Emergence of the Superbugs

Antibiotic resistance is therefore an ancient mechanism used by microorganisms to protect themselves against the antimicrobials.

Antibiotic resistance refers to the ability of certain organisms to resist or counteract the effects of these drugs. In this article, I will focus on bacteria. However, drug resistance can also be found in fungi, parasites and viruses (1).

Resistance to antimicrobials is not a new phenomenon. However, the increasing number of resistant bacteria, the phenomenon of multidrug resistance (MDR), and the spread/appearance of resistant strains across the world is unparalleled (1).

Resistance started appearing in hospitals in the 1930s-1940s, not so long after the first antibiotic, penicillin, was introduced (1).

Antimicrobial resistance is not a phenomenon to be taken lightly. It has cost many lives, especially in countries where no prescription for antibiotics is required. Low healthcare budgets also limit access to more effective, but expensive drugs, and poor sanitation and hygiene is not helping (1).

MDR also increases the time patients stay at hospitals, which in itself is a big issue, as hospitals have a limited capacity, and the rate of patient turnover is therefore significantly decreased.

Added to this is the well-known problem of nosocomial (hospital-acquired) infections with MDR strains that often increases patients’ burdens rather than alleviating them.

It therefore goes without saying that the costs associated with increased bacterial resistance are ever increasing, ranging in the billions of dollars per year.

Origin of Antimicrobial Resistance

Fig. 1: Penicillium mold inhibition of bacterial growth (L), photo of original plate where Fleming observed bacterial growth inhibition by the mold Penicillium. (R) A more clear plateshowing a circle of bacterial inhibition around Penicillium.

Antibiotics are not man-made. They are naturally produced compounds used by organisms such as fungi and bacteria.

The famous coincidental discovery of penicillin by the Scottish bacteriologist Alexander Fleming was made when he saw a bacteria-free circle around a mold that had accidentally contaminated his bacterial culture plate (Fig. 1) (2), suggesting that antimicrobials are a natural survival/defense mechanism used by organisms long ago.

In fact, 30,000 year old DNA from bacteria in permafrost (frozen soil) collected from the Canadian territory of Yukon showed the presence of resistance genes against many classes of antibiotics used today (3).

Antibiotic resistance is therefore an ancient mechanism used by microorganisms to protect themselves against the antimicrobials produced by others in their struggle for life.

Transfer of Antimicrobial Resistance

Since antibiotic resistance is increasing, it is logical to assume that this is an acquired mechanism. The question is how?

Also, since many bacteria are susceptible to antibiotics, we can safely say that it is not an essential trait, but confers a selective advantage only when challenged with an antimicrobial.

Fig. 2: Mechanisms of acquiring resistance in bacteria. Bacteria can acquire resistance genes by several methods, including plasmid conjugation, bacteriophage infection, or by taking up ‘free’ DNA. Adapted from Levy and Marshall, 2004.

Resistance genes were therefore initially not thought to be found on the chromosome (the main bacterial DNA), but on an extra piece of circular DNA called a plasmid, which is not found in all bacteria (Fig. 2).

This perception has changed as these resistance genes can be found within transposons (jumping genes) that may ‘jump’ between plasmid and chromosomal DNA.

This plasmid can be transferred between bacteria through a process called ‘conjugation’ either by direct cell-to-cell contact, or by a bridge-like connection  (1).

Other ways of taking up foreign DNA can be via bacteriophages (viruses) which infect bacteria by injecting their DNA into them. Bacteria can also take up ‘free’ or ‘naked’ DNA from the environment released by another microorganism (1). All these DNAs may contain resistance genes that give the bacteria this selective advantage.

Mechanisms of Antimicrobial Resistance

There are several ways in which bacteria neutralize the effects of antibiotics, some of which are shown in figure 2. These include making proteins that degrade or modify the antibiotic, or that serve as pumps that eject the antibiotic after its entry (Fig. 3).

Fig. 3: Bacterial resistance mechanisms. Bacteria can resist antibiotics in several ways, including antibiotic efflux, degradation, or alteration. They can also modify its target and inhibit its entry. Adapted from Levy and Marshall, 2004.

Bacteria can also inhibit antibiotic entry through their cell walls, or modify the internal target of the antibiotic, thereby averting its effect (1,4).

Reasons for the Spread of Antimicrobial Resistance

It must be clear that the emergence of resistance is based on two elements. One being the antibiotic itself, and the other being the internal genetic makeup of bacteria that may or may not carry resistance genes (1).

Imagine you are infected with harmful bacteria, most of which are susceptible to a certain antibiotic. However, some carry resistance genes. Once they are exposed to an antibiotic, all susceptible bacteria are eliminated, whereas the resistant ones persist and multiply under the selective pressure of the antibiotic, creating an antibiotic-resistant bacterial population.

