Only new bacteriophage breakthroughs at-scale will solve ABR—that requires innovation

Nicola Principi, Ettore Silvestri, and Susanna Esposito, "Advantages and Limitations of Bacteriophages for the Treatment of Bacterial Infections," Front. Pharmacol. 10:513, 5-8-2019, 

Potential Advantage of Bacteriophage (BP) Use to Treat Bacterial Infections

Theoretically, there are no bacteria that cannot be lysed by at least one BP. In this regard, BPs are significantly more effective than antibiotics, as, although some antimicrobial drugs have a very large spectrum of activity, an antibiotic able to kill all the bacterial species does not exist. However, the most attractive characteristic of BPs is their specificity of action, i.e., their ability to kill only the pathogen that they can recognize.

They have a very narrow spectrum of activity, which avoids the most important problem strictly related to the antibiotic administration, i.e., the influence on the entire microbiome with elimination of potentially beneficial bacteria, the overgrowth of secondary pathogens and the emergence of resistant bacteria (Domingo-Calap and Delgado-Martínez, 2018). Use of BPs without modification of the microbiota has been reported by several studies in both animals and humans. In mice, oral administration of four T4-like BPs effective against diarrhea-associated E. coli did not lead to any collateral damage of non-pathogenic bacteria of the same species (Chibani-Chennoufi et al., 2004). In humans, data confirming the specificity of BP action were shown in the study conducted by Sarker et al. (2012). These authors administered for 2 days an oral cocktail of nine T4-like E. coli BPs to 15 healthy adults. After a wash-out of 5 days, even though the given BPs could be detected in the feces of almost all treated subjects, no modification of gut microbiota composition was evidenced.

In comparison to antibiotics, BPs are supposed to have several other advantages. It is thought that BPs are significantly safer and better tolerated, as they replicate only in the target bacterium but cannot infect mammalian cells. This conclusion seems supported by all the experiences gathered in the past in Eastern Europe and all the studies carried out more recently in experimental animals and humans, which have not reported significant adverse events following BP administration (Kakasis and Panitsa, 2018). Moreover, administration is easier, as BPs do not need repeated administrations shortly after one another over several days, as is commonly required for antibiotics because they can remain in the human body for relatively prolonged periods of time, i.e., up to several days (Bogovazova et al., 1991, 1992). In general, very few doses are needed because of the increase in BP concentration in the site of infection after the initial administration. Contrarily to antibiotics, their effect is limited to the site of infection that can be reached, even when bacteria are situated in a body organ or system in which antimicrobials can hardly penetrate. A lytic phage, EC200(PP), active against S242, a fatal neonatal meningitis E. coli strain, was evaluated in models of meningitis with 100% fatality. Though low titres of the BP were detected in the central nervous system, treatment 1 and 7 h post-infection rescued 100% of pups (Pouillot et al., 2012).

Using the new cost-effective, large-scale DNA sequencing and DNA synthesis technologies, BPs can be engineered to be able to overcome some limitations of antibiotic treatment. A good example of this is given by the evidence that BPs can disperse biofilm, a structure that makes infections difficult to eradicate with standard antibiotic therapy even if bacteria are sensitive to the administered drug. In an in vitro study, Lu and Collins engineered a BP affective against an E. coli producing biofilm to express a biofilm-degrading enzyme (Lu and Collins, 2007). A simultaneous attack to the bacterial cells and the biofilm matrix was possible. The results were very encouraging, as the engineered BP reduced bacterial biofilm cell count by approximately 99.9%. Moreover, BP genetic modifications can help to fight bacterial resistance to antibiotics. Edgar et al. (2012) introduced in lysogenic phages the genes rpsL and gyrA, which confer sensitivity in a dominant fashion to two antibiotics, streptomycin and nalidixic acid, respectively. They found that, after engineering, the minimal inhibitory concentrations of bacterial strains previously defined resistant to these drugs were significantly reduced to levels usually found in sensitive pathogens.

Finally, the use of BPs might be less expensive than that of antibiotics whose targets are multidrug-resistant pathogens. In a small group of patients suffering from methicillin-resistant Staphylococcus aureus infection, Miedzybrodzki et al. (2007) found that use of BPs significantly reduced healthcare costs.