Part 1: What is multidrug resistance?
Tickle in your throat? Take some antibiotics! Got the flu? More antibiotics! Antibiotics do not help cure the common cold or the flu, but they are some of the most over-prescribed drugs in the world. The Centre for Disease Control (CDC) estimates that at least 30% of all antibiotics prescribed in the US are unnecessary. But why should we care? Imagine you’re a coffee addict (probably you are!). It all started with one cup of coffee that woke your brain up and made you feel good. Over time, you realized one cup was not enough and started drinking more. Eventually, you started to notice that caffeine no longer had the same effect. You had developed a tolerance to caffeine and the drug now had no stimulatory effect on you. In a similar fashion, bacteria develop tolerance to antibiotics over time. Unlike caffeine tolerance, however, multidrug resistance, as this phenomenon is called, is irreversible and far more dangerous.
Since the discovery of penicillin in 1928, some bacteria have evolved resistance to each antibiotic that has been added to the arsenal since. In fact, in Alexander Fleming’s paper on the antibacterial properties of penicillin, he noted the presence of Staphylococcus aureus colonies that appeared to be resistant to the antibiotic. Antimicrobial resistance is not restricted to bacteria, however. Antifungal resistance is emerging as a serious threat, particularly in the case of invasive fungi such as some species of Candida and Aspergillus. In 2013, the CDC published the first Antimicrobial Resistance (AMR) report, which listed the bacteria and fungi species that they considered to be threats. Most of these include familiar suspects such as MRSA (methicillin-resistant Staphylococcus aureus) and Carbapenem-resistant Acinetobacter, but the list also includes Candida auris(which is resistant to a few anti-fungals)and Azole-resistant Aspergillus fumigatus. In addition to antibiotic and antifungal resistance, antiviral drug resistance, particularly amongst Herpesviruses and Cytomegalovirus (CMV) is becoming a grim reality, predominantly amongst immuno-compromised individuals.
These resistant microbes not only pose a serious public health risk but also come with a huge economic burden. As of 2019, Europe reported an expenditure of 9 billion euros per year, while in the US, AMR led to 20 billion dollars in direct healthcare costs. According to estimates by the World Bank, AMR will adversely impact low-income countries and exacerbate poverty due to high treatment costs. They estimate that the global GDP could drop by 1%, with low-income countries facing a 5-7% loss by 2050.
Multidrug resistance is not a phenomenon limited to microorganisms. In cancer patients undergoing chemotherapy, it rears its ugly head as antineoplastic resistance and is a major reason for the failure of chemotherapy. Antineoplastic resistance confounds anti-cancer drug development due to the bewildering capacity of tumor cells to evade therapy. Early chemotherapeutics such as aminopterin and nitrogen mustard caused a lot of excitement as they caused rapid tumor remission. However, this excitement was quickly dampened when it was discovered that the cancer often relapsed due to drug resistance. The reasons for cancer drug resistance are manifold and complex. Cancers can be immediately resistant to frontline therapies, or they can acquire resistance over the course of the treatment. However, conditions that involved many types of tumor cells and a diverse tumor microenvironment are far more complex. As with AMR, cancer cells also develop resistance to chemotherapeutics over time, resulting in an increasing population of drug-resistant cells. Cancer cells, being quite sneaky, can activate pathways that are alternate to the ones being targeted by the therapy, allowing them to survive. After the initial failure of single-drug chemotherapy, a page was taken out of the AMR therapy playbook and polychemotherapy was implemented as a treatment strategy. Nearly half a century following this change, however, the therapeutic potential of polychemotherapy appears to have realized its maximum potential and now is usually supplemented with additional strategies such as radiation therapy and/or surgery.
In the war against cancer, antineoplastic resistance has proved to be a formidable, and often insurmountable, opponent. Mortality due to antineoplastic resistance is sobering. It is estimated that over 90% of cancer patient mortality is due to drug resistance. Cancer is also incredibly expensive to treat. In the US, roughly two-thirds of cancer patients are over the age of 65. Hence, most of their treatment costs are borne by Medicare, which is expected to cost the federal government about $8.5 trillion by 2022. These costs are exacerbated by the use of new, more expensive therapies to combat cancer drug resistance. These expenses can prove to be fatal for younger people who may be un- or underinsured. Similar problems are faced by residents in the European Union (EU). Within the EU, there is the additional complication of the economic discrepancy between Western and Eastern Europe, resulting in a lack of access to advanced and expensive medication at subsidized rates and increased out-of-pocket expenses in most of Eastern Europe.
Due to the economic, public health, and social costs of multidrug/ antineoplastic resistance, early detection and monitoring of emerging resistance is imperative. In the case of AMR, this is rather complicated due to globalization. Resistant organisms are able to gain passports and cross international borders, which makes tracking AMR an epidemiological nightmare. Although the World Health Organization (WHO) and some pharmaceutical companies are attempting to improve surveillance of AMR, there is a severe lack of effective methods. Antineoplastic resistance is more straightforward to track, but quicker and cheaper methods are imperative to keep up with rapidly developing resistance.
Antimicrobial and antineoplastic resistance are very real threats to human health. The next two articles in this series will delve deeper into the mechanisms leading to multidrug resistance, and what we can do to overcome, or at least alleviate this phenomenon in the future.
Author:
Swathi Lingam is a postdoctoral 
scientist at BioMedX institute in Heidelberg, where she is working to identify pro-resolution factors in rheumatoid arthritis. She had been a Ph.D. student at the University of Manchester, followed by postdoctoral stints at the University of Oxford and A*STAR in Singapore before moving to Germany. She is passionate about science communication and loves doing that through her blog “The Very Curious Biochemist”. Follow her on Twitter.
Editors:
Saurja Dasgupta is originally from Kolkata, India. He obtained his Ph.D. at the University of Chicago, where he studied the structure, function, and evolution of catalytic RNA. He is currently doing his postdoctoral research at Massachusetts General Hospital, Boston, where he is trying to understand the biochemical milieu that could have given birth to life on earth (and elsewhere) and reconstruct primitive cells. One of his scientific dreams is to observe the spontaneous emergence of Darwinian evolution in a chemical system. When not thinking about science, Saurja pursues his love for the written word through poetry and song-writing (and meditating on Leonard Cohen’s music). His other passions are trying to make science easier to understand, and fighting unreason and pseudoscientific thinking with a mixture of calm compassion and swashbuckling spirit.
Sumbul Jawed Khan is a Ph. D. in Biological Sciences and Bioengineering from the Indian Institute of Technology Kanpur, where she studied the role of microenvironment in cancer progression and tumor formation. During her post-doctoral research at the University of Illinois at Urbana-Champaign, she investigated the gene regulatory networks that are important for tissue regeneration after damage or wounding. She is committed to science outreach and communication and believes it is essential to inspire young people to apply scientific methods to tackle the challenges faced by humanity. As an editor, her aim is to simplify, translate, and excite people about current advances in science.
Illustrator:
Atharva Deshpande is a 4th-year student at IISER Mohali pursuing a Biology major and minor in Science Education who eventually wants to become a full-time science illustrator. He believes blending science, art, and storytelling makes for an interesting recipe. You can follow him on Instagram and Twitter or connect with him on LinkedIn.
The contents of Club SciWri are the copyright of Ph.D. Career Support Group (DBA STEMPeers) for STEM trainees, experts, and professionals. This work by Club SciWri is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
