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Phage Therapy: A Potential Solution to Multidrug-Resistant Bacteria

Wednesday, June 20, 2018  
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Joshua Hildebrand, Pharm.D. Candidate 2020, Duquesne University

Dr. David E. Zimmerman, Pharm.D., BCPS, BCCCP

Introduction

            One of the biggest problems we face in modern medicine is the growing issue of antibiotic resistant “super bugs”. Otherwise known as multi-drug resistant, or MDR bacteria, these super bugs have been created by over-prescribing antibiotics.1 Too frequently healthcare providers administer antibiotics for illnesses that are not even bacterial in origin, or give an antibiotic that has too broad of spectrum for a specific disease. As these bacteria strains gain resistance to antibiotics we have less and less treatment options. A promising new form of treatment is bacteriophages, which are yielding promising results. These naturally occurring viruses attack and replicate only within specific bacteria.2 This is useful in humans because not only do the bacteriophages not attack human cells, but they also do not affect our normal flora.3 There are still many hurdles to overcome for this treatment to become useable and require FDA approval. One such hurdle is the cost of upkeep for ‘phage banks’. Since bacteriophages have such a high specificity for their targets, several different kinds are often needed to treat one infection as bacteria can slightly differ.4 Thus we need to perpetually maintain a bank of many different types of bacteriophages.5 Despite the current obstacles facing phage therapy the potential for its clinical use is extremely high and could become a mainstay in the treatment of bacterial infections.

Background

            Bacteriophages are a type of naturally-occurring virus that only infect bacteria.2 They rely on bacteria in order to be able to survive and reproduce. Phages attach themselves to the surface of the bacteria and release their genetic material into the cell. From here the genetic material is incorporated into the bacteria’s genome and can either be passed onto another cell after reproduction, or it can be used to force the bacterial cell to recreate more virions. Once enough virions are produced they lyse the cell membrane, are released from the cell, seek a new target, and restart their life cycle. The receptors needed for the phage to bind to the surface of the bacterial cell are often very specific, thus the variety of bacterial targets of each phage are very limited.

 

A bacteriophage attaching to a bacterial cell6

 

History

            It is widely considered that bacteriophages were first “officially” discovered by a French-Canadian scientist named Felix d’Herelle during a dysentery outbreak amongst French troops in 1915.7 After spreading bacterial samples from these troops onto an agar culture, d’Herelle discovered clear areas that were free of bacterial growth.8 In 1919 d’Herelle used phages to treat dysentery in a child. The patient’s symptoms stopped after one dose of phage therapy, and the patient eventually made complete recovery. These results were not published immediately however, and in 1921 the first published results of phage therapy were released.7 Here bacteriophages were injected into and around lesions on a patient with a topical staphylococcal infection. The disease regressed after 1-2 days. Soon more studies with similar results were published, thus kickstarting a major interest in bacteriophage research.

Benefits

            Phage therapy provides a few major advantages for the treatment of bacterial infections that antibiotics do not. Possibly the biggest disadvantage of antibiotics is that bacteria are able to develop resistance mechanisms to defend themselves. With phage therapy on the other hand, we are using viruses that are able to develop their own resistance mechanisms to bacteria.9 So it is possible that as bacteria evolve to resist phage therapy, bacteriophages will evolve to resist bacteria’s defense mechanisms. Another benefit of phage therapy is they do not appear harmful to humans, with very little reports of any major complications. As an example, a study was done where fifteen volunteers drank water that contained different doses of Escherichia Coli bacteriophages.10 There were no adverse events related to the phages reported, nor were there any phage-specific antibodies found to be produced. The phages were undetectable after a week for all doses, which shows that any potential adverse events would have ended in after about a week. Besides studies, we also know about the safety of phages because we have been employing their use in different medical assessments in the United States. A study to observe the roles of cell-surface interactions in the immune response was done using bacteriophages for example.11 Here the phage was used to initiate an immune response that could be measured with creating any negative side effects in the study subject. Also bacteriophages are very ubiquitous in the environment, thus they enter our bodies every day. One measurement found that there can be up to 2.5 x 108 virions/mL in natural waters.12 Safety is an important property to note when in comparison to antibiotics. The reason that phages can potentially be a safer treatment option than antibiotics is due to their specificity. Since phages are only able to target such a limited number of bacteria, they do not affect our normal flora.13 This is a common issue with many antibiotics and can lead to opportunistic infections, like C. Difficile for example. Yet another positive feature for phage therapy is the ability to degrade biofilm.14 Certain strains of bacteria have evolved to produce a slimy layer called biofilm that the bacteria live in. Biofilm acts to protect bacteria from foreign substances and can create a network that allows the bugs to share nutrients and genetic information.15 Antibiotics usually have a hard time penetrating this layer of slime, but phages are equipped with enzymes that can degrade biofilm.16 One method that phages used to navigate through biofilm is a “Trojan Horse” type of entry. Here the phage will enter an organism that is phagocytosed by bacteria and will act like the trojan horse, like Mycobacterium smegmatis for example. Mycobacterium tuberculosis will then phagocytose this organism. Now inside the bacterial cell, the phages will lyse the “trojan horse”, exit, and is now safely inside its target.

