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.
Highlights
The counts do not give information about the pharmacokinetics of the antibiotics and population and evolutionary dynamics of the bacteria and phage during treatment, and our tests of synergy and facilitation are limited to single time points
The results sections is partitioned according to (A) simultaneous, combination treatment of ‘pure’ biofilms on polystyrene ( ‘plastic’), (B) staggered, combination treatment of biofilms grown on plastic, (C) combination treatment of drug-resistant and drug-sensitive cells grown on plastic, and (D) simultaneous, combination treatment of biofilms grown on epithelial cells
In response to the increasing frequencies of pathogens resistant to multiple antibiotics, there has been a resurgence of interest in theoretical and experimental studies exploring the efficacy of bacteriophage in combination with antibiotics to treat bacterial infections [14,15,16, 28, 47]
Summary
A few studies demonstrated the efficacy of phage and antibiotic combinations on planktonic cultures of P. aeruginosa [14,15,16] and biofilms [30]. We provide additional support for the clinical potential of using combinations of antibiotics and phage to treat biofilm infections with P. aeruginosa. (4) These biofilm cultures were treated in one of two ways, (4a) Fresh LB with the phage
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