This conference served as an excellent opportunity to address difficulties in the antimicrobial and infection prevention industries. Most notably, product development and testing required by the regulatory agencies were discussed, along with the lack of direction for marketing claims and FDA/EPA acceptance of anti-biofilm products. Additionally, the process of Pre-Submission through the FDA was outlined and further highlighted the challenges of getting products to market without adequate regulatory guidelines put in place.
Skin injection and material colonization were assessed for dermal fillers (DF). Injection testing showed variability in bioburden and suggested that differences in techniques yielded inconsistency in infections. Skin preparation testing of 70% ethanol, chlorhexidine, and povidone iodine wipes showed performance differences based on both composition and texture. Increasing stiffness of DF reduced bacterial adhesion; however, stiffer materials created a niche for bacterial biofilm. Results may be used to develop guidelines for clinicians on how to reduce contamination and show that infection rates might be lowered with DF that can reduce bacterial adhesion but also self-seal.
Research described how biofilms initiate on a device and how an established biofilm persists amid host defenses and antimicrobial chemistry. Failure of an antimicrobial to fully penetrate the biofilm was observed. Mechanisms of biofilm tolerance depend on nutrient reduction within the biofilm leading to slow growth or dormancy and consequently, reduced susceptibility. This diffusion predicts thicker biofilms will become progressively more protected.
Four clinical cases were reviewed to evaluate medical device infections in which biofilms affect clinical management. The medical literature and treatment guidelines were reviewed for each case and the roles of diagnostics were presented in the context of current standards of care. The FDA Pre-Submission program was discussed in reference to regulatory considerations for expediting anti-biofilm device submissions.
Animal models that center on implant associated infections were explained. Monitoring tissue concentrations of antibiotic compounds by means of sampling various tissue compartments from a joint model designed to study efficacy of intervention was found to be most effective.
The FDA Pre-Submission program is formatted as a formal request for feedback from the FDA to help guide product development and preparation. A Phase-1 clinical study on Microbion’s Bismuth Thiol (BT) topical gel was completed in 2011. This study, along with GLP toxicology studies supported a 2013 IND application with the FDA for a Phase-2 clinical trial to evaluate the safety and efficacy of BT gel for local treatment of post-surgical orthopedic device-related infections, in combination with surgery. In 2012, a long term GLP toxicology study was completed and supported future development of BT gel as a treatment for chronic wound infections. These evaluations, along with a recently completed topical clinical trial, were provided to the FDA for further guidance on generating an approval process for an anti-biofilm drug product.
Multiple antibiotic resistant organisms are often isolated from hospital environments. The persistence of these bacteria in the environment is due to their incorporation into biofilms contaminating dry hospital surfaces, which renders them tolerant to desiccation and cleaning procedures. Surfaces of a hospital were sampled and the presence of drug resistant bacteria incorporated into biofilms was determined using a combination of PCR, FISH, next-generation sequencing, confocal microscopy, and SEM. A model test system was developed that visually resembled clinical dry surface biofilms.
Biofilm formation has extensive implications in a variety of applications, ranging from industrial processes like oil drilling, paper production, and food processing, to medicine and dentistry. The challenges of biofilm detection and control were discussed with the use of case studies from these fields. An industry perspective of standard biofilm methodologies and performance standards for EPA regulation of biofilm control suggests that there is dissatisfaction with the lack of testing methods for anti-biofilm claims.
The EPA is considering the use of the ASTM Single Tube Method (ASTM E2871-13) as an efficacy method to support the registration of antimicrobial products with anti-biofilm claims. In 2014, a collaborative study was conducted to evaluate the method’s performance. This study yielded unexpected variability in log reduction values for the high-efficacy treatments. A splashguard was developed to reduce this variability and was utilized in additional 2015 collaborative testing, where bleach and a quaternary-ammonium product (at high and low level concentrations) were tested against a P. aeruginosa biofilm. The preliminary findings suggest this may be an acceptable route and the industry expectation is that the method may be approved by the agency within 2 to 4 years. Upon acceptance by the EPA, BioScience Laboratories, Inc. has the capability to meet our customer's testing needs.
A performance standard (PS) for an antimicrobial test method defines an acceptable outcome for a product. The PS also specifies the number of tests that should be performed and the number of laboratories utilized for product evaluation. The specifications set by a PS can be evaluated by two statistical characteristics: the confidence level of the PS, which is the percentage of ineffective products that the PS correctly fails; and the power of the PS, which is the percentage of efficacious products that the PS correctly passes. This approach was recently applied to reset the PS for the use-dilution method required by US EPA for registration of surface disinfectants.
An update to the EPA’s current registration pathway for products making anti-biofilm efficacy claims was presented. The EPA is considering registration of antimicrobial pesticides including those products making efficacy claims against biofilm. The EPA’s framework for registering anti-biofilm products was highlighted. Performance standards and the role of test parameters will be explored, focusing on the specific data requirements and their relationship to test methodology and label claims. The EPA representative could not comment on a timeline.
P&G have developed a system for the photocatalyzed generation of aqueous chlorine dioxide. Photocatalysis allows for product application without build-up of high concentrations. Initial results suggest that ClO2 can disrupt biofilms, resulting in partial removal of the biofilm from the test surface. Future tests will seek to better understand the ability of photo-ClO2 to remove and/or kill biofilms. This research will hopefully initiate a dialogue with the EPA about biofilm removal claims versus efficacy claims.