ABSTRACT:

Phages are also known as bacteriophages which are normally viruses that infect and replicate within the bacteria. Phage therapy is the clinical use of these bacteriophages to treat infections caused by superbugs (bacteria that have acquired resistance against antibiotics). Phages when administered into bacteria, cause the lysis of the bacterial cells in the lytic phase of the phage life cycle. Phage therapy has acquired its importance in recent years after its successful use in managing some life-threatening infections and helped in saving lives. Phage therapy is currently being used as antimicrobial therapy in some western countries. this paper mainly discusses using phage therapy in treating infections caused by superbugs, and also discusses what measures should be taken by different countries to successfully introduce phage therapy in clinical use. Apart from this phage therapy has got some disadvantages which show that phage therapy can never be an effective alternative for antibiotics. We conclude that phage therapy can be the best choice for treating infections caused by superbugs, where antibiotics can’t work but can’t be used again once used before in a particular patient.

Key-Words: bacteriophages, replicate, superbugs, resistant, lytic phase, antimicrobial, therapy.

INTRODUCTION:

Phages are also known as bacteriophages which are normally viruses that infect and replicate within the bacteria. Phages were first discovered by Frederick W. Twort (1915) and also by Félix d'Hérelle (1917) [1] . In 1920 some scientists and physicians used phages in humans for treating various bacterial infections when antibiotics were not yet discovered. Later phage therapy was promoted by F.dHerelle who used to travel to many countries and helped others on how to use phage therapy in humans. In 1940 phages have lost their importance due to the discovery of antibiotics. G. ELIAVA institute of bacteriophages in Georgia has never lost its interest in phage therapy, they never quit their research on phages till now. The researchers used to collect phages from Environment sources and store them in a phage bank. This collection of phages by the ELIAVA institute has provided information on which phages can be selectively used against bacteria isolated for personalized therapies. However, data from a single institute is not sufficient to approve medicines all over the world. Due to widespread in antibiotic resistance, it became very hard for the healthcare provider to treat bacterial infections, so the rest of the world along with G. ELIAVA institute has kept their interest in utilizing phage therapy for treating infections in humans caused by superbugs[2]. But there is a misconception that phage therapy can be the best alternative to antibiotic therapy. We can’t completely replace antibiotics with phages, instead, we can use them as adjuvant therapy. To approve phage therapy in clinical practice more data is needed which can be obtained by conducting more clinical trials. Studies that were conducted years ago do not provide enough data to approve phage therapy for clinical use. So, phage therapy will not be approved by the FDA until it clears all the stages of clinical trials. However, there are very

  

few situations that phage therapy was very effective where antibiotics failed to do so. These are abundant in nature and are present wherever the bacteria are found like soil, water, deep within the earth's crust. Oceans are a large source of phages it is estimated about 1030 bacteriophages in this world[3].

 

WHY PHAGES CAN’T REPLACE ANTIBIOTICS?

1. Phage are cleared rapidly from the bloodstream and provoke a response from the immune system. Using them for a systemic infection would be challenging, and you couldn’t use them a second time on a patient [4].

2. Phage is intrinsically narrow-spectrum agents. Not solely square measure they restricted to one microorganism species, however sometimes to a set of strains inside that species. Dozens of virus strains square measure therefore required to hide the seemingly sources of any given infection. constant level of coverage may be earned with 1–2 antibiotics[4].

3. The phage efficacy data from Russia and elsewhere is very little. Most infections resolve even without treatment. Placebo-controlled antibiotic trials square measure seldom done currently, thanks to moral considerations [4].

But trials from the Thirties and Nineteen Forties show 40–80% resolution of infections within the management arm [4].

4. Supportive care (these were mostly pneumonia patients) is much better now so that these numbers are lower bounds. A convincing demonstration of efficacy requires a very careful trial design, and no one has come close to meeting a modern standard of proof with phage therapy [4].

5. Antibiotics work most of the time. And they are cheap. This means that the market is tiny (phage would be used solely as second- or third-line therapy) and rating power would be less. There is not much hope of making money in phage therapy [4].

 

DISADVANTAGES OF PHAGE THERAPY [5].

1. Narrow host range

2. Bacteria can also become resistant to phages.

3. Some phages can’t conquer the bacterial immune system.

4. Infections whose agents are hidden in the human cells may be inaccessible to phages.

5. One type of phage can only be used once for intravenous use.

6. The self-life of phages varies greatly.

7. Requires regular monitoring.

8. Phages are more difficult to administer than antibiotics which need special training.

WHEN AND HOW THESE PHAGES DESTROY THE BACTERIA?

Lytic phase is a part of a phage life cycle, during which these phages produce specialized protein-based enzymes called lysins and send them into bacterial cytoplasm that is capable of degrading the bacterial cell wall and finally causes the lysis of bacteria[6].

How phages destroy the bacteria: phages after invading the bacteria undergo the following steps[6].

1) Attachment

2) The entry of DNA of the phage and host DNA degradation

3) Synthesis of viral (phage) genomes and proteins

4) Assembly

5) Release

With their tail fibers these phages get attached to the bacterial cell wall. After the process of attachment, these phages release their DNA into the host cell or bacterial cell, which causes the degradation of bacterial DNA after being incorporated into it. Then these phages their viral genomes and proteins, all these genomes and proteins are assembled to form a new phage. All these steps take place during the lysogenic phase of the phage life cycle[6].

