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Antimicrobials can exert specific physiological effects when used in combination that are different from those when applied alone. These effects include physiological effects (i.e. synergy, antagonism and suppression) as well as evolutionary effects on the selection of resistant strains (i.e. cross-resistance and collateral sensitivity). While combination effects have been extensively mapped for antibiotic-antibiotic combinations, the combination effects of antibiotics with antimicrobials used as biocides or antiseptics have not been systematically investigated.
Here, we investigated the physiological and evolutionary consequences of combinations of antibiotics (meropenem, gentamicin and ciprofloxacin) and substances used as biocides or antiseptics (octenidine, benzalkonium chloride, cetrimonium bromide, chlorhexidine, povidone-iodine, silver) on growth and selection of Pseudomonas aeruginosa. We find prevalent physiological combination effects with synergy occurring 6 times and antagonism occurring 10 times. The effects are specific to the antibiotic-biocide combination with meropenem showing a tendency for antagonism with biocides (6 of 7), while gentamicin has a tendency for synergy (5 of 7). A particular strong antagonism is apparent for the meropenem-chlorhexidine combination, for which we conducted an in-depth study on the underlying molecular mechanism using RNASeq. Moreover, we find widespread effects of the biocide-antibiotic combinations on selection of P. aeruginosa strains resistant to the antibiotics, including cross-resistance and collateral sensitivity.
In conclusion, antibiotics and biocides or antiseptics exert physiological and evolutionary combination effects on the pathogen P. aeruginosa. These effects have consequences for the efficacy of both types of substances and for the selection of antimicrobial resistant strains in clinical applications with combined exposure (e.g. wound care, coated biomaterials).