Center for Biofilm Engineering

Culprit in Ear Infections is a 'Biofilm' that Protects Bacteria

by Cathryn M. Delude

Parents whose children have recurrent ear infections often feel they spoon gallons of antibiotics into their children, only to hear a troubling diagnosis from the doctor: Yes, the drugs cured the infection, but there's still fluid in the ear. That fluid is supposedly harmless, except for the worrisome fact that it can partially block hearing. Now, scientists think that remaining fluid might be even more menacing. 

Scientists are finding that many persistent infections, including many middle-ear infections, may be caused by bacteria lurking in a dormant state inside a slimy film that protects them from antibiotics. The seemingly innocuous fluid behind the ear drum is actually a microbe-laden ''biofilm,'' harboring bacteria that become activated under the right conditions, according to a paper published in last month's Journal of the American Medical Association. 

In other words, children with recurring ear infections are not re-infected by new bacteria from the outside world, as once surmised. Rather, they are re-infecting themselves with their own biofilm. Casting the spotlight on the true culprits, biofilms, may lead to future treatments that could prevent recurring infections and get rid of that worrisome fluid once and for all. 

''This research provides a theoretical model that explains why this fluid doesn't respond to antibiotics, and why some kids don't get better,'' said Dr. Bruce Mirvis, a pediatrician in Columbus, Ohio. ''It helps us understand why these infections can take so long to clear up.'' 

This revised understanding of ear infections is part of a paradigm shift in microbiology. Traditionally, scientists studied bacteria in their free-floating form, the way microbes grow in a petri dish. They assumed that bacteria lived the same way in nature - as solo, planktonic organisms, each doing its own thing. Nothing could be farther from the truth, according to Dr. William Costerton, a longtime biofilm researcher at Montana State University's Center for Biofilm Engineering. ''In nature, probably 99 percent of bacteria live in biofilms.'' 

This is how an ear infection could progress, according to this new theory about biofilms. The initial pain and fever of acute ear infections are caused by free-floating, ''planktonic'' bacteria that actively attack the ear's tissue, Costerton said. Antibiotics kill off those free-floating bacteria, and the symptoms disappear. 

The ear drum, however, is coated with a slimy reservoir of hibernating bacteria. Those inactive bacteria don't cause the symptoms of an active infection, but eventually some bacteria ''shower off'' and become free-floating aggressors again. They re-infect the ear, causing renewed inflammation, and another round of doctor's visits. See illustration from Your World. (pdf file)  Currently, American doctors write 25 to 30 million antibiotic prescriptions a year for ear infections, and more than 2 million children a year undergo surgery, in which tiny tubes are inserted to drain the fluid from their ears. 

Biofilms form when bacteria settle on a wet surface, whether on a rock in a stream, a water pipe, your tooth, or your eardrum. The bacteria secrete a sticky substance that glues them to the surface. Then, they signal others to settle down with them. Like ants in a colony, they specialize, building intricate architectural structures in the film. Towers and mushroom shapes appear, creating high-rise housing for multiple species of bacteria and even fungi. Tunnels emerge, channeling nutrients and wastes around like a primitive circulatory system. 

Dr. Roberto Kolter, professor of microbiology and molecular genetics at Harvard Medical School, describes them as a multicellular, social ''macro-organism.'' 

Bacteria prefer the slimy, communal life because it protects them from toxins in their environment, Costerton said. Killing bacteria in a biofilm requires up to 1,000 times more antibiotics than it takes to kill free-floating bacteria. The film physically prevents antibiotics from reaching the bacteria in the interior. In addition, those bacteria are dormant and nondividing, and most antibiotics act only against dividing cells. Thus, even if antibiotics do seep in, they may not kill the bacteria. 

Dr. Garth Ehrlich, executive director of the Center for Genomic Sciences at Allegheny Singer Research Institute in Pittsburgh, came across Costerton's work in 1996. He wondered whether biofilms could explain some of the perplexities of ear infections. 

Medical literature describes the fluids or ''effusions'' from the middle ear as ''culturally sterile,'' meaning bacteria cannot be isolated from them to grow in the lab. Yet researchers had found tell-tale genetic traces of living bacteria in biofilms - pieces of bacterial RNA, a product of a living organism that lasts for only seconds. ''That was strong circumstantial evidence that there were living bacteria in the effusion,'' Ehrlich said. 

Still, it was like finding suspicious fingerprints on a bank vault, without finding the thieves. To catch the culprits, he needed a surveillance system. He teamed up with Costerton to see if they could catch bacteria in the act of forming biofilms in the ear. 

First, they infected the ears of chinchillas with Haemophilus influenzae, one of the bacteria known to cause ear infections. (The rodents succumb to the same ear infections as humans.) They took samples from the middle ears at regular intervals and produced 3-D images of them, using high-tech microscopic photography. These images showed the characteristic pillars and mushrooms of biofilms developing over a three-week period. Furthermore, a dye taken up by living bacteria revealed bacteria living throughout the biofilm - colorful, visual evidence that the fluids are not sterile after all. 

This research appeared in the April 3 Journal of the American Medical Association, which usually does not publish articles on basic research without immediate implications for clinical practice. ''They published in [the Journal] for a reason,'' said Dr. Margaret Kenna, an ear, nose, and throat specialist at Children's Hospital in Boston. ''In the long run, it could have a big impact on our ability to treat ear infections.'' 

Doctors caution, however, that it may take years before new biofilm drugs are available. First, scientists must unravel the genes that enable bacteria to build biofilms. ''Bacteria use a different genetic program when they form biofilms,'' Ehrlich explained. ''They undergo a metamorphosis, like a caterpillar turning into a moth.'' 

Driving this metamorphosis are molecular communication signals - known as ''quorum sensing'' - that bacteria use to take stock of their surroundings. Microbia Inc. in Cambridge is developing small molecule drugs that will jam these signals and dissolve the biofilms, forcing bacteria into their free-floating state. ''Then we can clean them out with antibiotics,'' Dr. Bart Henderson explained. 

During the metamorphosis to a biofilm, bacteria also flip a genetic switch to become more resistant to antibiotics, reported Eliana Drenkard and Frederick Ausubel of Harvard Medical School in a study of the biofilms recently implicated in the lung infections in cystic fibrosis, published in the April 18 Nature. A drug that disables that switch could, in effect, kill two birds with one stone: making the bacteria both free-floating and more antibiotic-susceptible. 

''The development of biofilm control agents could have a profound impact on medicine and public health,'' said Kolter, the Harvard microbiologist. 


This story ran on page C5 of the Boston Globe on 5/28/2002. 

Published with permission:

Cathryn M. Delude
The Writing Company
http://www.thewritingco.com
Cathryn@thewritingco.com

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