Biofilms implicated in chronic disease.

One way that organisms protect themselves from antimicrobials and the body's immune system is by forming biofilms. A biofilm is a community of organisms, encased in a sticky polysaccharide matrix, that live cooperatively. They share resources and communicate via chemical signals. The sticky film allows the colony to cleave to wet surfaces, including living tissue, catheters, metal and synthetic prostheses, and medical and dental implants. Biofilms lie at the heart of many recurrent bacterial and fungal infections and account 80% of all microbial illness, according to the National Institutes of Health's Center for Integrative Biology and Infectious Diseases. Biofilms in themselves do not cause tissue damage. Rather, damage is primarily due to inflammation incited by biofilms.

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Most of our current understanding about infectious illness comes from studies of lone (planktonic) bacteria that readily succumb to antibiotics; but "it is now clear that bacteria in the clinical environment live more often as communities of microorganisms (biofilms) than as single cell suspensions," says NIH. Microbial survival greatly increases when organisms live in communities. In a sense, they create a protective fort that withstands the body's defenses and resists antimicrobial therapies. Even if antibiotics kill much - even most - of a community, "persister" cells survive to rebuild. Some researchers, like N. G. Cogan, believe that these persister cells exhibit "a different phenotype whose expression is regulated by the growth rate [of the biofilm] and the antibiotic concentration."

In vitro research and mathematical models indicate that low-dose, periodic dosing of specific antimicrobials can diminish biofilms. Timothy D. Starner and colleagues found that azithromycin "at subinhibitory concentrations" inhibits nontypeable Haemophilus influenzae (NTHi) biofilm formation and significantly lessens biofilm mass. NTHi causes otitis media, chronic bronchitis in emphysema, and early airway infections in cystic fibrosis. Curiously, this decrease in biofilm formation and mass occurs even though bacteria remain viable. The researchers found that gentamicin, whose antimicrobial action resembles azithromycin, does not inhibit biofilm formation even though it delays bacterial growth. Antibiotic "shock and awe" bombardment may be counterproductive when dealing with biofilms. Cogan and P. De Leenheer, biological mathematicians at University of Florida (Gainesville, Florida), report in a 2008 study that "genuine periodic protocols can be more advantageous [than continuous antibiotic administration] in treating a wide variety of bacterial infections."

Pulsed, low-dose antibiotic therapy is not the only way to deal with biofilms. In her review article, Kim Lewis of Tufts University says that electromagnetic fields or ultrasound in conjunction with antibiotic therapy showed promise in early studies. William Costerton, former director of Montana State University's renowned Center for Biofilm Engineering, wants to use the bacteria's chemical language. He says, "The strategy has changed from killing the bacteria, which creates an antibiotic resistance, to instead getting the bacteria to stop making toxins or to leave their protected slime caves and take their chances with the body's defenses.'" Costerton has also suggested using immune modulators to treat chronic illnesses caused by biofilms. Other strategies may arise as we learn more about the body's natural defenses. For example, mucous membranes apparently have an innate biofilm-defense system that normally inhibits the formation of these microbial communities. To learn more, NIH's National Institute of Dental and Craniofascial Research (NIDCR) is funding research studies that focus on a host body's response to bacterial biofilms.

Arthur J. Costerton retires from MSU's Center for Biofilm Engineering [press release]. Montana State University News. April 27, 2004. Available at: www.montana.edu/cpa/news/nwview.php?article-1673. Accessed April 18, 2009.

Cogan NG. Effects of persister formation on bacterial response to dosing [abstract]. J Theor Biol. February 7, 2006; 238(3):694-703. Available at: www.pubmed.gov.Accessed April 18, 2009.

De Leenheer P, Cogan NG. Failure of antibiotic treatment in microbial populations [abstract]. J Math Biol. Epub December 16, 2008. Available at: www.pubmed.gov. Accessed April 18, 2009.

Lewis K. Riddle of biofilm resistance. Antimicrob Agents Chemother. April 2001;45(4):999-1007. Available at: http://aac.asm.org. Accessed April 14, 2009.

National Institute of Dental and Craniofascial Research. Immunology of biofilms. December 20, 2008 [last update]. Available at: www.nidcr.nih.gov/GrantsAndFunding/See_Funding_Opportunities_Sorted_By/ConceptClearance/CurrentCC/lmmuneBiofilm.htm. Accessed April 18, 2009.

Starner TD, Shrout JD, Parsek MR, Appelbaum PC, Kim CH. Subinhibitory concentrations of azithromycin decrease nontypeable Haemophilus influenzae biofilm formation and diminish established biofilms. Antimicrob Agents Chemother. January 2008;52(1):137-145. Available at http://aac.asm.org. Accessed April 14, 2009.

briefed by Jule Klotter

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