Burkholderia cepacia Complex Phage-Antibiotic Synergy (PAS): Antibiotics Stimulate Lytic Phage Activity

Abstract

The Burkholderia cepacia complex (Bcc) is a group of at least 18 species of Gram-negative opportunistic pathogens that can cause chronic lung infection in cystic fibrosis (CF) patients. Bcc organisms possess high levels of innate antimicrobial resistance, and alternative therapeutic strategies are urgently needed. One proposed alternative treatment is phage therapy, the therapeutic application of bacterial viruses (or bacteriophages). Recently, some phages have been observed to form larger plaques in the presence of sublethal concentrations of certain antibiotics; this effect has been termed phage-antibiotic synergy (PAS). Those reports suggest that some antibiotics stimulate increased production of phages under certain conditions. The aim of this study is to examine PAS in phages that infect Burkholderia cenocepacia strains C6433 and K56-2. Bcc phages KS12 and KS14 were tested for PAS, using 6 antibiotics representing 4 different drug classes. Of the antibiotics tested, the most pronounced effects were observed for meropenem, ciprofloxacin, and tetracycline. When grown with subinhibitory concentrations of these three antibiotics, cells developed a chain-like arrangement, an elongated morphology, and a clustered arrangement, respectively. When treated with progressively higher antibiotic concentrations, both the sizes of plaques and phage titers increased, up to a maximum. B. cenocepacia K56-2-infected Galleria mellonella larvae treated with phage KS12 and low-dose meropenem demonstrated increased survival over controls treated with KS12 or antibiotic alone. These results suggest that antibiotics can be combined with phages to stimulate increased phage production and/or activity and thus improve the efficacy of bacterial killing.

Synergistic antimicrobial activity of bacteriophages and antibiotics against Staphylococcus aureus

“…1A). This is in good agreement with previous studies showing that sublethal concentration of antibiotics stimulated phage production and thus enhanced phage lytic activity (14,15). The lytic activity was positively influenced by the changes in the state of the host cells exposed to antibiotics, resulting in enhanced free phages (15).…”

“…Many researchers have demonstrated that combining phages with antibiotics can be a promising way to improve antimicrobial activity, known as phageantibiotic synergy (PAS) (13)(14)(15)(16)(17). The lytic activity of phageshas been shown to be synergistically enhanced in the presence of antibiotics (14). However, this phenomenon is still not clearly understood, and relatively little knowledge exists on antibiotic-resistant S. aureus.…”

Rapid evolution of generalized resistance mechanisms can constrain the efficacy of phage–antibiotic treatments

“…This is in contrast with previous studies reporting beneficial effects of phage–antibiotic combinations on Escherichia coli biofilms (Ryan, Alkawareek, Donnelly, & Gilmore, 2012) and planktonic P. aeruginosa cultures (Torres‐Barceló et al., 2016). However, phage–antibiotic effects are not always observed (Verma et al., 2009), which could be due to the specific phage species and class of antibiotic as PAS often requires mechanistic compatibility between the two (Chan et al., 2016; Comeau et al., 2007; Kamal & Dennis, 2015). For example, it has recently been reported that associations between phage and gentamycin resistance are predominantly positive, while associations between phage and ciprofloxacin resistance are mainly negative with natural and clinical E. coli isolates (Allen, Pfrunder‐Cardozo, Meinel, Egli, & Hall, 2017).…”

“…Positive correlation between phage selection and antibiotic resistance is in contrast with previous studies showing an opposite effect where phage treatment reduced the emergence of antibiotic resistance (Jalasvuori, Friman, Nieminen, Bamford, & Buckling, 2011; Zhang & Buckling, 2012). One explanation for this discrepancy is that phage–antibiotic synergies could be very specific to the given phage species and type of antibiotics, whereas antibiotic selection‐mediated susceptibility to phages could have been driven by some degree of collateral sensitivity (Chan et al., 2016; Comeau et al., 2007; Kamal & Dennis, 2015). …”

Targeting Enterococcus faecalis Biofilms with Phage Therapy

“…Phage therapy is being considered, again, for use both in the food industry and in medicine (25). In addition, several reports showed that phage therapy improved (26)(27)(28), and in some cases was even more successful than (29,30), antibiotic treatment.…”