 conjugate vaccine is now routinely used in infants and toddlers to prevent invasive pneumococcal disease. This vaccine is a mixture of seven purified pneumococcal capsular molecules taken from the seven different bacteria that cause 80 percent of invasive pneumococcal disease in children and approximately 60 percent of pneumococcal acute otitis media.
A study more than 10 years ago showed that inactivated influenza A virus vaccine reduced the incidence of acute otitis media associated with influenza A by 83 percent and decreased the overall incidence of acute otitis by 36 percent. Results of another study done in the United States also showed that in comparison to control groups, vaccinated children had 32 percent fewer episodes of acute otitis media during the influenza season. Moreover, children vaccinated with an intranasally delivered, live-attenuated influenza virus vaccine had a 30 percent drop in episodes of acute otitis media in which the patient had a fever. The vaccine was shown to be 93 percent effective against culture-confirmed influenza.
Bringing a vaccine to market can take many years. The first step is for scientists to identify antigens that can be targeted by the vaccine. Obtaining sufficient numbers of patients on which to perform these trials can be difficult, especially for vaccines, where larger numbers are needed to screen for rare complications that might occur in response to antigen injection. Once the clinical trials have been completed and have proven successful, an application is then sent to the FDA to obtain formal approval to use the target antigen as a vaccine. Development of vaccines is not a trivial process. The initial research can take years to find suitable target antigens; the initial production of vaccines for the clinical trials requires an expensive batch facility; the clinical trials have to be designed and suitable patients have to be identified.
We think of a vaccine as a way of preventing painful childhood diseases. Yet another benefit of vaccines that are effective in preventing otitis media is the reduction of antibiotic use and the possibility of creating antibiotic-resistant strains of disease.
Paul Webster, Ph.D., is a scientist and head of the Ahmanson Advanced EM and Imaging Center at the House Ear Institute (HEI) in Los Angeles, Calif. He received his education in the United Kingdom (B.Sc. at Sheffield and Ph.D. at Brunel University in London) where his long-standing interest in finding out how pathogens affect cells and how cells counter attacks from pathogens was first stimulated. He has over 100 peer-reviewed publications on this subject. Hired by HEI from Yale University, where he ran a shared imaging facility, Dr. Webster has also lived and worked in Germany and Kenya.
Jose N. Fayad, M.D., is an associate at the House Clinic in Los Angeles, Calif. He received his medical degree from University Paul Sabatier in Toulouse, France, followed by residency at the University’s Hospital Purpan in Toulouse and a research fellowship at HEI in Los Angeles. Formerly on the faculty of the University of Southern California and the College of Physicians and Surgeons, Columbia University, N.Y., Dr. Fayad sits on the editorial review board of several peer-reviewed publications. He has authored and co-authored more than 50 papers and book chapters on hearing disorders and has presented more than 100 papers at medical conferences.
Ali Andalibi, Ph.D., is director of New Technology and Project Development and section chief for Gene Based Therapy in HEI’s Cell and Molecular Biology Department. He is principal and co-investigator on research studies including those focused on the pathogenesis of ear diseases. Dr. Andalibi oversees multiple cell and molecular biology projects including, among others, the role of innate immunity in otitis media. He has co-authored numerous articles for publications. A native of California, Dr. Andalibi attended the University of California at Los Angeles to earn his doctorate in Microbiology and Molecular Genetics.
