Phage therapy: are we already in the post-antibiotics era?

The incidence of lung infections is increasing, especially from resistant bacteria: phage therapy can represent a valid treatment

05/04/2022

R & D

All the conditions involving an immune compromission, whether they are pathologies (such as those mucus-obstructive, e.g. cystic fibrosis), or precedures (such as transplantation or chemiotherapy) increase the risk resistant respiratory infections.

In the last few years, the widespread of these kind of resistance mechanisms determined an increasement in the incidence of a number of transmissible illness.

Respiratory disease burden

Low respiratory tract conditions, related to a number of deaths of more than 4 million, represents one of the most relevant death cause, and are associated with a very low quality of life.

Besides, the number of deaths due to MDR pulmonary infections is more than doubled  between 2007 and 2015.

Even from the economic point of view, these pathologies represent a consistent burden. Data from USA prove that overall treatment associated costs of a patient with cystic fibrosis could reach 50.000 $/year. This expense is legitimated by the medical assistance needed for recurrent respiratory infections.

That scenario is worsening with the years because of the aggravation of the antibiotic resistance. Uno scenario che peggiora di anno in anno a causa del peggioramento dell’antibiotico resistenza.

Phage therapy: what is it

Phage tharapy (PT) is not a new method, since its introduction dates back to the first years of ‘900, and it has been extensively used (and it is currently used) in some countries of the East Europe, especially Poland and Russia.

It consists in the administration of high dose of virulent bacteriophages, with the purpose of treating bacterial infections.

What is the mechanism of action?

Phages can bind to the bacterium external surface target, by means of a specific receptor, injecting in its cell their genetic material, and they can seize its intracellular mechanisms for its own replication.

At the moment of the cellulare lysis, a progeny from phages is released. It determines a quick reduction in the bacterial population in the infection site, even with resistance problems.

The cycle can then start again with a secondary infection: it allows to quickly increase the number of phages in the target.

Unconventional mechanisms of action

Next to this conventional mechanism of action, phages claim an anti-biofilm activity too, which is particularly relevant to the therapies purpose of many pulmonary infections.

This action can be explained both by means of an inhibition component with respect to the biofilm formation itself, and by means of the ability to destroy the biofilm already deposed and attacking the bacteria in its interior.

It increases the chances to eradicate the infection.

Another aspect of their activity is the one of the immunomodulating action. By means of mediators release with the goal of turning the infection off, the phages presence in the lungs reduces the risk of excessive and persistent immune system response associated with definitive injury formation.

Due to its characteristics, phage therapy represents a potential promising alternative, or s valid support to antibiotic treatment, in the MDR infections eradication.

However, many points still need to be investigated.

Pulmonary phage therapy

For most cases of resistant pulmonary infection, when phage therapy is applied (as a therapy or as a prevention tool), it is used in a bacteriophages cocktail designed for aerosol inhalation. 

The fine-tuning of a phage therapy implies that active phages against microrganisms, such as Staphylococcus aureusEscherichia coliKlebsiella pneumoniae and Pseudomonas aeruginosa must be available “on demand”.

Often, it is complex to cultivate phages heterogeneous and stable populations. In particular, sometimes, there are very few phages able to infect specific targets such as MRSA.

Since the experimentation is still premature, the only data we have about this therapeutic tool comes from compassionate usage in the pulmonary bacterial infection treatment of S. aureusP. aeruginosa or E. coli MDR, or pan-drug-resistant, when all the therapeutic options are sold out. In theese kind of settings, phages cocktails proved to have a good safety profile.

Phages therapy is applied in groups of patients suffering from cystic fibrosis, bronchiectasis, primary ciliary dyskinesia, BPCO and in tuberculosis MDR.

Phage therapy state of art

A recent review, published on Current Opinion in Pulmonary Medicine examined the recent steps foreward in the application of becteriophages for pulmonary infections treatment, especially those caused by resistant Gram-negatives, including Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae and Burkholderia spp.

The review takes stock of the situation.

Despite the promising data in terms of efficacy and safety, ethics and practical questions still exist and limit the phage therapy potential development.

In the first place, all the microrganisms colture and selection procedure phases must comply with very high standards, in order to prevent possible repercussions on the safety.

It is quite complicate to obtain a phage population with the needed characteristics to render the therapeutic cocktail too, since it must be designed according to quite severe and specific criteria.

Since the experimentation is still very premature, even from the perspective of getting data to confirm the expectations, the approval time would be very long. Certainly, not consistent with the real therapeutic need.

In the publication, researchers underlined how this treatment could have a significative impact especially on specific groups of patients, such as those affected by cystic fibrosis. 

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