In the hunt for more effective approaches against biofilms, combined modalities are emerging as the most promising, being the biofilm a multifactorial and multicom-ponent structure [i]. These approaches have the same relevance both in clinical trials and in basic research studies and consist of the combination of two or more antibiotics or other functional molecules/agents to enhance their effect and hit multiple targets in the unique and complex structure of biofilms (e.g., combination of an antibiotic with an AMP against both planktonic and biofilm forms [ii,iii]).
The combination of several antibiotic drugs is widely explored in the search for appropriate synergies between molecules to enhance their therapeutic effect and minimize antagonistic effects between chosen agents [iv,v]. The combination of antimi-crobial compounds with mechanical or physical strategies for biofilm removal is also investigated; techniques such as ultrasound or laser therapy are studied to improve antibiotic diffusion inside the slime [vi] and are conventionally used in orthopedics or dentistry [vii,viii].
Moreover, in basic research more than in clinical practice, metals (such as gold or silver nanoparticles), natural extracts, and phages sometimes replace or enhance con-ventional antibiotics [ix,x,xi,xii,xiii].
For instance, Al-Khafaji et al, 2019 found a synergistic effect between biosynthesized AuNPs with amoxicillin/clavulanate against clinical isolates, providing an opportunity to minimize antibiotic concentration [xiv].
Dickey and Perrot, 2019 demonstrated the synergistic effect of phages with low antibiotic concentration against S. aureus biofilm to prevent development of antimi-crobial resistance [xv].
Generally, these studies have successful results [xvi], at least in vitro, suggesting that promising combination strategies will be probably implemented into the clinical practice in the near future.
In contrast to the variety of strategies found in basic research studies, combination approaches tested in clinical trials only include conventional drugs, likely due to the lack of effective substitutes for antibiotic molecules. Despite all the promising and in-novative strategies investigated, the use of antibiotics, even in combination with other approaches, is still essential.
Zhang, Z.; Wagner, V.E. Antimicrobial Coatings and Modifications on Medical Devices. Berlin, Springer. 2017.
Grassi, L.; Maisetta, G.; Esin, S.; Batoni, G. Combination strategies to enhance the efficacy of antimicrobial peptides against bacterial biofilms. Front. Microbiol. 2017, 8:2409.
Algburi, A.; Comito, N.; Kashtanov, D.; Dicks, L.M.; Chikindas, M.L. Control of biofilm formation: antibiotics and beyond. Appl. Environ. Microbiol. 2017, 83(3):e02508-16.
Spoorthi, N.J.; Vishwanatha, T.; Reena, V.; Divyashree, B.C.; Aishwarya, S.; Siddhalingeshwara, K.G.; Ramesh, I. An-tibiotic synergy test: Checkerboard method on multidrug resistant Pseudomonas aeruginosa. IRJP. 2011, 2(12):196-198.
Doern, C.D. When does 2 plus 2 equal 5? A review of antimicrobial synergy testing. J. Clin. Microbiol. 2014, 52(12):4124-4128.
Teirlinck, E.; Xiong, R.; Brans, T.; Forier, K.; Fraire, J.; Van Acker, H.; Matthijs, N.; De Rycke, R.; De Smedt, SC.; Coenye, T.; Braeckmans, K. Laser-induced vapour nanobubbles improve drug diffusion and efficiency in bacterial biofilms. Nat. Commun. 2018, 9(1): 4518.
Quintas González, V.; Prada López, I.; Carreira, M.J.; Suárez Quintanilla, D.; Balsa Castro, C.; Tomás, I. In Situ Anti-bacterial Activity of Essential Oils with and without Alcohol on Oral Biofilm: A Randomized Clinical Trial. Front. Microbiol. 2017, 8:2162.
Peel, T.N. Studying Biofilm and Clinical Issues in Orthopaedics. Front. Microbiol. 2019, 10: 359.
Dettweiler, M.; Lyles, J.T.; Nelson, K.; Dale, B.; Reddinger, R.M.; Zurawski, D.V.; Quave, C.L. 2019, American Civil War plant medicines inhibit growth, biofilm formation, and quorum sensing by multidrug-resistant bacteria. Sci. Rep. 9(1): 7692.
Kannappan, A.; Balasubramaniam, B.; Ranjitha, R.; Srinivasa, R.; Abraham, S.V.P.I.; Balamurugan, K.; Ravi, A.V. In vitro and in vivo biofilm inhibitory efficacy of geraniol-cefotaxime combination against Staphylococcus spp. Food Chem. Toxicol. 2019, 125:322-332.
Salini, R.; Santhakumari, S.; Ravi, A.V.; Pandian, S.K. Synergistic antibiofilm efficacy of undecanoic acid and auxins against quorum sensing mediated biofilm formation of luminescent Vibrio harveyi. Aquaculture. 2019, 498:162-170.
Torres, N.S.; Montelongo-Jauregui, D.; Abercrombie, J.J.; Srinivasan, A.; Lopez-Ribot, J.L.; Ramasubramanian, A.K.; Leung, K.P. Antimicrobial and antibiofilm activity of synergistic combinations of a commercially available small compound library with colistin against Pseudomonas aeruginosa. Front. Microbiol. 2018, 9:2541.
Dickey, J.; Perrot, V. Adjunct phage treatment enhances the effectiveness of low antibiotic concentration against Staphylococcus aureus biofilms in vitro. PloS One. 2019, 14(1):e0209390
Al-Khafaji, M. H.; Hashim, M. H. The synergistic effect of biosynthesized gold nanoparticles with antibiotic against clinical isolates. J. Biotech. Res. 2019, 13(1), 58-62.
Dickey, J., Perrot, V. Adjunct phage treatment enhances the effectiveness of low antibiotic concentration against Staphylococcus aureus biofilms in vitro. PloS One, 2019, 14(1), e0209390.
Pollini, S.; Boncompagni, S.; Di Maggio, T.; Di Pilato, V.; Spanu, T.; Fiori, B.; Blasi, F.; Aliberti, S.; Sergio, F.; Rossolini, G.M.; Pallecchi, L. In vitro synergism of colistin in combination with N-acetylcysteine against Acinetobacter baumannii grown in planktonic phase and in biofilms. J. Antimicrob. Chemother. 2018, 73(9):2388-2395.