title: Comparison of the antibiotic activities of Daptomycin, Vancomycin, and the investigational Fluoroquinolone Delafloxacin against biofilms from Staphylococcus aureus clinical isolates.
abstract: Biofilm-related infections remain a scourge. In an in vitro model of biofilms using Staphylococcus aureus reference strains, delafloxacin and daptomycin were found to be the most active among the antibiotics from 8 different pharmacological classes (J. Bauer, W. Siala, P. M. Tulkens, and F. Van Bambeke, Antimicrob. Agents Chemother. 57:2726-2737, 2013, doi:10.1128/AAC.00181-13). In this study, we compared delafloxacin to daptomycin and vancomycin using biofilms produced by 7 clinical strains (S. aureus epidemic clones CC5 and CC8) in order to rationalize the differences observed between the antibiotics and strains. The effects of the antibiotics on bacterial viability (resazurin reduction assay) and biomass (crystal violet staining) were measured and correlated with the proportion of polysaccharides in the matrix, the local microenvironmental pH (micro-pH), and the antibiotic penetration in the biofilm. At clinically meaningful concentrations, delafloxacin, daptomycin, and vancomycin caused a ≥25% reduction in viability against the biofilms formed by 5, 4, and 3 strains, respectively. The antibiotic penetration within the biofilms ranged from 0.6 to 52% for delafloxacin, 0.2 to 10% for daptomycin, and 0.2 to 1% for vancomycin; for delafloxacin, this was inversely related to the polysaccharide proportion in the matrix. Six biofilms were acidic, explaining the high potency of delafloxacin (lower MICs at acidic pH). Norspermidine and norspermine (disassembling the biofilm matrix) drastically increased delafloxacin potency and efficacy (50% reduction in viability for 6 biofilms at clinically meaningful concentrations) in direct correlation with its increased penetration within the biofilm, while they only modestly improved daptomycin efficacy (50% reduction in viability for 2 biofilms) and penetration, and they showed marginal effects with vancomycin. Delafloxacin potency and efficacy against biofilms are benefited by its penetration into the matrix and the local acidic micro-pH.
authors.affiliation: Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Wafi
authors.initials: W
authors.lastname: Siala
authors.affiliation: Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Marie-Paule
authors.initials: MP
authors.lastname: Mingeot-Leclercq
authors.affiliation: Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium.
authors.forename: Paul M
authors.initials: PM
authors.lastname: Tulkens
authors.affiliation: Laboratoire de Microbiologie et Centre de Référence Belge des Staphylocoques, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Marie
authors.initials: M
authors.lastname: Hallin
authors.affiliation: Laboratoire de Microbiologie et Centre de Référence Belge des Staphylocoques, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.
authors.forename: Olivier
authors.initials: O
authors.lastname: Denis
authors.affiliation: Pharmacologie Cellulaire et Moléculaire, Louvain Drug Research Institute, Université Catholique de Louvain, Brussels, Belgium francoise.vanbambeke@uclouvain.be.
authors.forename: Françoise
authors.initials: F
authors.lastname: Van Bambeke
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D018441:Biofilms / Q000187:drug effects*; D017576:Daptomycin / Q000494:pharmacology*; D024841:Fluoroquinolones / Q000494:pharmacology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000302:isolation & purification; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability / Q000187:drug effects; D011073:Polyamines / Q000494:pharmacology; D011135:Polysaccharides, Bacterial / Q000096:biosynthesis; D013095:Spermidine / Q000031:analogs & derivatives / Q000494:pharmacology; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D014640:Vancomycin / Q000494:pharmacology*
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D011073:Polyamines; D011135:Polysaccharides, Bacterial; D013096:Spermine; C017921:norspermine; C006760:norspermidine; D014640:Vancomycin; D017576:Daptomycin; D013095:Spermidine
references.citation: BMC Microbiol. 2009 Oct 28;9:229
references.pmid: 19863820
references.citation: J Antimicrob Chemother. 2013 Jul;68(7):1642-9
