The problem of antimicrobial resistance

Eric Walker, May 25, 2019

Each day I open an email in my inbox with the title “Google Alerts” and follow dozens of links. The links are to articles that Google has discovered that match keyword searches like “Carbapenem resistant,” “MRSA” and “superbug.” Each link brings up an article from Vox, the New York Times or The Guardian, or, more often, lesser-known sites such as Bovine Veterinarian and KRTV Great Falls News.

The articles discuss the growing problem of antimicrobial resistance. The antibiotics we’ve relied on and taken for granted since the 1940s to make surgery and recovery from cuts and grazes straightforward are gradually losing their effectiveness. Instead of recovering quickly, a young man who fractures his foot might die of a drug-resistant infection a few days later, because doctors are unable to find an antibiotic that can deal with the infection in time. I read or skim through the articles in the email, and, if they look like they might be of interest to others, I enter the URL into a form on Reddit and submit the link to the r/DrugResistanceBugs, a forum I started a few weeks ago.

Here I’m going to set out some of the things I’ve learned in the course of this project as well as how it relates to Digraph, the tool I’m using to keep track of everything.

Antimicrobial resistance

There are at least three broad categories of microscopic creatures that are trying to kill us: bacteria, viruses and fungi. We use antibiotics to keep bacteria under control, vaccines to protect against viruses and fungicides to kill fungi. When we talk about “antimicrobial resistance,” or AMR for short, we’re generally talking about bacteria and fungi.

We’ve had reason to worry about about the threat of antibiotic resistance since the dawn of antibiotics. Our bodies are teeming with bacteria, good and bad, and antibiotics kill not only the undesirable bacteria, but also the desirable kind as well. Use of an antibiotic has two important side effects. First, it accelerates evolution, selecting for any small fraction of the target bacteria that we might be trying to get rid of that has some kind of trick that will thwart the antibiotic. Second, by killing off the good bacteria, a space is created for any remaining bacteria to take over.

The threat of antifungal resistance is only gradually gaining attention, most recently with an outbreak of pan-resistant Candida auris, a lethal strain of Candida. It was an article in the New York Times on this topic that motivated me to start this project. In 2018, The Atlantic ran a story about another fungus, Aspergillus fumigatus, which has been killing not only tulips in the Netherlands but also immunocompromised hospital residents as well.

The U.N. Interagency Coordination Group on Antimicrobial Resistance estimates that by 2050 as many as 10 million people could die each year from complications arising from antimicrobial resistance if the world does not step up to the challenge. Strains with names like E. faecalis, C. difficile, Shigella, A. baumannii, Enterobacteriaceae, Klebsiella, P. aeruginosa and MRSA are already a big challenge to deal with, especially in developing countries, where the rates of infection by drug-resistant bugs are relatively high.

Antibiotic and antifungal resistance both arise in similar conditions, with resistant bacterial infections a much bigger problem at the moment. Resistance is created through the misuse of antibiotics and antifungals in humans, when, for example, antibiotics are over-prescribed or not taken through a full course. In addition, when someone arrives at a hospital and is deathly ill, an antibiotic will often be prescribed on the basis of symptoms alone, before the infection has been accurately identified, in the hope that it will deal with the infection. Bacteria are transmitted to humans via privacy curtains, dirty hands, stethoscopes and endoscopes, among other things.

Resistance is also thought to arise in the context of industrial agriculture. Farm animals are routinely given medically important antibiotics in their feed and drinking water. This is done partly to protect against the kinds of infections that occur under cramped and unsanitary conditions. But farm animals are also given antibiotics to fatten them up and to accelerate their growth; why this works is not yet understood. But the routine use of antibiotics turns large scale farms into Petri dishes for the development of new drug-resistant strains of bacteria.

The situation with antifungals is perhaps more worrying. In the case of antibiotics, there are numerous varieties that can be used and others under active development. As resistance arises in one antibiotic, there is a possibility that an infection will respond to another, possibly somewhat toxic, antibiotic. In the case of fungicides, there are only three man classes that are currently available, so there are effectively no backups.

Which has more impact on the development of antibiotic and antifungal resistance — the misuse of antimicrobials in humans in a medical context, or the routine use of antimicrobials in an agricultural context? This is a question that is still being investigated, and the answer will probably depend on the specific medically important antibiotic or fungicide in question.

There’s an even more vexing problem. It seems that existing market mechanisms do not provide adequate incentives for pharmaceutical makers to research and invest in new antimicrobials. As one example, the startup Achaogen, which had a promising new antibiotic, could not cover its expenses and filed for bankruptcy. Over the last few decades, more and more pharmaceutical companies have ceased researching new antibiotics, and now only a handful continue.

There are a number of strategies that can be used to address the problem of antibiotic resistance. These include simple things such as educating hospital workers about the need for washing their hands with soap, as well as more challenging approaches, such as attempting to adjust market incentives for the development of new antimicrobials. Technological strategies include robots that go from room to room in a hospital, disinfecting the room with ultraviolet light while no one is around. An important strategy is that of antimicrobial stewardship, a careful set of controls around the use antibiotics so that they continue to be effective.

Antimicrobial resistance, Digraph and Reddit

This description only scratches the surface. We won’t get into some Civil War–era medicinal plants that show promise, the use of phages to selectively attack specific strains of bacteria, or some of the mechanisms that are thought to underlie the development of antimicrobial resistance. No matter how deep you go into a question, there always seems to be a more specific topic that looks at some aspect in even greater detail.

This research confirms for me what you might call the fractal nature of knowledge. However far you zoom in to a topic, you can often zoom in even further, subject only to the limitations of what science has discovered so far. The topics discussed above were arrived at empirically, through a process of anthropological observation of the language used by medical professionals and journalists, of asking what buckets an article might be placed in, and whether there were any recurring themes that had not yet been noted.

How do you capture all of that information in a form that can be revisited later on without too much difficulty, and is there a way to make the process collaborative? These are some of the questions that motivated me to write Digraph.

Another thing that I wanted to be able to do was to have a place to put every link I came across, so that I didn’t have to be selective. If there’s a link that’s vaguely relevant or interesting, I wanted there to be a place for it, without having to make a judgment at that time about whether to keep it around or not. From the outset I had a sense, and I now better appreciate, just how many articles there are out there in the world. On a given topic, some articles describe studies, some summarize the studies, some of them summarize the summaries, some of them reprint the summaries verbatim, and yet others give broad overviews many weeks later. How do you both keep all those links around, and also make things easy to navigate and find later on? Part of the answer must involve filters of different kinds. This article was in a quality publication, so sort it to the top. This other article was a reprint of an earlier one, so filter it out by default. None of these or other filters have been added yet, so things are still a little bit messy.

Going through the daily emails from Google, sifting through the articles and putting them up on r/DrugResistanceBugs on Reddit has been a useful exercise. It has helped me to better understand what features to prioritize and build out in Digraph, and I think I’ll continue to do it for a little while longer.