Antibiotic Resistance - Has the COVID-19 pandemic fast-tracked us towards a pre-antibiotic era?

Written by Aidan Kendrick, Edited by Caroline Babisz, Charlotte Pugsley and Anna Tchorzewska

What is antimicrobial resistance?

Throughout this series, we’ll be focusing onto antibiotics and the problem associated with antimicrobial resistance. Antimicrobial resistance (AMR) can occur when microorganisms gain mechanistic advantages which allow them to survive exposure to therapeutic agents such as antibiotics, antifungals, or antivirals. There are many ways microbes can obtain resistance, such as genetic mutations and the transfer of genes, but what proliferates and pushes resistance to happen more rapidly are selective pressures.

What is a selective pressure?

In the case of a bacterial infection, an antibiotic prescription should provide the patient with instructions for a set dosage as well as length of treatment (e.g. 2 tablets a day for 14 days). However, many of us find ourselves asking the question, “why should I continue a full course of antibiotics when I feel better?”.

The answer comes down to a multi-faceted cascade of events. A bacterial infection can hold thousands, if not millions, of bacteria. Ideally, when bacteria are exposed to an antibiotic, those susceptible are destroyed, leading to the successful treatment of the infection. However, the absence of symptoms can be misleading. You can be completely asymptomatic, whilst thousands of bacteria could remain present in your system. This can mistakenly lead patients to end their antibiotic course prematurely. A bacterium has not only now survived exposure to an antibiotic but may have also acquired a resistance mechanism that can be passed on to later generations through reproduction; the antibiotic has therefore acted as a selective pressure for a drug resistant, infectious microorganism.

Before you know it, after several rounds of prematurely terminated courses of antibiotic, you have a multi-drug resistant (MDR) infection on your hands that can spread from person to person. This classic example of Darwin’s Natural Selection on a microbial level, emphasises the need for completing a full course of medication, which is more likely to clear the entire infection, reducing the chances of MDR infections.

The Problem with AMR

AMR has left society with a big dilemma. Simply put, the more we use antibiotics, the more likely resistance is. Whether by choice, or absence of other treatment options, the lack of using antimicrobial agents would leave us in a time reminiscent of a pre-antibiotic society, causing us to experience an ‘Antibiotic Winter’ – where no antibiotics are considered effective. This would mean something as simple as a throat infection could end up killing millions annually when left untreated.

Since the widescale use of antibiotics, we have been part of a continuous battle with bacteria, termed the ‘antimicrobial [antibiotic] arms race’. As we discover novel antibiotics and begin prescribing them, the targeted bacteria inevitably develop resistance from continued use, thus requiring further efforts to discover newer antibiotics to fight back. This is where we are beginning to lose our grip on the ‘arms race’, whereby research and development into new antibiotics is not keeping up with the accelerating emergence of antimicrobial resistance.

Our methods of tackling  the emergence of antibiotic resistance has largely been through the discovery of new antimicrobial agents, or chemically altering our current stores of antibiotics to restore their effectiveness against newer, now resistant bacteria. This fight has been ongoing and was effectively backed by a ‘golden age of natural product discovery’ where many novel antibiotics were frequently discovered, however, this has been hugely scaled back by the lack of investment and research since the 1980s. Furthermore, we have seen an exhausted list of alterations to older antibiotics, which are no longer able to tackle the new threat of multi-drug resistant organisms. Could this be the beginning of the end of the antibiotic era?

FIGURE 1 :  Chemical alteration of the structure of penicillin gave rise to a newer derivative of the antibiotic, amoxicillin, which belongs to the same group of antibiotics (characterised by the presence of the beta lactam ring structure highlighted in green).

In 2014, the economist Jim O’Neill was commissioned by the Prime Minister David Cameron to analyse the global problem of antimicrobial resistance. In doing so, he discovered many worrying statistics. For example, despite 700,000 deaths attributed to AMR in 2014, it was projected that this could reach 50 million a year in 2050.

"If we fail to act, we are looking at an almost unthinkable scenario where antibiotics no longer work and we are cast back into the dark ages of medicine" – David Cameron, former UK Prime Minister.

However, this pre-pandemic report may have underestimated the challenge, with the COVID-19 pandemic drawing this scenario closer to today’s reality.

The Impact of COVID-19 on AMR

“Since the emergence of Covid-19, collected data have shown an increase in antibiotic use, even though most of the initial illnesses being treated have been from Covid-19 viral infection” – Dawn Sievert, senior science advisor for antibiotic resistance at the US Centers for Disease Control and Prevention (CDC).

As part of the national curriculum, even GCSE students are required to know that antibiotics shouldn’t be used for viral infections. With COVID-19 being a viral disease, you may ask why this has exacerbated AMR? Why were antibiotics even used in the first place?

Many patients that were hospitalised with severe COVID-19 symptoms were given a course of last-resort antibiotics, aimed at treating life-threatening secondary infections. Simultaneously with COVID-19 treatments, patients were administered with antibiotics as a prophylaxis, to prevent secondary infections such as pneumonia, caused by the bacterium Klebsiella pneumoniae. Often diseases like COVID-19, which severely weaken your immune system, allow the secondary bacterial infection to sneak in, which has the potential to kill the patient.

The demand that medical professionals faced throughout the COVID-19 pandemic, made it impossible to do susceptibility testing (checking infections for resistance) or to seek alternative medicines prior to selecting the course of antibiotics. In such dire situations, doctors are given two choices: treat patients with all possible therapies to increase the chance of survival or negate the use of therapies and risk death. Consequently, the indiscriminate use of antibiotics shouldn’t be overly criticised in this case, but rather seen as an unfortunate result of the rapidly escalating pandemic.

What was the guidance during the pandemic?

The World Health Organisation (WHO) advised the use of antibiotics only for severe cases of COVID-19, when the risk of secondary bacterial infections posed the risk of death. However, following a review, data suggested that 70% of patients received antimicrobial treatment despite less than 10% having any form of bacterial or fungal coinfections. This raises the question: did we act too rashly, consequently escalating the issue of antimicrobial resistance, and what should be learnt from this experience for future pandemics?

What does the future hold?

Following the COVID-19 pandemic, understanding the implications of the O’Neill report , and providing more funding for natural product discovery is vital if we are to avoid a pre-antibiotic era. A follow-up to the O’Neill report could be beneficial to aid a global movement in both guidance for antibiotic prescriptions and the approaches towards research and development, to help us in the arms race we are currently falling behind in.

References[1] - https://www.bmj.com/content/369/bmj.m1983

[2] - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2802854/

[3]- https://academic.oup.com/jac/article/67/9/2062/880174

[4] - https://agsjournals.onlinelibrary.wiley.com/doi/abs/10.1046/j.1532-5415.50.7s.2.x

[5] https://www.nature.com/articles/509S2a

[6] https://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf

‍