Can Bacteriophages Really Protect Us From Antibiotic Resistance?

What Is Antibiotic Resistance And Why Does It Matter?

Prior to the beginning of the 20th century, infectious diseases such as cholera, smallpox, tuberculosis, syphilis, typhoid fever, pneumonia, typhus, and the plague accounted for a massive percentage of the mortality rate worldwide (1).

However, when Sir Alexander Fleming came across the discovery of penicillin in 1928, the use of broad-spectrum antibiotics emerged as a way of treating and curing infection and preventing a resurgence of widespread disease.

As a result, globally, the primary causes of death changed from communicable diseases (aka contagious ones) to non-communicable ones such as cardiovascular disease and diabetes, instead (2).

In other words, modern medicine owes a lot — if not everything it is — to the handy class of antimicrobial drugs we refer to collectively as antibiotics.

There is, however, a slight problem.

“The more we look at drug resistance, the more concerned we are. It basically shows us that the end of the road isn’t very far away for antibiotics.”

— Tom Frieden

If you’ve ever been prescribed antibiotics by your doctor or pharmacist, then you may already be familiar with the necessity of fully completing your course, i.e. finishing all of the pills in the pack even once symptoms have subsided. When antibiotics are used to treat a particular strain of pathogenic bacteria — but perhaps not 100% of the bacteria are killed in the process — the strain of bacteria then has the chance to mutate and form a resistance to the drugs being used against it.

This is referred to as antibiotic resistance, and while we currently possess the rough tools of medicine to combat it on a case-by-case basis — we might be facing a much bigger problem of superbugs and antibiotic resistance, on a much larger scale, a whole lot sooner than we’d like to think.

Due to the major threat that antibiotic resistance poses to human health on a global scale, the medical community is tasked with following strict safety guidelines when prescribing antibiotics to humans in order to ensure they are only being used as and when necessary.

This is because one of the best ways to prevent antibiotic resistance is to use antibiotics sparingly, and only when absolutely necessary.

Unfortunately for us, this is where the problem only begins.

First and foremost, it’s important to understand that it takes scientists 10 or more years to develop a new antibiotic and receive approval for it from the FDA (3).

Meanwhile, a whopping 80% of all medically important antibiotics (aka the ones we really need for humans) produced — in the entire world — are given to the animals we raise for food in the West (4).

That’s right: the farming industry uses more antibiotics than all other sectors combined. Despite the fact that repeatedly exposing animals to small doses of antibiotics is one of the fastest ways to encourage antibiotic resistance, the animal agriculture industry employs almost indiscriminate use of these drugs (5).

Three years ago, the World Health Organization (WHO) released a series of warnings about the dangers of antibiotic resistance and strongly suggested the “complete restriction of these antibiotics for growth promotion and disease prevention in animals without diagnosis (6).”

But not only do antibiotics promote faster growth (and therefore profit) on industrial farms where livestock, poultry, and fish are raised, but they also help to compensate for the unsanitary conditions the animals are kept in, allowing less ‘product’ to be spoiled by disease (7, 8).

Subsequently, a study from Princeton revealed that the number of unnecessary antibiotics given to animals has more than tripled since the year 2000. This comes alongside evidence from the CDC indicating that 3 out of 4 new or emerging infectious diseases in people will come from animals (9, 10).

“There is a glaring reason that the necessary total ban on nontherapeutic use of antibiotics hasn’t happened: The factory farm industry, allied with the pharmaceutical industry, has more power than public-health professionals.”

— Jonathan Safran Foer

In addition, research has shown that approximately 75 % of all antibiotics given to animals are not fully digested and will eventually pass through the body of animals and into the external environment. When this occurs, there exists a high risk of the antibiotic coming into contact with new bacteria and creating additional antibiotic-resistant strains of pathogenic bacteria, as a result (11).

All in all, we’re creating the perfect environment for multiple future pandemics to emerge, yet we knowingly haven’t done anything about it — in fact, we really just keep making the problem worse…

That is unless science offers us another solution.

What Are Bacteriophages And How Do They Work?

Bacteriophages are a type of virus that outnumber all other organisms on earth combined — even including bacteria. They exist as a category of viruses that are completely harmless and non-pathogenic to humans, strictly selecting bacteria as their living host instead. These bizarre creatures are made of protein or proteolipid capsides containing fragments of nucleic acids, and they’re worth googling a picture of if you have the time or the curiosity to spare (12).

Bacteriophages come in two types or ‘development cycles’ as they are scientifically known: lytic (aka virulent) wherein the bacteriophages invades and destroys a cell of bacteria, or lysogenic (aka temperate) wherein the bacteriophage inserts its genetic material into a bacterial cell, thereby granting it future immunity to infection by an identical phage (13).

In the context of therapeutic use, only lytic phages, the ones that specialize solely in the destruction of bacteria, are relevant — which is why they’re often brought up in discussions of antibiotic resistance.

You see, for a while now scientists have been able to isolate active phages, amplify them, and administer them to both humans and non-human animals, allowing them to completely obliterate the bacteria or pathogen responsible for an infection.

As it follows, phages could not only totally replace the use of antibiotics within the animal agriculture sectors, but they could also make it possible for doctors to treat a number of critical patient cases, potentially playing a huge role in the mitigation of the effects of antibiotic resistance in the process. The keyword here is: potentially (14).

