Bacteriophages (phages) offer several advantages over antibiotics. First, their high specificity ensures the destruction of target bacteria while preserving the beneficial microbiota of the host organism. Second, phage numbers self-regulate depending on the presence of target bacteria: a reduction in the number of target bacteria as a result of phage therapy leads to inhibition of phage reproduction and their gradual elimination, following the bacteria. Third, phages are able to change just as easily as bacteria, therefore they can adapt and infect bacteria that were previously insensitive to them.

Read also: Antibiotics and bacteriophages: stronger together?

Although the widespread use of phages as monotherapy for severe infections is currently impossible for various reasons (primarily due to the lack of data from large, controlled clinical trials), it is known that their use in combination with antibiotics can significantly improve treatment effectiveness. Here are several key points that explain this phenomenon.

Bacteriophages and antibiotics can exhibit synergy , which is manifested in particular by a decrease in the minimum inhibitory concentration (MIC) – the lowest concentration of an antimicrobial drug that prevents the growth of microorganisms. The synergy between phages and antibiotics was first described by Comeau et al. (2007), who found that sublethal concentrations of antibiotics can stimulate the production of virulent phages. They studied the activity of the fMFP phage against Escherichia coli (MFP strain) in the presence and absence of the antibiotic cefotaxime. Cefotaxime at a concentration of 50 ng/ml was found to enhance the effect of phages. In another study, Oechslin et al. (2017) examined the interaction of a phage cocktail and several antibiotics when used against Pseudomonas aeruginosa . The combined effect of meroponem, ciprofloxacin and phage cocktail resulted in a reduction in bacterial growth that was significantly greater than that achieved with antibiotic or phage monotherapy.

Biofilms are polysaccharide matrices that bacteria form to protect themselves from antimicrobial agents and immune factors. Phages secrete enzymes, such as depolymerases and endolysins, that can degrade biofilms. In vitro analysis of biofilms formed by P. aeruginosa showed that a combination of phages and antibiotics had the highest activity against the pathogen (Chaudhry et al., 2017).

Read also:Bacteriophages against biofilms in chronic wounds

Decreasing a bacterium's sensitivity to one agent (a phage) can restore its sensitivity to another (an antibiotic) . The presence of phages is responsible for a certain selection process in bacterial cultures: those that have developed resistance to the phages present in the environment gain an advantage. However, it often happens that a mutation that confers resistance to a phage simultaneously makes the bacterium more sensitive (or restores previously lost sensitivity) to a particular antibiotic (Chan et al., 2016). Ho et al. (2018) cites an example of such a phenomenon, where an epaR mutation resulted in decreased sensitivity of the bacterium Enterococcus faecalis (OG1RF) to a bacteriophage and increased sensitivity to the antibiotic daptomycin.

Clinical cases of antibiotic and phage synergy have also been described. In particular, Schooley et al. (2017) treated necrotizing pancreatitis caused by multidrug-resistant Acinetobacter baumannii in a 68-year-old patient using intravenous and intracavitary administration of two pathogen-specific phage cocktails and the antibiotic monocycline. All previously used antibiotic regimens had been ineffective in this patient.

The results of randomized, placebo-controlled phase II clinical trials are presented, according to which, in patients with Staphylococcus aureus bacteremia, a combination of antibiotics (standard therapy) with phage endolysins provided a better response than antibiotics and endolysins alone (Fowler et al., 2019).

The addition of bacteriophages to standard therapy for bacterial diseases has many advantages, but a number of issues still need to be clarified, including optimal combination treatment regimens, treatment duration, long-term impact on bacterial resistance to antibiotics, etc.

Literature

Chan BK, Sistrom M, Wertz JE, Kortright KE, Narayan D, Turner PE. Phage selection restores antibiotic sensitivity in MDR Pseudomonas aeruginosa. Sci Rep. 2016;6:26717. doi: 10.1038/srep26717.

Chaudhry WN, Concepción-Acevedo J, Park T, Andleeb S, Bull JJ, Levin BR. Synergy and order effects of antibiotics and phages in killing Pseudomonas aeruginosa biofilms. PLoS One. 2017;12(1):e0168615. doi: 10.1371/journal.pone.0168615.

Comeau AM, Tétart F, Trojet SN, Prère MF, Krisch HM. Phage-antibiotic synergy (PAS): beta-lactam and quinolone antibiotics stimulate virulent phage growth. PLoS One. 2007;2(8):e799. doi: 10.1371/journal.pone.0000799.

Fowler VG, Das A, Lipka J, Schuch R, Cassino C. Exebacase (Lysin CF-301) improved clinical responder rates in methicillin-resistant Staphylococcus aureus (MRSA) bacteremia including endocarditis compared to standard-of-care antibiotics alone in a first-in-patient phase 2 study. Presented at: 29th European Congress of Clinical Microbiology and Infectious Diseases; April 13-16, 2019; Amsterdam, Netherlands. Presentation L0012

Ho K, Huo W, Pas S, Dao R, Palmer KL. Loss-of-function mutations in epaR confer resistance to fNPV1 infection in Enterococcus faecalis OG1RF. Antimicrob Agents Chemother. 2018;62(10):e00758-18. doi: 10.1128/AAC.00758-18.

Oechslin F, Piccardi P, Mancini S, et al. Synergistic interaction between phage therapy and antibiotics clears Pseudomonas aeruginosa infection in endocarditis and reduces virulence. J Infect Dis. 2017;215(5):703-712. doi: 10.1093/infdis/jiw632.

Schooley RT, Biswas B, Gill JJ, et al. Development and use of personalized bacteriophage-based therapeutic cocktails to treat a patient with disseminated resistant Acinetobacter baumannii infection. Antimicrob Agents Chemother. 2017;61(10):e00954-17. doi: 10.1128/AAC.00954-17.