Tolerance of Biofilms to Antimicrobials

TOLERANCE OF BIOFILMS TO ANTIMICROBIALS

With the discovery of antibiotics the world changed. Acute infectious diseases, the leading cause of morbidity and mortality in humans, became treatable, resulting in an increase in life expectancy and quality of life. While infections continue to be a leading contributor to mortality, they are often associated with pre-existing conditions that compromise the patient. However, what became known as the ‘antibiotic era’ is now being compromised itself by the emergence of more and more antibiotic-resistant strains of bacteria that have caused modern medicine to question if we are not now entering the ‘post-antibiotic era’.

What is often ignored in these discussions of antimicrobial resistance and our reduced ability to treat infection is the fact that even in the halcyon times of antimicrobial therapy chronic or recurrent infections were poorly resolved with antibiotics. In fact, the designation of these infections as chronic was presumably derived due to their lack of responsiveness to antimicrobial therapy allowing them to become chronic or to recur in the face of therapy. Diseases such as recurrent ear infections in children, recurrent UTIs in women, and medical device-associated infections were and still remain a challenge to antimicrobial therapy, even when the isolates of these infections have been shown in vitro to be susceptible to antibiotics used in their treatment.

It is now recognized that these chronic infections involve bacteria associated within biofilms. In fact the US Food and Drug Administration (FDA) and Centers for Disease Control (CDC) both state that more than 60% of North American infections involve biofilms. We also now recognize that the confounding issue in the treatment of chronic infections is the inherent tolerance of biofilms to antibiotics predicted to have efficacy against the organism on the basis of planktonic susceptibility testing. In fact, Ceri and colleagues demonstrated that for an antibiotic to be effective in biofilms can require a concentration over 1000 times that needed to treat the same planktonic population (Ceri et al. 1999); concentrations that cannot be achieved or used safely in patient treatment. This altered tolerance to drugs is an adaptation of the biofilm, as bacteria derived from the biofilm show the same susceptibility profile as planktonics when the organisms are returned to the planktonic growth phase.

This reduced susceptibility to antibiotics differs from antibiotic resistance in a number of fundamental ways. First, this tolerance is only demonstrated when the isolate is in the biofilm mode of growth and is lost when the culture is returned to planktonic growth, hence it is not a permanent genetic change. Secondly, tolerance implies that the biofilm is not killed by the antimicrobial but it may not necessarily be able to grow in the presence of the drug, whereas in resistance the organism can grow in the presence of the antimicrobial. The tolerance of biofilm populations to antimicrobials would imply that in many instances of chronic infections microbes are in fact exposed to sublethal concentrations of drug, which may be an important implication in the development of classical antimicrobial resistance.