Fighting Pathogenic Bacteria on Two Fronts: Phages and Antibiotics as Combined Strategy

Abstract

With the emerging threat of infections caused by multidrug resistant bacteria, phages have been reconsidered as an alternative for treating infections caused by tenacious pathogens. However, instead of replacing antibiotics, the combination of both types of antimicrobials can be superior over the use of single agents. Enhanced bacterial suppression, more efficient penetration into biofilms, and lowered chances for the emergence of phage resistance are the likely advantages of the combined strategy. While a number of studies have provided experimental evidence in support of this concept, negative interference between phages and antibiotics have been reported as well. Neutral effects have also been observed, but in those cases, combined approaches may still be important for at least hampering the development of resistance. In any case, the choice of phage type and antibiotic as well as their mixing ratios must be given careful consideration when deciding for a dual antibacterial approach. The most frequently tested bacterium for a combined antibacterial treatment has been Pseudomonas aeruginosa , but encouraging results have also been reported for Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Enterococcus faecalis , and Burkholderia cepacia . Given the immense play area of conceivable phage-antibiotic combinations and their potential excess value, it is time to recapitulate of what has been achieved so far. This review therefore gathers and compares the results from most relevant studies in order to help researchers and clinicians in their strategies to combat multidrug resistant bacteria. Special attention is given to the selected bacterial model organisms, the phage families and genera employed, and the experimental design and evaluation (e.g., in vitro vs. in vivo models, biofilm vs. planktonic culture experiments, order and frequency of administration etc.). The presented data may serve as a framework for directed further experimental approaches to ultimately achieve a resolute challenge of multidrug resistant bacteria based on traditional antibiotics and phages.

High-throughput mapping of the phage resistance landscape inE. coli

“…Moreover, identifying phages that select for resistance that have interrelated phenotypic consequences with, for example, antibiotic sensitivity is a recent advancement in the field that could directly benefit from these screening approaches [52,89]. By combining fitness datasets for phages and antibiotics or phage-antibiotic combination therapies [235][236][237], such screens could provide an avenue for performing high-throughput search for genetic trade-offs or 'evolutionary traps' [52,89] that could provide a much-needed solution to overcome the antibiotic resistance pandemic.…”

Phage-Antibiotic Synergy is Driven by a Unique Combination of Antibacterial Mechanism of Action and Stoichiometry

“…One of the more attractive and feasible use of phages is to combine them with clinicallyused antibiotics, a sort of one-two punch on pathogenic bacteria (13). The combined use of phage and antibiotics may result in a number of outcomes.…”

“…However, the recent awareness of antagonism has propelled some in vitro assessment of phageantibiotic action prior to treatment to select for synergistic combinations, a personalized approach that has led to satisfactory therapeutic outcomes (15,16). Several phage-antibiotic combinations have been investigated in vitro and in vivo in multiple bacterial species (17,18) but there have been mixed results with combinatorial treatment (13,19,20). For instance, quinolones can be synergistic with phages against P. aeruginosa in one study while antagonistic in another (21,22).…”

Strategies to Combat Multidrug-Resistant and Persistent Infectious Diseases

“…Phage-antibiotic synergy (PAS) was demonstrated both in vitro and in vivo [94] and, even when no benefits were obtained, the emergence of antibiotic-or phage-resistant phenotypes was greatly minimized. The combination of phage therapy and antibiotics would also be of benefit because of the improved bacterial clearance together with the reduced bacterial capacity of developing resistance to one or both therapies, as concluded by Torres-Barceló and Hochberg [95] and Tagliaferri and colleagues [96]. Moreover, as with synthetic molecules with potential antibacterial effects, phages or phage-derived endolysins can be biochemically modified to extend the range of susceptible organisms.…”