You then take a more effective antibiotic to which little resistance has been documented. However, there is still a risk that the same cycle occurs, resulting in multidrug resistance. These MDR strains can then easily move from person to person, especially in hospitals, contributing to the spread of antimicrobial resistance.

Moreover, it is now not surprising to find resistant bacteria in one country that originated in another. Globalization is forcing us to contribute to the spread of resistance worldwide (1).

Our Contribution to the Problem

We have not only applied selective pressure on bacteria in terms of our increased use and abuse of antibiotics on ourselves, but we have extended this to animals, plants and fish.

Antibiotics are now heavily used in agriculture as an additive to animal feed, both to treat and prevent disease, as well as to improve growth rates. However, since only a small proportion of these antibiotics is absorbed in their guts, most is excreted in urine and feces, which is commonly used as a natural fertilizer (5), adding to the selective pressure for the survival of resistant bacterial strains.

In addition, to prevent infections, some fruit trees are treated with antibiotics, as well as aquatic cultures where fish are grown (6). This only adds to the ways in which antibiotics can spread, whether through the water from aquacultures, or in the air, by spraying the antibiotics on plants.

Moreover, resistant bacteria also spread through sewage from human waste material. The more people using antibiotics, the higher their concentration in our sewage, and the higher the density of resistant strains (1).

In countries where sewage is not properly treated, or where it is dumped in rivers or oceans, or where sewage contaminates drinking or tap water, one can imagine how antibiotic resistant bacteria can spread and thrive.

In each of these situations, the effects of antibiotics extend beyond its intended use, and spreads regardless if its use has been discontinued.

Efforts Conducted to Overcome Resistance

Certainly, scientific research is ongoing in this field, and there are continuous efforts to produce new antimicrobials with improved efficacy and which are not affected by bacterial resistance mechanisms.

Indeed, clinical trials are ongoing with derivatives of natural antibiotics that are potentially less prone to bacterial efflux pumps, and which bind their targets more tightly (4).

In addition, new natural antibiotics are also being discovered, and efforts to chemically modify them to increase their effectiveness and decrease their unwanted side effects are underway (4), whether these efforts will bear fruit remains to be seen in the near future.

However, it is likely that bacteria will find a way to avert these antimicrobials and become resistant. Are we therefore contributing to the development of the ever-increasing strength of multidrug resistant superbugs (7)?

How We Can Help

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Light is always at the end of the tunnel. However, the question is whether we can clearly see it. There are several solutions, both short- and long-term, to this seemingly endless cycle, and their effectiveness is multiplied if we begin to apply them all together.

I will start by the relatively easier, short-term solutions and list those that can be logically concluded from the current situation:

1. Isolating individuals in hospitals suspected of having MDR bacterial infections. Application of this by some countries has led to some of the lowest levels of MDR strains in hospitals (1).
2. Increased hospital hygiene and patient awareness of the devastating effects of MDR.
3. Controlling antibiotic use by people (only when necessary and after visiting a physician), by physicians (only after prior confirmation of bacterial infection and only when necessary), and by governments (controlled antibiotic distribution, requirement of prescription, and public awareness campaigns).

Of course, vital to public awareness is providing alternative solutions so as to encourage people to change. Here I mention one long-term, yet long-lasting and multifaceted solution, which is that of overall public health. It is crucial to see that one of the root causes of antibiotic use is a compromised immune system.

We usually use antibiotics if our own defense mechanisms are not strong enough to deal with the infectious agent. Natural ways of maintaining healthy immunity are plenty, and would be a great step forward in combating many diseases if incorporated in public awareness campaigns and workshops.

One often neglected feature of antibiotics is their poor selectivity between good and bad bacteria. This means that although an antibiotic may eliminate an infectious strain in your gut, it also kills any susceptible beneficial bacteria that are living in your gut (often called ‘microflora’). These normally aid in processes such as nutrient absorption and immunity, helping to fight off harmful bacteria.

Needless to say, it is as important to make the public aware of the health risks of an unhealthy diet and lifestyle, and its consequences on the immune system. No one can deny the deleterious health effects of a typical Western diet, or the health benefits of a Mediterranean diet.

Combining available knowledge from microbiology, statistics, nutrition, and other disciplines to contribute to positive public health education is therefore a fundamental aspect in combating, and ultimately preventing, drug resistance, disease, or unwanted health issues in general.

Humanity Has Hope

The World Health Organization (WHO) has recently issued a report in April 2014 about the severity of antimicrobial resistance, and about its consequences worldwide in which it said “A post-antibiotic era – in which common infections and minor injuries can kill – far from being an apocalyptic fantasy, is instead a very real possibility for the 21st Century” (8).

Will this change our use of these drugs, or will we just wait for someone else to solve the problem? A very relevant verse in the Quran (Surat Ar-Ra’d: 13:11)translates as follows: “Indeed, Allah (God Almighty) will not change the state/condition of a people until they (first) change what is in their hearts/souls.” So take action, and start by yourself, for that is what your judgment will be based upon.