We tried to identify some of the causes of the discrepancy between the innovative strategies evaluated in basic research and those that eventually reach clinical testing. We considered issues directly related to the antibiofilm agents, including toxicology, safety profile, insurgence of resistance, and regulatory framework; and discrepancies due to the heterogeneous approaches used to study a multifactorial system such as a biofilm.
First, the properties of an antimicrobial strategy are not only linked to efficacy and potency, but also to its application, cost, environmental impact, materials compatibility, cytotoxicity, and safety [i]. A revolution in the concept of traditional antibiotics, antiseptics and disinfectants is underway and the term “antibiofilm”, introduced in the ‘90s [ii], describes a paradigm shift in microbiology [iii]. New approaches under consideration include new antibiotic molecules [iv] and alternative strategies, such as the use of metal ions [v], cationic compounds [vi], quorum sensing inhibitors [vii], enzymes [viii], bacteriophages [ix], peptides [x], proteins, and other compounds interfering with bacterial metabolism, for instance sequestering necessary metal ions [xi].
Antibiotic concentrations that kill planktonic cells could be ineffective on their biofilm counterpart [xii]. Yet, many studies only consider minimal inhibitory concentration (MIC) values to assess the potential strength of a treatment, even though this parameter is inferred from tests conducted on planktonic cells. This turns into poor predictability or negative outcomes from clinical trials [xiii,xiv]. Similarly, the parameters used to predict antibiofilm activities, such as minimal biofilm inhibitory concentration (MBIC) and minimal biofilm eradication concentration (MBEC), which are typically higher than MIC, do not find correspondence in clinical translations [xiii]. Stoodley et al 2011 [xv], for example, described that during orthopedic infections, sessile cells within biofilms could survive for six weeks, in spite of very intensive antibiotic therapy. Slime functions as a protection for bacterial communities and the defense mechanisms of each strain inside the matrix could protect other strains from external attacks, making them more resistant than free cells.
Other factors worthy of note are the emergence of drug resistance, the impact on host microbiome, and the toxicological profile of new antibiofouling therapies. Resistance, defined as the ability of a strain to multiply in the presence of an antimicrobial compound, affects clinically relevant bacterial strains such as the so-called ESKAPEE: Enterococcus faecalis, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumanii, Pseudomonas aeruginosa or Enterobacter spp [xvi,xvii]. Intense antimicrobial administration and their slow release in the case of modified devices have a strong impact on the emergence of resistant strains. Horizontal gene transfer, by means of transduction, transformation, bacterial conjugation or biofilm creation, may spread resistance to antimicrobial molecules [18]. Other approaches are affected too, since metal ions, such as silver, seem to lead to resistance [xix,xx,xxi,xxii]. Furthermore, intensive and prolonged antimicrobial treatments can negatively influence intestinal and oral microbiomes, resulting in side effects that could reduce the patient’s quality of life [ii]. In the case of biofilms, resistance becomes even more complex, as these structures display different kinds of defense mechanisms than planktonic cells. Once biofilms are established, bacteria can survive to otherwise lethal treatments, such as UV light, acidity, dehydration, and chemicals. Conventional therapies based on high doses of antibiotic molecules are often insufficient to achieve complete eradication, due to a number of characteristics of bacteria in biofilms, community structure and resilience [xxiii,xxiv].
Moreover, bacteria in biofilms typically display the presence of both antibiotic tolerance and resistance mechanisms, which contribute to biofilm recalcitrance to treatments [xxv].
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