The Antibacterial Therapeutic Potential of Bacteriophages in the Age of Multidrug Resistance

The Antibacterial Therapeuty
The Antibacterial Therapeuty


Antibiotics revolutionized the anti-infectious therapy, becoming rapidly indispensable for both human medicine, veterinary medicine and agriculture. However, in recent years, the development of antibiotic-resistant bacteria has become a major global concern. Thus, in the European Union, antimicrobial resistance is responsible for 25,000 deaths per year, and the costs are about 1.5 billion euros. In September 2017, the World Health Organization released a report according to which only

8 out of 51 antibiotics belong to new classes, indicating a real problem in the development of antimicrobial medication. For these reasons, the return to the pre-antibiotic era” is rethought, and bacteriophage therapy is reconsidered as an alternative to antibiotics. Bacteriophages are the most abundant entities on Earth (approximately 1031 viral particles), having a fundamental role in the regulatory mechanisms of bacterial populations.

Anti-infectious therapy with bacteriophages was developed almost a decade before penicillin was discovered, and the increase in the number of multidrug-resistant pathogens has revitalized the interest in this therapy. Thus, several animal studies using bacteriophages to treat infections with Pseudomonas aeruginosa, Clostridium difficile, vancomycin-resistant Enterococcus faecium, β- lactamase-producing Escherichia coli, β-lactamase-producing Staphylococcus aureus have been performed. Clinical trials have also been performed, particularly in Staphylococcus aureus and Pseudomonas aeruginosa infections, which primarily focused on the safety of bacteriophages, as this still represents a major barrier to the development of bacteriophage therapy.

Research on the development of bacteriophages as antibacterial pharmaceuticals remains open and prospects for the future are optimistic.


Table of contents

1. Introduction

2. Animal models and clinical trials

3. Bacteriophages or antibiotics?

4. Conclusions


1. Introduction

Antibiotics have been critical in curing bacterial infections. [1]. However, bacteria are remarkably resilient and over time have developed numerous approaches to survive the attack by many of the antibiotics used today [2]. Although the evolution of resistant strains is a natural phenomenon, the overuse and misuse of antibiotics not only in human and veterinary medicine, but also in agriculture and commercial/industrial settings may have contributed to the dramatic rise in the prevalence of these antibiotic resistant bacterial strains [3].

Since the initial observations of phage-induced bacterial lysis, the biological nature of phage, as well as their therapeutic value, has been controversial.

Frederick Twort first described the characteristic zone of lysis associated with phage infection in 1915, but it was Felix d’Herelle who identified the source of this phenomenon, attributed the plaques to bacterial viruses, and coined the term bacteriophage”.

It was also d’Herelle who conceived of the idea to use phages therapeutically and is responsible for the first documented clinical use of phage in 1919 when phages were successfully used to treat 4 pediatric cases of bacterial dysentery [4]. Despite several successful trials, d’Herelle’s early experiments were poorly controlled and his research was disputed by the scientific community.

Felix dHerelle proposed the use of bacteriophages for the therapy of human and animal bacterial infections at the beginning of the 20th century.

This approach, however, was not widely accepted in the western countries.

After the emergence of antibiotics in 1940s, phage research was diverted to a more fundamental level.

At the same time, phage therapy was widely practiced in the Soviet Union due to collaboration of Felix dHerelle with his Georgian colleagues.


2. Animal models and clinical trials

Recent investigations using animal models have explored phage treatment against a range of clinically significant pathogens. When challenged with gut-derived sepsis due to P. aeruginosa, oral administration of phage saved 66.7% of mice from mortality compared to 0% in the control group.

In a hamster model of Clostridium difficile (C. difficile)-induced ileocecitis, a single dose of phage concurrent with C. difficileadministration was sufficient prophylaxis against infection; phage treatments post-infection saved 11 of 12 mice whereas control animals receiving C. Difficile and clindamycin died within 96 h [5, 6, 7].

