It has been reported that the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) for biofilm bacteria are 10 to 1000 times higher than the corresponding values for isolated, planktonic bacteria.2 Therefore, it is much more difficult to obtain sufficiently high antibiotic concentrations to eradicate biofilm pathogens without risking renal or hepatic toxicity.
Biofilm infections should be suspected in the following settings3:
1. Chronic respiratory infections in patients with cystic fibrosis (often caused by Pseudomonas aeruginosa)
2. Clinical signs of infection or inflammation that are nonresponsive or only temporarily responsive to antibiotic administration (even in the absence of positive cultures)
3. Poorly healing wounds
4. Presence of implantable devices, in-dwelling catheters, or orthopedic prosthetic devices
Biofilms may elude detection via traditional culture and sensitivity methods. To diagnose and characterize biofilm infections properly, specialized techniques may be required: tissue biopsy, removal of the implicated device, precision microscopy, sonication of tissue or device specimens, immunochemistry, polymerase chain reaction (PCR) detection, or, in the case of certain pathogens, antibody response.
Treating biofilm infections
Combating biofilm infections requires a concerted multidisciplinary approach4 comprising the following steps5:
1. Removal of the affected foreign body (or draining of abscesses or debridement)
2. Proper selection of biofilm-active and well-penetrating antibiotics to which the infecting bacteria are sensitive
3. Topical or systemic administration of antibiotics in high doses and often in combination
4. Administration of newly identified agents that retard the formation of or promote the dispersal of biofilms
Identification of new treatment agents that act against biofilms is the target of much ongoing research because in many cases, even the highest doses of combinations of conventional or novel antibiotics given for prolonged periods may result in treatment failures.
One promising avenue of research seeks to identify “anti-quorum sensing” agents. These compounds interdict the intra-organism signaling that prompts individual microbes to form aggregates. Once a quorum is reached, the bacteria or fungi change their gene expression, close ranks, and elaborate mucopolysaccharides that comprise the biofilm matrix.
Candidate anti-quorum sensing agents include furanones (modeled after red algae, which produce this substance on their surface to retard microbial colonization); the antibiotic azithromycin; and ebselen, an inhibitor of cyclic dimeric GMP (c-di-GMP), a bacterial signaling agent.
While we await the development and mainstreaming of innovative pharmacologic strategies for combating quorum sensing, some studies have confirmed the anti-quorum sensing potential of natural agents. Chinese ginseng5 and garlic6 possess documented anti-quorum sensing properties. Ginseng offers an additional mode of action against biofilms via its ability to promote bacterial motility while retarding bacterial swarming.7
Another strategy to combat biofilms currently being researched is to interfere with the formation of amyloid-like fibers that contribute to bacterial aggregation. While research is under way to identify candidate agents, the Food and Drug Administration (FDA) has yet to approve any. On the botanical side, it is of interest that parthenolides, which are natural derivatives of the feverfew plant, invoke this mechanism to disrupt preexisting biofilms. Parthenolides have also been found to prevent the formation of bacterial biofilms.8
Lactoferrin, a component of the innate defense against pathogens, is another natural substance that is under consideration for attenuating biofilms.9 Lactoferrin is a natural iron sequestrant. By analogy, the metal and mineral chelator disodium EDTA (ethylenediaminetetraacetic acid) has also been found to exert anti-biofilm effects.10
Natural enzymes have been proposed as a way of “digesting” the mucopolysaccharide matrix that comprises a biofilm. A screening of proteases and polysaccharidases revealed specificities for certain biofilm constituents.11
Among the most intriguing and readily available agents available for retarding the formation of biofilms is the 5-carbon polyol sugar xylitol. Xylitol has long been incorporated in chewing gum, toothpastes, and mouthwashes, and it has been used as a low-calorie sugar substitute. Along with a related polyol sweetener erythritol, xylitol has been reported to have inhibitory effects on growth and adherence in some oral bacteria.12