Disadvantages

            Despite all of the promising results and potential benefits to phage therapy, there are some drawbacks. Possibly the biggest obstacle phage therapy faces in clinical use today is the lack of reliable data.17 Most of the information we have in regards to phage therapy are from papers published a long time ago in foreign countries. The ethical standards that the scientists followed in these times do not meet today’s standard. An example of poor ethics displayed by these researchers was an exaggeration of the benefits of phage therapy in their findings. One claim that was made stated that bacteriophages could be used to treat herpes infections.7 Herpes is a viral disease and considering that phages only target bacteria, it can be deduced that this claim is false. In today’s world of research this paper would not be published due to such overstated findings. There were also many faults in the structure of these studies, like how many of the studies did not even include a control or placebo group. Another negative regarding phage therapy is its specificity. Earlier it was mentioned how having a specific target was an advantage for phage therapy, however this specificity can also be a problem. For example, a patient with a wound that is infected with multiple strains of bacteria will need to be treated with multiple types of bacteriophages.2 It is possible to treat patients like this, however constantly maintaining phage cocktails can be costly. There are phage cocktails that can contain over 50 specific phages, which seems like the ideal treatment for patients.5 However manufacturing these cocktails are much more expensive than creating monophage therapies. Yet another disadvantage of phage therapy is the possible development of antibodies against bacteriophages. Considering that phages are a foreign substance, it is obvious that our body will try to fight it off. One study found that when antibodies were produced against six different phages of Lactococcus Lactis, the lysis of this bacteria ceased.17 More data is needed to conclusively state the extent of the effect of antibody production on phage therapy though.

 

Table 1: Advantage and Disadvantage Summary

Advantages

Disadvantages

Bacteriophages can over come bacterial resistance using resistance mechanisms of their own

Lack of reliable evidence to support efficacy

No clear evidence of any adverse effects

Antibody development can decrease efficacy

High specificity will ignore normal GI flora

High specificity requires multiple types of phages to be employed

Ability to degrade and penetrate into biofilm

Multiphage therapy can be costly

 

 

Conclusion

            With the continually growing problem of evolved MDR bacteria, a new type of treatment is needed. Although it is not perfect, phage therapy is a potential option. Considering that phage therapy has less adverse effects than antibiotics, can overcome resistance more efficiently, and can more easily penetrate into biofilm. Before we can consider this as a real treatment option a few obstacles need to be overcome. For example, more research needs to be done in a proper way that is up to today’s standards which requires more funding, along with physiological drawbacks like the formation of antibodies. Perhaps one day phage therapy will be first line treatment for antibiotic infections.

 

References

1.     Fair RJ, Tor Y. Antibiotics and Bacterial Resistance in the 21st Century. Perspectives in Medicinal Chemistry. 2014;6.

2.     Lin DM, Koskella B, Lin HC. Phage therapy: An alternative to antibiotics in the age of multi-drug resistance. World Journal of Gastrointestinal Pharmacology and Therapeutics. 2017;8(3):162. doi:10.4292/wjgpt.v8.i3.162.

3.     Galtier M, Sordi LD, Maura D, et al. Bacteriophages to reduce gut carriage of antibiotic resistant uropathogens with low impact on microbiota composition. Environmental Microbiology. 2016;18(7):2237-2245.

4.     Chan BK, Abedon ST, Loc-Carrillo C. Phage cocktails and the future of phage therapy. Future Microbiology. 2013;8(6):769-783.

5.     Pouillot F, Blois H, Iris F. Genetically Engineered Virulent Phage Banks in the Detection and Control of Emergent Pathogenic Bacteria. Biosecurity and Bioterrorism: Biodefense Strategy, Practice, and Science. 2010;8(2):155-169.

6.     Bacteriophage infecting a bacterium. https://www.quora.com/Whats-the-meaning-of-bacteriophage. Accessed: 19 June 2018.

7.     Sulakvelidze A, Alavidze Z, Morris JG. Bacteriophage Therapy. Antimicrobial Agents and Chemotherapy. 2001;45(3):649-659.

8.     Summers WC. Felix d’Herelle and the origins of molecular biology. New Haven, Conn: Yale University Press; 1999.

9.     Örmälä A-M, Jalasvuori M. Phage therapy. Bacteriophage. 2013;3(1). doi:10.4161/bact.24219.

10.  Bruttin A, Brussow H. Human Volunteers Receiving Escherichia coli Phage T4 Orally: a Safety Test of Phage Therapy. Antimicrobial Agents and Chemotherapy. 2005;49(7):2874-2878.

11.  Ochs HD, Nonoyama S, Zhu Q, Farrington M, Wedgwood RJ. Regulation of Antibody Responses: The Role of Complement and Adhesion Molecules. Clinical Immunology and Immunopathology. 1993;67(3).

12.  Bergh Ø, Børsheim KY, Bratbak G, Heldal M. High abundance of viruses found in aquatic environments. Nature. 1989;340(6233):467-468.

13.  Rea K, Dinan TG, Cryan JF. The microbiome: A key regulator of stress and neuroinflammation. Neurobiology of Stress. 2016;4:23-33.

14.  Watnick P, Kolter R. Biofilm, City of Microbes. Journal of Bacteriology. 2000;182(10):2675-2679.

15.  Servick K. Beleaguered phage therapy trial presses on. Science. 2016;352(6293):1506-1506.

16.  Abedon S. Ecology of Anti-Biofilm Agents I: Antibiotics versus Bacteriophages. Pharmaceuticals. 2015;8(3):525-558. doi:10.3390/ph8030525.

17.  Geller B. L., Kraus J., Schell M. D., Hornsby M. J., Neal J. J., Ruch F. E. (1998). High titer, phage-neutralizing antibodies in bovine colostrum that prevent lytic infection of Lactococcus lactis in fermentations of phage-contaminated milk. J. Dairy Sci. 81 895–900 10.3168/jds.S0022-0302(98)75648-6


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