title: Synergy and Order Effects of Antibiotics and Phages in Killing Pseudomonas aeruginosa Biofilms.
abstract: In contrast to planktonic cells, bacteria imbedded biofilms are notoriously refractory to treatment by antibiotics or bacteriophage (phage) used alone. Given that the mechanisms of killing differ profoundly between drugs and phages, an obvious question is whether killing is improved by combining antibiotic and phage therapy. However, this question has only recently begun to be explored. Here, in vitro biofilm populations of Pseudomonas aeruginosa PA14 were treated singly and with combinations of two phages and bactericidal antibiotics of five classes. By themselves, phages and drugs commonly had only modest effects in killing the bacteria. However some phage-drug combinations reduced bacterial densities to well below that of the best single treatment; in some cases, bacterial densities were reduced even below the level expected if both agents killed independently of each other (synergy). Furthermore, there was a profound order effect in some cases: treatment with phages before drugs achieved maximum killing. Combined treatment was particularly effective in killing in Pseudomonas biofilms grown on layers of cultured epithelial cells. Phages were also capable of limiting the extent to which minority populations of bacteria resistant to the treating antibiotic ascend. The potential of combined antibiotic and phage treatment of biofilm infections is discussed as a realistic way to evaluate and establish the use of bacteriophage for the treatment of humans.
authors.affiliation: National University of Sciences and Technology, Islamabad, Pakistan.|Department of Biology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Waqas Nasir
authors.initials: WN
authors.lastname: Chaudhry
authors.affiliation: Department of Biology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Jeniffer
authors.initials: J
authors.lastname: Concepción-Acevedo
authors.affiliation: Department of Molecular Biosciences, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Taehyun
authors.initials: T
authors.lastname: Park
authors.affiliation: National University of Sciences and Technology, Islamabad, Pakistan.
authors.forename: Saadia
authors.initials: S
authors.lastname: Andleeb
authors.affiliation: Department of Integrative Biology, The University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: James J
authors.initials: JJ
authors.lastname: Bull
authors.affiliation: Department of Biology, Emory University, Atlanta, Georgia, United States of America.
authors.forename: Bruce R
authors.identifier: http://orcid.org/0000-0003-3600-2780
authors.initials: BR
authors.lastname: Levin
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D018441:Biofilms / Q000187:drug effects / Q000254:growth & development; D002460:Cell Line; D004847:Epithelial Cells / Q000378:metabolism / Q000382:microbiology; D006801:Humans; D008954:Models, Biological; D017105:Pseudomonas Phages / Q000378:metabolism*; D011550:Pseudomonas aeruginosa / Q000502:physiology / Q000821:virology
chemical_list: D000900:Anti-Bacterial Agents