The problem, so to speak, is that relying on bacteriophages as our last line of defense against superbugs and antibiotic-resistant strains of bacteria is not quite as simple as most people would like to believe.

There are a multitude of precise specifications required for bacteriophages to be successful in the destruction of pathogenic bacteria, and even more so when you factor in the difficulty of administration on a wider scale (such that treatment for the rapid spread of antibiotic-resistant bacteria would require).

In an effort to make this information as clear and un-confusing as possible, I thought I’d outline some of the pros and cons as articulated by research on the subject thus far.

What Are The Pros And Cons Of Using Bacteriophages?

Pros:

Kills bacteria (even antibiotic-resistant strains) — Here’s the thing: bacteriophages are really, really talented at killing bacteria. What’s more, is that any bacteria successfully infected by lytic phages becomes permanently unable to regain their viability as a result. A single phage treatment was found to protect 100% of commercially farmed Atlantic salmon from an experimentally induced infection of V. anguillarum. Understandably, this has a range of rather promising applications within the farming and medical communities alike (15, 16).
“Auto-dosing” or single-dose potential— Because phages are highly capable of self-multiplying during the bacteria-killing process, there is no need for medical “dosing” of bacteriophages in patients, because the phages themselves contribute to establishing their own highly effective dose. A single phage treatment was found to protect (17).
Low environmental impact — Unlike broad-spectrum antibiotics that — when improperly discarded or digested (as they often are) — can have serious implications for the local bacterial environment and the speeding up of antibiotic resistance, bacteriophages only have the ability to impact a very small and particular subset of environmental bacteria. In addition, external factors such as sunlight, temperature, light, lack of nutrients, and other environmental forces can all cause discarded bacteriophages to become rapidly inactive (18).
Minimally disruptive to natural flora — Studies have shown that bacteriophages only minimally impact health-protecting normal flora bacteria, in stark contrast to antibiotics which are highly effective at eliminating both good and bad bacteria alike (19).

Cons Of Using Bacteriophages:

High specialization — Unfortunately, herein lies the main issue. Bacteriophages only have the ability to target one distinct bacteria at a time. What this means, is that in order for scientists to make any use of bacteriophages to fight infection, they have to locate the specific phage with the ability to destroy that particular strain of infection-causing bacteria. This process is not only time-consuming, but it can also be easier said than done (20).
Limited resource — One of the main limiting factors for the widespread use of bacteriophages as a way of combatting antibiotic resistance is the number of phages available to doctors. Not only are regulations surrounding the use of phages extremely stringent, but the high specificity of these organisms (as illustrated above) means that there needs to be enough diversity in medically available phages that the treatment of a particular infection becomes likely. As it currently stands, we have a long way to go before this happens (21).
Low virulence— Bacteriophages are pretty unstable by nature. Not only must producers isolate, characterize, and purify phages, but they also have to stabilize them to prevent them from mutating. In some cases, the use of bacteriophages in the treatment of infection has been ineffective due to something referred to as low “virulence.” Low virulence can be a consequence of poor adsorption properties, the low potential to evade bacterial defenses, or poor replication characteristics all present within a bacteriophage (22).
Risk of cross-contamination — A subsequent problem faced by producers of therapeutic bacteriophages comes in the form of cross-contamination. Although for the most part phages are considered highly selective killers, research shows that they do retain to the ability to harm certain populations of non-targeted bacteria. According to studies focusing on the consequences of these effects within the dairy industry, it’s not uncommon for phages to destroy the bacteria necessary for the fermentation process, largely rendering their use counter-productive (23).
Difficulty of administration — Additionally, the success of bacteriophages against pathogenic bacteria can be highly dependent on the method of their administration. One study found that phages administered in drinking water could not cure experimental E. colirespiratory infections in broiler chickens — only direct intratracheal administration (aka inserting a needle into the trachea of each chicken). Meanwhile, another study found that despite injecting specialized phages into the mammary tissue of cows multiple times per day, no reduction in the mastitis-causing bacteria S. aureus was found (24, 25).
Development of phage-resistance — Lastly, just like fear of the very real risks posed by antibiotic resistance, there exists major concern that phage resistance could follow not too far behind. There is a range of mechanisms that could contribute to bacteria evolving in this way including modification of the phage surface receptors on the bacterial cell, integration of the phage genome into the bacterial chromosome, as well as CRISPR gene editing (26).

So, Can Bacteriophages Really Protect Us From Antibiotic Resistance?

When you take into consideration the various pros and cons of bacteriophage use, it becomes clear to see why depending on phages as a last line of defense is a completely and utterly unrealistic notion.

“While consumers may be more shocked by pink slime or the feeding of Prozac to poultry, the routine feeding of millions of pounds of human antibiotics to chickens presents a much graver threat.”

— Dr. Michael Greger

As the risk of antibiotic resistance and our relationship with the animals we eat for food stands, we’re on track to force the hand of mother nature in evolving the next new superbug or unstoppable pandemic.

While the scope of potential for bacteriophage use within the scientific world is extremely new and exciting for us — we’re currently lying to ourselves if we believe they provide any present solution to the problems we face.

Between cons such as their high specificity to bacterial cell hosts, to their ridiculously impractical suggested administration and application to factory-farmed animals, there is just no way we’re ready to place our bets on bacteriophages to protect us from antibiotic resistance.

I would love to know any thoughts you have on the topic, too.

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