After producing enough phages, these phages produce some proteins called lysins which causes the lysis of bacterial cell wall and are released out of the bacterial cell to attack another cell. This happens in the lytic phase of the phage life cycle[6]. ( Figure 1)

REASONS FOR ANTIBIOTIC RESISTANCE?

Bacteria are becoming resistant due to improper use of antibiotics. These bacteria have been developing different defence machanisms to protect them from antibiotics[7].

• Restrict access to the antibiotics: By limiting the number or reducing the size of pores in cell-walls, bacteria are inhibiting the entry of sufficient amount of antibiotic into their cytoplasm.

• Get rid of antibiotics: Some bacteria can uses active pumps present in their cell walls to flush out antibiotic that is being entered into it.

• Degradation of the antibiotic: Some bacteria uses enzymes to break down the antibiotic drug and make them inactive. Eg:beta-lactamase.

• Alter the antibiotic: Some bacteria uses enzymes to alter the antibiotics and make them inactive.

• Bypass the effect of antibiotic: some bacteria changes the composition or the structure of target in them, this can stop the antibiotics from binding with the target and makes the antibiotic ineffective[8].

Due to these reasons there is a need to find an alternative way to get rid of these resistant bacteria (superbugs) [9].

(Table 1 : Check below )

 

MEASURES TO BE TAKEN TO PREVENT ANTIBIOTIC RESISTANCE[9] :

 1. Judicious antibiotic use.

2. Use of specific antibiotics.

3. Surveillance and infection control

4. Only use antibiotics for bacterial infections. Antibiotics will not treat viral infections like colds, flus, and bronchitis.

5. Don’t use antibiotics if you don’t need them.

6. Don’t pressure your doctor to prescribe antibiotics for you or your child.

7. Take all antibiotics exactly as prescribed.

8. Complete the full dosage of antibiotics, even if you feel better.

9. Don’t take expired antibiotics.

10. Throw away expired or unused antibiotics.

 

These measures are helpful in controlling the further resistance but can’t treat infections caused by bacteria which are already resistant to antibiotics. So the world is focussing on different methods to treat infections caused by superbugs[9].

So the only weapon that we have now to overcome antibiotic resistance is phage therapy but this can not be used more than once in a patient.

 

WHEN AND HOW TO USE PHAGE THERAPY IN HUMANS?

The phage therapy involves the use of bacteriophages, which are perfect weapons to kill the bacteria. These superbugs are dangerous to human body cells which make the person ready to die [10].

1. We should start the antibiotics as usual.

2. Follow up the patient for improvement of symptoms.

3. If the symptoms are still worsening, then go for microbial sensitivity test.

4. If the microbe is sensitive to a particular antibiotic but the symptoms are still there, increase the dose of antibiotic.

5. If still the symptoms are there or the microbe is not sensitive to any antibiotic then go for phage therapy with caution

 

Note : Always choose antibiotic therapy as 1st line therapy

If any other alternative is available, consider it as 2nd line therapy

If there is no option and the patient is about to die then consider phage therapy as 2nd or 3rd line therapy

 

 

DISCUSSION:

 In almost all cases where phage therapy was used, the scientists tried these phages only when the patient is about to die, this shows us that how danger the phage therapy is to humans. Apart from that we only have case reports which were successful. Phages are very dangerous when compared to antibiotics,One of the best described disease-specific alterations in the gut phagobiome is associated with inflammatory bowel disease, where phages have pathogenic effects by inducing dysbiosis and microbiota disease. So we should not use phages for treating infections which can be treated by antibiotis. We can use phages therapy as a last line therapy when there is no choice. Apart from that we can help to prevent antibiotic resistance by increasing awareness among the people[10,11].

 

CONCLUSION:

 So we conclude that phage therapy can only be a last choice for treating infections and can also be used as a supportive therapy but will never replace antibiotics.

 

REFERENCES:

1. Phage therapy: An alternative to antibiotics in the age of multi-drug resistance Derek M Lin, Britt Koskella, Henry C Lin World J Gastrointest Pharmacol Ther 2017 August 6; 8(3): 162-173 ISSN 2150-5349 (online) 

2. Phage Therapy in the Postantibiotic Era Fernando L. Gordillo Altamirano, Jeremy J. Barr DOI: 10.1128/CMR.00066-18

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4. Answer by Drew Smith, Former CSO at MicroPhage, on Quora: Mar 28, 2018, 01:21pm

5. Bacteriophages as New Human Viral Pathogens George Tetz and Victor Tetz

6. Bacteriophage Structure and Mechanism of Action, and their Application in Medical and Industrial Biotechnologies - Online Event (17th-19th of January, 2017) - Research and Markets

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8. Mechanisms of bacterial resistance to antibiotics. Dever LA1, Dermody TS. 1991 May;151(5):886-95.

9. United Nations. PRESS RELEASE: High-Level Meeting on Antimicrobial Resistance. 2016; Accessed Mar 29, 2017. Available from: URL: http://www.un.org/pga/71/2016/09/21/press-release-hlmeeting- on-antimicrobial-resistance/

10. Abedon ST, Kuhl SJ, Blasdel BG, Kutter EM. Phage treatment of human infections. Bacteriophage. 2011 Mar;1(2):66-85. doi: 10.4161/bact.1.2.15845. PMID: 22334863; PMCID: PMC3278644.

11. Limitations Of Bacteriophage Therapy . Jama. 1931;96(9):693. Doi:10.1001/Jama.1931.02720350045014