In a 1938 clinical trial, 219 patients with bacterial dysentery (138 children and 81 adults) were treated solely with a phage cocktail consisting of a variety of phage targeting Shigella flexneri, Shigella shiga, E. coli, Proteus spp., P. aeruginosa, Salmonella typhi, Salmonella paratyphi A and B, Staphylococcus spp., Streptococcus spp. And Enterococcus spp.; cocktails were administered both orally and rectally.

Within 24 h, 28% of patients with blood in their stools were relieved of this symptom, with a further 27% showing improvement within 2-3 d. Overall, 74% of the 219 patients showed improvement or were completely relieved of symptoms [9].

Additionally, during a 1974 typhoid epidemic, a cohort of 18577 children was enrolled in a prophylactic intervention trial using typhoid phages. Phage administration resulted in a 5-fold decrease in typhoid incidence compared to placebo [10].

Currently there are no phage therapy products approved for human use in the EU or United States. However, in the food industry, there are several commercial phage preparations used for biocontrol of bacterial pathogens that are approved by the FDA under the classification of generally considered as safe.” These preparations are used against Salmonella spp., Listeria monocytogenes, MRSA, E. Coli O157:H7, Mycobacterium tuberculosis, Campylobacter spp., and Pseudomonas syringae, among others [10, 11].


3. Bacteriophages or antibiotics?

Both antibiotics and phages function as antibacterials that disrupt bacterial colonies through lysis or inhibition, yet several key differences make each antibacterial more or less appropriate depending on the situation.

Adverse reactions to antibiotics are well documented and include instances of anaphylaxis, nephrotoxicity, cardiotoxicity, hepatotoxicity, and neurotoxicity, as well as a number of gastrointestinal and hematological complications.

The majority of adverse reactions; in these rare instances the anaphylaxis is associated with specific classes of antibiotics or is the product of high tissue concentrations [12, 13].

In contrast to the comprehensive literature on antibiotic safety, phage therapy has only recently gained attention by western medicine and, as a result, much of the available information on phage safety is new.

Although oral phage administration is generally considered to be safe [14, 15], a major consideration for phage therapy is the translocation of phage across the intestinal epithelium where they subsequently circulate within the blood [15].

Some data show that phage translocation may benefit the host by downregulating the immune response to indigenous gut microbe antigens through the inhibition of interleukin-2, tumor necrosis factor, and interferon gamma production [16].

In stark contrast to antibiotics, phages tend to be specific towards both species and strain.

In certain situations, this can be a major advantage, considering the well-documented, collateral effects of broad-spectrum antibiotics on commensal gut microbes, which are notorious for secondary outcomes such as antibiotic-associated diarrhea and C. Difficile infection [17, 18].


4. Conclusions

Antibacterial therapies, whether phage- or antibiotic-based, each have relative advantages and disadvantages; accordingly, many considerations must be taken into account when designing novel therapeutic approaches for preventing and treating bacterial infections.

Although much is still unknown about the interactions between phage, bacteria, and human host, research on the development of bacteriophages as antibacterial pharmaceuticals remains open and prospects for the future are optimistic.


Contributo selezionato da Filodiritto tra quelli pubblicati nei Proceedings “17th Romanian National Congress of Pharmacy - 2018”

Per acquistare i Proceedings clicca qui:



Contribution selected by Filodiritto among those published in the Proceedings “17th Romanian National Congress of Pharmacy - 2018”

To buy the Proceedings click here:



1. Georgescu, M., Ginghină, O., Raita, S., Tăpăloagă, D., Ilie, L., Negrei, C., Popa, D.E.,Varlas, V., Muescu, R., Roșca, A.C., Mirică, R., Georgescu, D. (2018). Natural alternative remedies in the background of updated recommendations for the prophylactic and therapeutic approach of Clostridium difficile infections. Farmacia 66(4), pp 563-572.

2. Toshikawa, T.T. (2002). Antimicrobial resistance and aging: beginning of the end of the antibiotic era? J Am Geriatr Soc 50, pp. S226-S229.

