THE CLINICAL CHALLENGE
Chronic infections affect 17 million people annually in the US, and approximately 550,000 people die as a result of their chronic infections.2 Modern medicine is beginning to acknowledge the significance of biofilms and their role in the pathogenesis and perpetuation of chronic disease and infection, as it is estimated that over 90% of chronic wound infections involve biofilm.19,20 With the explosion of diabetes and vascular disease, the world is seeing a rise in untreatable chronic wounds, resulting in an increased burden that impacts patients’ quality of life.10,16,21 Collectively, these chronic wounds contribute to significant morbidity, mortality, and increased healthcare expenditures.22
THE IMPACT OF BIOFILM IN THE TREATMENT OF CHRONIC INFECTION
Bacteria in biofilms are intrinsically resistant to antimicrobials, host immune response and biocides, with biofilm-bacteria exhibiting up to 1000-fold more antimicrobial resistance when compared to planktonic bacteria.23 This renders current therapeutic options inadequate to successfully eradicate the infection. Furthermore, for the treating clinician there is often an absence of definitive diagnostic data confirming the presence of biofilm, making the decision to remove infected hardware and/or tissue and treat with antimicrobial agents even more difficult.24 The decision involves balancing the relative risks of treating or not treating the infection, versus exposing a patient to the potential adverse effects of the available treatment strategies.
In the context of biofilm-based infections, dosages of antimicrobial drugs up to 500-1000 times the minimum inhibitory concentration are often required. However, even if these dosages were to be administered, they would have limited efficacy in successfully eradicating the infection.23 This is largely due to the difficulty antimicrobials encounter in penetrating the biofilm to expose the bacteria for elimination and removal.
In terms of optimal treatment of a biofilm-associated infection, it is essential that an approach involving multiple concurrent strategies is employed, including the use of an anti-biofilm agent.12
CHRONIC INFECTIONS AFFECT
ANNUALLY IN THE US
people die as
a result of
Bacteria in biofilm exhibit up to 1000-fold more antimicrobial resistance when compared to planktonic bacteria23
CHALLENGES IN DETECTING AND MANAGING BIOFLIM
Biofilm-associated chronic infections remain a diagnostic challenge. Typically, they are not visible to the naked eye and are difficult to confirm via the traditional culture methods that are commonly used to confirm acute infections resulting from planktonic phenotype bacteria. Such culture tests are not without cost, are slow to be processed in the hospital setting (taking up to 72 hours) and are most often inadequate to detect the presence of biofilm.18 PCR is a faster alternative, but this is also limited by cost and availability. Compounding this further is the common requirement for a positive culture result to be returned prior to the initiation of many pharmacological treatments.
From a diagnostic standpoint, bacteria that inhabit chronic infections set up complex polymicrobial biofilm communities that can only be detected by culture techniques when they happen to detach a sufficient bolus of planktonic cells that can be grown on conventional culture media.24 Consequently, chronic biofilm infections often yield negative culture results even when multiple clinical signs point to infection. This poses a significant challenge for the treating clinician in terms of how to proceed in treating what is a clinically diagnosed chronic biofilm infection, despite it returning negative culture results and generating insufficient data on antibiotic resistance and susceptibility.
ANTIMICROBIAL RESISTANCE AND BIOFILM
The continuing rise in antimicrobial resistance necessitates effective diagnosis and management of biofilm-associated infections.19 Biofilm cells have been demonstrated to exhibit a higher resistance to antibiotics and biocides25 than planktonic cells, up to 1000-fold.23 The mechanism of resistance is not completely understood, with research implicating multiple factors, including:
- EPS Matrix:
The majority of the resistance of the bacteria in a biofilm population is conveyed by the EPS matrix16, whereby the polymeric slime layer creates a physical barrier impeding penetration of antimicrobials to reach the biofilm bacteria.16,17 Additionally, various products within the EPS, such as waste products, RNA, and proteins, react with the antimicrobials further preventing antimicrobial interaction with the biofilm bacteria.16
- Metabolic Adaptation25:
Bacteria within the biofilm slow or arrest their growth rate, which is known as metabolic quiescence. When bacteria are in this dormant state antimicrobials that act by targeting a cellular synthetic process are rendered useless due to the relative lack of cellular synthetic activity, ultimately resulting in a 15-fold greater resistance to antimicrobials when compared to planktonic bacteria.17
- Altered Genetics:
Differential gene and protein expression amongst the biofilm community creates varying levels of resistance and methods of resistance throughout the community. It also enables resistance to be shared amongst the community via horizontal gene transfer.25
- Altered Stress Response:
The host immune response and the presence of free radicals and reactive oxygen species creates low levels of oxidative stress, which favours the development of biofilm and induces a local inflammatory response.26 The initiation and regulation of this self-protective response is facilitated by quorum sensing.25
- Presence of Persister Cells:
Persister cells are bacterial cells that maintain a state of dormancy and as such are highly tolerant to antimicrobial treatment. These cells facilitate the re-establishment of the biofilm matrix following antimicrobial treatment that is not completely effective.27,16
THE CONTINUING RISE IN ANTIMICROBIAL RESISTANCE NECESSITATES EFFECTIVE DIAGNOSIS AND MANAGEMENT OF BIOFILM-ASSOCIATED INFECTIONS.19