The Catastrophic Case of Antibiotic Resistance

The Catastrophic Case of Antibiotic Resistance
By Aparajita Biswas 



“WE REALLY ARE FACING, IF WE DON'T TAKE

ACTION NOW, A DREADFUL POST ANTIBIOTIC APOCALYPSE”

-Chief Medical Officer UK, Dame Sally Davies



The Earth circles, and days go by, in this mysterious order , where life, is often survival , reeked  with struggle, and owing much to this struggle for life, any variation, however subtle and derived from whatever, cause progression, of behaviour and features, if it may be in any degree, advantageous to an individual of any species, in its infinitely complex relations to other beings and to the environment, will result in the continued preservation of that individual, and will generally be inherited by its offspring. Those who fail, go extinct, while others undergo evolution, no matter how evil it may be to the survival of others, but such is the struggle for survival that dictates the ugly mechanism of life.

Bacteria, are clearly the malicious weapons, glorified in the name of winners, in this race of adaptive evolution, better known as the Darwinian selection. Human survival, is our battle against them, primarily fought by biotechnologists, when the responsibility lies in every human, in the ways that will be elaborated further below.

The battle against microbial infections in ancient civilizations is well found. The modern spring of antibiotics set off with the discovery of penicillin by Sir Alexander Fleming in 1928.Ever since, several antibiotics have transformed what defines modern medicine and treatment and, in the process, saved several millions of lives.

Unfortunately, microbes undergo Darwinian selection to develop some mechanisms to go past the effects of these antimicrobial medications. Organisms may evolve defensive phenomena against them, such as, alterations in the target site, inhibition of drug from entering or drug distribution. Alternatively, they may produce enzymes that may work to degrade antimicrobials. 

Perhaps it is best that we start by defining what is antibiotic resistance all about.

To put it as plainly as possible, antibiotic resistance happens when germs such as bacteria and fungi eventually build up the ability to defeat the drugs designed to destroy them. 

That means that the germs are not killed and continue to grow. 

These infect humans and animals, and then the infections they cause become harder to treat due to the resistant strains developed. Hence, antibiotic resistance has to higher medical costs, prolonged hospital stays, and increased mortality, which, based on the pattern of the increased intensity of the previously mentioned consequences, call for a global, medical emergency.





What has led to cause this issue to the point that it has come to be a persistent global emergency?
Experimentations in evolutionary selection pressure, with the immense amount of antibiotics thrown upon to the planet, to treat diseases and to promote growth in animals used for poultry and food production has eventually led to consequences that are depressingly obvious: the fatal issue of antibiotic resistance in bacteria, rather pathogenic microbes in all. 

OVERUSE
The first and the most primary cause of antibiotic resistance is given over to its overuse. 
Sir Alexander Fleming had himself, in fact, raised his feared concern seeing regarding antibiotic overuse where he had clearly warned that the “public will demand [the drug and] … then will begin an era … of abuses”, and that is what it is today. This major crisis of increasing anti biotic resistance.
The overuse of antibiotics evidently drives the evolution of resistance. 
Studies have proven a direct relationship between antibiotic consumption and the occurrence of resistant strains of bacteria. 
In bacteria, genes can be inherited from related species or from non-related species on motile genetic structures such as plasmids. For instance, the horizontal gene transfer (HGT) mechanism allows for antibiotic resistance transfer between different species of bacteria. 
Sub-inhibitory and sub-therapeutic antibiotic concentrations lead to the development of antibiotic resistance by supporting genetic alterations, such as, but not limited to changes in gene expression, HGT, as mentioned previously, and of course, mutagenesis. Changes in antibiotic-induced gene expression may increase virulence, while the increased mutagenesis and HGT lead to antibiotic resistance and spread.
Resistance may also occur spontaneously through mutation. Antibiotics remove drug-sensitive competitors, leaving resistant bacteria behind to reproduce as a result of natural selection.
Despite the warnings of the consequence of overuse, antibiotics are often overprescribed, or wrongly prescribed, either by medical practitioners or by non-professional recommendations.

UNDERDOSE
Underdose, again is an issue too. Underdose of antibiotics may either happen because of wrong prescription or because some people do not follow the course of antibiotics correctly, abandoning the course of medication just because they think they feel better. This again, is more prevalent in lesser privileged areas, where it comes from the act of saving those medications for later use.
 Fleming himself, had stated,” The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.”
Annually, several thousands of people die from infections acquired from hospitals, a lot of them being multi-drug resistant. Hospital-acquired infections (HAIs) is now a single regular term that is infamously related the adverse health effects of multiple drug resistance (MDR). This has come to be an additional burden to regulate and resolve by the hospital team. 
Infections caused by antibiotic-resistant germs are difficult, and sometimes impossible, to treat. In most cases, antibiotic-resistant infections require extended hospital stays, additional follow-up doctor visits, and costly alternatives.

AGRICULTURAL USES
Another issue of antibiotic resistance, rather, a rather significant one, while being the most ignored one, is the extensive use of antibiotics in agriculture.
Antibiotics are extensively implemented as growth supplements in livestock.
Almost 4/5th of the antibiotics sold in the United States, for instance, are used in animals, mainly allow growth and prohibit diseases. Treating livestock with antibiotics apparently improves the overall health of the animals, allowing a larger amounts of higher quality products. However, these very antibiotics that are used rather carelessly in livestock, are taken into human systems during consumption of these products.  The transfer of resistant bacteria to humans brings with its terrible consequences. 
So, this is how the sequence goes:
antibiotic use in food-producing animals kills or suppresses susceptible bacteria, but antibiotic-resistant bacteria to thrive
resistant bacteria are transmitted to humans through the food supply
these bacteria can cause infections in humans that may lead to adverse health consequences

This agricultural use of antibiotics also affects the environmental microbiome. Up to ninety percent of the antibiotics given to livestock are excreted in urine and stool, then widely dispersed through fertilizer, groundwater, and surface runoff. So, it is even more extensive than it meets the eye. Tetracycline, for instance, is often sprayed onto fruit trees in the form of pesticides. 