3. Călina, D., Docea, A.O., Rosu, L., Zlatian, O., Rosu, A.F., Anghelina, F., Rogoveanu, O., Arsene, A.L., Nicolae, A.C., Drăgoi C.M., Tsiaoussis, J., Tsatsakis, A.M., Spandidos, D.A., Drakoulis, N., Gofiță E. (2016). Antimicrobial resistance development following surgical site infections. Molecular Medicine Reports 15, pp. 681-688.

4. Chanishvili, N. (2012). Phage therapy-history from Twort and dHerelle through Soviet experience to currenapproaches. Adv Virus Res. 83, pp 3-40.

5. Hodyra-Stefaniak, K., Miernikiewicz, P., Drapała, J., Drab, M., Jończyk-Matysiak, E., Lecion, D., Kaźmierczak, Z., Beta, W., Majewska, J., Harhala, M., et al., (2015). Mammalian Host-Versus-Phage immune response determines phage fate in vivo. Sci Rep 5, 14802.

6. Wang, J., Hu, B., Xu, M., Yan, Q., Liu, S., Zhu, X., Sun, Z., Tao, D., Ding, L., Reed, E., et al., (2006)Therapeutic effectiveness of bacteriophages in the rescue of mice with extended spectrum beta-lactamase- producing Escherichia coli bacteremia. Int J Mol Med 17, pp. 347-355.

7. Wills, Q.F., Kerrigan, C., Soothill, J.S. (2005). Experimental bacteriophage protection against Staphylococcus aureus abscesses in a rabbit model. Antimicrob Agents Chemother 49, pp. 1220-1221.

8. Wright, A., Hawkins, C.H., Anggård, E.E., Harper, D.R. (2009). A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy. Clin Otolaryngol 34, pp. 349-357.

9. Watanabe, R., Matsumoto, T., Sano, G., Ishii, Y., Tateda, K., Sumiyama, Y., Uchiyama, J., Sakurai, S., Matsuzaki, S., Imai, S., et al., (2007). Efficacy of bacteriophage therapy against gut-derived sepsis caused by Pseudomonas aeruginosa in mice. Antimicrob Agents Chemother 51, pp. 446-452.

10. Ramesh, V., Fralick, J.A., Rolfe, R.D. (1999). Prevention of Clostridium difficile-induced ileocecitis with bacteriophage. Anaerobe 5, pp. 69-78.

11. Kutateladze, M., Adamia, R. (2008). Phage therapy experience at the Eliava Institute. Med Mal Infect 38, p426-430.

12. Monk, A.B., Rees, C.D., Barrow, P., Hagens, S., Harper, D.R. (2010). Bacteriophage applications: where are we now? Lett Appl Microbiol 51, pp. 363-369.

13. Tătărîngă, G., Tuchiluș, C., Jităreanu, A., Zbancioc, A.M. (2018). Antimicrobial prospection of some coumariderivative. Farmacia 66(2), pp. 323-330.

14. Nannapaneni, R., Soni, K.A. USA: John Wiley & Sons, Ltd; (2015). Use of Bacteriophages to Remove Biofilms of Listeria monocytogenes and other Foodborne Bacterial Pathogens in the Food Environment. Biofilms in the Food Environment, Second Edition, pp. 131-144.

15. Endersen, L., OMahony, J., Hill, C., Ross, R.P., McAuliffe, O., Coffey, A. (2014). Phage therapy in the food industry. Annu Rev Food Sci Technol 5, pp. 327-349.

16. Górski, A., Wazna, E., Dabrowska, B.W., Dabrowska, K., Switała-Jeleń, K.  (2006).  Miedzybrodzki RBacteriophage translocation. FEMS Immunol Med Microbiol 46, pp. 313-319.

17. Rea, K., Dinan, T.G., Cryan, J.F. (2016). The microbiome: A key regulator of stress and neuroinflammationNeurobiol Stress 4, pp. 23-33.

18. Mirea, L., Nițipir, C., Grințescu, I.C., Băetu, A., Gîngu, R, Arsene, A.L., Grințescu, I.M. (2017). Efficacy otigecycline treatment in severe and complicated Clostridium difficile infection. Farmacia 65(40), pp. 600-604.