references.pmid: 23515247
references.citation: Infect Immun. 2014 Mar;82(3):1017-29
references.pmid: 24343648
references.citation: Antimicrob Agents Chemother. 2012 Dec;56(12):6366-71
references.pmid: 23070152
references.citation: Appl Environ Microbiol. 2005 May;71(5):2501-10
references.pmid: 15870340
references.citation: Antimicrob Agents Chemother. 2006 Mar;50(3):841-51
references.pmid: 16495241
references.citation: J Antimicrob Chemother. 2012 Nov;67(11):2682-5
references.pmid: 22796888
references.citation: Antimicrob Agents Chemother. 2006 Dec;50(12):4011-7
references.pmid: 17015630
references.citation: Antimicrob Agents Chemother. 2004 Sep;48(9):3625-9
references.pmid: 15328144
references.citation: Antimicrob Agents Chemother. 2005 Jun;49(6):2467-73
references.pmid: 15917548
references.citation: PLoS One. 2009 Jun 09;4(6):e5822
references.pmid: 19513119
references.citation: Antimicrob Agents Chemother. 2011 Sep;55(9):4081-9
references.pmid: 21709082
references.citation: FEMS Immunol Med Microbiol. 2006 Jun;47(1):75-82
references.pmid: 16706790
references.citation: Trends Microbiol. 2001 Jan;9(1):34-9
references.pmid: 11166241
references.citation: Antimicrob Agents Chemother. 2000 Jul;44(7):1818-24
references.pmid: 10858336
references.citation: Antimicrob Agents Chemother. 2004 Jul;48(7):2771-7
references.pmid: 15215148
references.citation: Int J Med Microbiol. 2002 Jul;292(2):107-13
references.pmid: 12195733
references.citation: J Infect. 2014 Jun;68(6):548-52
references.pmid: 24412247
references.citation: Annu Rev Med. 2008;59:415-28
references.pmid: 17937586
references.citation: Am J Physiol. 1998 Dec;275(6):H1937-47
references.pmid: 9843791
references.citation: J Bacteriol. 1997 May;179(9):2863-71
references.pmid: 9139901
references.citation: Int J Antimicrob Agents. 2007 Oct;30(4):366-8
references.pmid: 17616359
references.citation: Cell. 2014 Feb 13;156(4):844-54
references.pmid: 24529384
references.citation: Carbohydr Polym. 2013 Sep 12;97(2):253-61
references.pmid: 23911443
references.citation: Antimicrob Agents Chemother. 2012 Jun;56(6):3349-58
references.pmid: 22450986
references.citation: Antimicrob Agents Chemother. 2011 Jul;55(7):3510-6
references.pmid: 21576433
references.citation: Antimicrob Agents Chemother. 2013 Jun;57(6):2726-37
references.pmid: 23571532
references.citation: FEMS Microbiol Lett. 2006 Feb;255(1):11-6
references.pmid: 16436056
references.citation: J Antimicrob Chemother. 2010 Sep;65(9):1955-8
references.pmid: 20615927
references.citation: J Biomed Biotechnol. 2012;2012:976972
references.pmid: 22701309
references.citation: Antimicrob Agents Chemother. 2011 Feb;55(2):649-58
references.pmid: 21135179
references.citation: Antimicrob Agents Chemother. 2008 Apr;52(4):1446-53
references.pmid: 18195062
references.citation: Antimicrob Agents Chemother. 2009 Sep;53(9):3880-6
references.pmid: 19564363
references.citation: J Intern Med. 2012 Dec;272(6):541-61
references.pmid: 23025745
references.citation: Cell. 2012 Apr 27;149(3):684-92
references.pmid: 22541437
references.citation: Antimicrob Agents Chemother. 2007 Dec;51(12):4255-60
references.pmid: 17923487
references.citation: Antimicrob Agents Chemother. 2012 Feb;56(2):613-7
references.pmid: 22123684
references.citation: J Antimicrob Chemother. 2005 Dec;56(6):1103-6
references.pmid: 16223937
references.citation: J Bacteriol. 2003 Mar;185(5):1485-91
references.pmid: 12591863
references.citation: Int J Antimicrob Agents. 2012 Apr;39(4):356-9
references.pmid: 22364716
references.citation: J Antimicrob Chemother. 2007 Feb;59(2):246-53
references.pmid: 17220162
references.citation: Science. 1999 May 21;284(5418):1318-22
references.pmid: 10334980
references.citation: Antimicrob Agents Chemother. 2010 Oct;54(10):4329-34
references.pmid: 20696880
references.citation: J Bacteriol. 2012 Sep;194(17):4494-504
references.pmid: 22661688
references.citation: Antimicrob Agents Chemother. 2012 Jun;56(6):2967-75
references.pmid: 22450987
references.citation: Antimicrob Agents Chemother. 2009 Aug;53(8):3505-7
references.pmid: 19451285
references.citation: J Bacteriol. 2008 Feb;190(3):1097-107
references.pmid: 17993532
references.citation: J Antimicrob Chemother. 2012 Dec;67(12):2814-20
references.pmid: 22875850