LACK OF NEW ANTIBIOTICS/EFFECTIVE RESEARCH FINDINGS
Availability of Few New Antibiotics as well as lack of funding research opportunities also poses a worrying issue. Among one of the issues, if antibiotics are used, they are generally used for the short-term, not like the long-term therapies that help bring in revenues for companies.
A lot of the products being approved are second, third or fourth generation antibiotics, without a new mechanism of action. 
Mahesh Patel, the director of drug discovery research at Wockhardt, has said that the largest issue for companies is the regulatory procedures. “The costs of trials are so high and society is not willing to pay the high price for antibiotics; so that is the paradox. Society wants a cheaper antibiotic, but the costs of development will be high. So, we need to manage these two conflicting needs.”
“Helen Davis, executive editor of the UK Medicines Information horizon scanning document Prescribing Outlook, which collates data on new antibiotics, says: “In recent years, new antibiotics have struggled to reach the market due to difficulties in demonstrating efficacy or they have had unacceptable side effects. In addition, in order to gain a licence, new antibacterial will have to demonstrate they are not inferior to existing drugs where the comparator is available generically. This makes establishing a market share difficult.” 
The quick development of antibiotic resistance has also reduced investments in research, demotivating researchers in the field. Comprise all these, and you have a world of a maddening spree of antibiotic resistance spreading through the struggle of bleak developments of new antibiotics.

Just some mechanisms through which Antibiotic resistance may occur:



Restriction of access of the antibiotic
Microbes may prevent entry by changing or limiting the number of paths of entry of antibiotics.
Example:
 Gram-negative bacteria consist  of an outer membrane that shall protect them from external conditions.

Getting rid of the antibiotic
Germs may get rid of antibiotics that have entered with the use of pumps present in cell walls.
Example: 
Pseudomonas aeruginosa can produce pumps to get rid of fluoroquinolones.

Changing or imposing destruction of the antibiotic
Microbes may change or destroy the antibiotics with enzymes.
Example: 
Klebsiella pneumoniae produce carbapenemases, which break down carbapenem drugs and other beta-lactam drugs

Avoidance of the effects that the antibiotic is designed to perform
Germs develop new cell processes that avoid using the antibiotic’s target. 
Example: 
Some Staphylococcus aureus bacteria can bypass the drug effects of trimethoprim

Manipulating the targets for the antibiotic, resulting in incapability of functioning
Many antibiotic drugs are designed to single out and destroy specific parts (or targets) of a bacterium. Microbes can change the antibiotic’s target so the drug can no longer fit and do its job.
Example: Escherichia coli bacteria with the mcr-1 gene can add a compound to the outside of the cell wall so that the drug colistin cannot latch onto it.
The Centres for Disease Control and Prevention (CDC) has recommended 4 solutions to curbing or limiting this crisis:

“PREVENTING INFECTIONS,
PREVENTING THE SPREAD OF RESISTANCE"

Avoiding infections in the first place reduces the amount of antibiotics that have to be used and reduces the likelihood that resistance will develop during therapy. There are many ways that drug-resistant infections can be prevented: immunization, safe food preparation, handwashing, and using antibiotics as directed and only when necessary. In addition, preventing infections also prevents the spread of resistant bacteria.

TRACKING
CDC gathers data on antibiotic-resistant infections, causes of infections and whether there are particular reasons (risk factors) that caused some people to get a resistant infection. With that information, experts can develop specific strategies to prevent those infections and prevent the resistant bacteria from spreading.

IMPROVING ANTIBIOTIC PRESCRIBING/STEWARDSHIP
Perhaps the single most important action needed to greatly slow down the development and spread of antibiotic-resistant infections is to change the way antibiotics are used. Up to half of antibiotic use in humans and much of antibiotic use in animals is unnecessary and inappropriate and makes everyone less safe. Stopping even some of the inappropriate and unnecessary use of antibiotics in people and animals would help greatly in slowing down the spread of resistant bacteria. This commitment to always use antibiotics appropriately and safely, only when they are needed to treat disease, and to choose the right antibiotics and to administer them in the right way in every case,is known as antibiotic stewardship.

DEVELOPING NEW DRUGS AND DIAGNOSTIC TESTS
Because antibiotic resistance occurs as part of a natural process in which bacteria evolve, it can be slowed but not stopped. Therefore, we will always need new antibiotics to keep up with resistant bacteria as well as new diagnostic tests to track the development of resistance. “


Much more than 2.8 million antibiotic-resistant infections occur in the U.S.  alone each year, and more than 35,000 people die as a result, which is an alarming amount, clearly.
Antibiotic resistance has risen pretty dangerously. New resistance mechanisms have come up and are spreading worldwide, threatening our ability to treat common infectious diseases. Increased time of treatment and procedures due to antibiotic resistance have given rise to a catastrophic financial burden on healthcare systems across the world.  A rising amount of infections, such as tuberculosis, , gonorrhoea,  food borne diseases and pneumonia are becoming more complex to treat, or often even impossible, since lesser antibiotics are now effective. Without any immediate action, we will lead to that treacherous, hopeless, post-antibiotic climate, where even the most common infections and minor injuries could destroy us.

Sarbajit Ray on behalf of SBE-VIT

Author & Editor

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