Improving Antibiotic Prescription Can Help Address the Antibiotic Resistance Crisis
Mastering the Microbiome: December 2023
Introduction
Thanks for tuning in to Mastering the Microbiome! In writing this newsletter, our goal is to uncover all the different ways that researchers studying the microbiome are driving research forward.
For researchers, the idea of this newsletter is to show what successful, publishable work in the field looks like right now. At the same time, it also aims to encourage new kinds of research projects that push the field in new directions, towards new translational goals. For non-researchers, the idea is to pull back the curtain to show what research work actually looks like, and why it matters for society at large.
We’re trying out a new, narrative-driven format this month. Check it out below!
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Research Story
The crisis of antibiotic resistance – millions of people across the world experience antibiotic-resistant infections every year. Many die as a result. Often, this crisis is attributed to the fact that our modern arsenal of antibiotics is simply not effective against certain strains of bacteria. To stop these infections and save lives, we need to find new antibiotics and find them fast.
For many infections, however, there may in fact be a simpler solution – one that does not necessarily require the discovery of new antibiotics. In some cases, antibiotic treatment can fail not because there is no antibiotic to treat a patient’s infection, but because the wrong antibiotic was chosen. Typically, when deciding on an antibiotic to treat a patient’s infection, a medical clinic will take a sample from the patient, grow it on a plate in the lab, expose it to a bunch of antibiotics, and see which ones perform best (a process called antibiotic susceptibility testing, or AST)A. The most effective antibiotic from this test is then administered to the patientB.
But if you consider what we know about the biology of the human lungs, there is an obvious reason why this approach often fails. Imagine that an invasive pathogen has entered the airways and is waging war with the immune system. Immune cells are working hard to clear the infection, but also inflaming the airways and damaging lung tissue in the process. In addition, before the invasive pathogen even sets foot in the lungs, there is community of other microorganisms – the lung microbiome. Though many of these microbes play a positive role in supporting lung health, some of them may actively assist the invasive pathogen in its quest to colonize the lungs.
This is the case for people with cystic fibrosis – a genetic disease where a single dysfunctional protein (the CFTR chloride channel) causes the buildup of thick, sticky mucus in the airways. The mucus-laden lungs of someone with CF are a haven for unhealthy bacteria and fungi that trigger inflammation and damage lung tissue. Prior laboratory experiments have shown that when you grow two CF pathogens together in the lab and treat with antibiotics, one pathogen can sometimes protect the other from antibiotic killingC.
If you were to isolate a pathogen from the lungs and perform traditional antibiotic susceptibility testing, will it behave like the pathogen does in the lungs, when it is in the company of many other microbes that may influence its behavior? The answer is probably no. An antibiotic that works against this lonely isolate in the lab may be completely ineffective against the pathogen in its natural setting.
The authors of a recent paper in the Journal of Clinical Microbiology recognized this fact and have developed a system called AtbFinder that considers the broader microbial community when making antibiotic prescriptions. The AtbFinder system works like this: on a surface, there is a series of wells, each containing a special kind of growth medium that can support multiple different species of bacteria at once. Into each well goes the bacteria isolated from a patient. But unlike traditional antibiotic susceptibility testing methods, where a single pathogen is isolated for antibiotic testing, multiple pathogens are allowed to grow at once. Once the bacteria are cultured, a different antibiotic or combination of antibiotics can be tested in each well to see which is the most effective at killing the target pathogen and any other pathogenic microbes in the sample. With this approach, you can take into account potential interactions between species – which could make certain antibiotics less effective, and others more effectiveC.
Featured Study: AtbFinder Diagnostic Test System Improves Optimal Selection of Antibiotic Therapy in Persons with Cystic Fibrosis (Tetz et al., 2023)
The AtbFinder team has already achieved a lot of success with this approach. In their paper, they present a before-and-after story of 35 CF patients who were all prescribed antibiotics using AtbFinder – showing dramatic improvements in bacterial killing and clinical measures like lung function and the rate of hospitalization in the several years after starting to use AtbFinder compared to the several years before. The paper’s lead author George Tetz is the CEO of a company, TGV-Dx, which is currently engaged in a series of clinical trials to see how helpful AtbFinder can be for people with other diseases, including pneumoniae and recurrent urinary tract infectionsD.
The AtbFinder story is a powerful example of how a relatively simple concept – testing antibiotics against multiple bacteria that coexist in the lung rather than just the main pathogen of interest – can lead to dramatic clinical improvementsE. If the success in clinical trials continues, the AtbFinder system and others like it may soon be commonplace in hospitals across the world and used to treat a wide variety of diseases.
Broader Trends
(A) If you are interested in learning more about the traditional antibiotic susceptibility testing approach, here is a short article that describes it in more detail.
(B) In reality, clinicians also need to consider other factors. Patients can be allergic to specific antibiotics (see here). And the most effective antibiotic in the test may also be the most damaging to the broader lung microbiome (and the gut microbiome as well) – which performs functions that are important for health. The microbiome plays an important role in resisting colonization by invasive pathogens. Treating with broad-spectrum antibiotics can actually increase the risk for future infection. For example, hospitalized patients treated with broad-spectrum antibiotics are at great risk for C. diff infections. According to the CDC, there are almost half a million of these infections in the US each year and many people experience recurrent infections due to the disruption of the microbiome by antibiotics.
(C) This effect can happen with two separate species – for example, studies have shown that CF pathogen P. aeruginosa can protect another CF pathogen, S. aureus, from some kinds of antibiotics when they are grown together, though this combination of species is also more susceptible to other kinds of antibiotics (see here). You can also have two distinct populations of the same species that have evolved together in the lungs, one of them being a mutant form that can protect its fellow bacteria from antibiotic killing (see here)
(D) This video gives a nice overview of the AtbFinder with good visuals. At the end, it also describes the ongoing clinical trials for the AtbFinder system.
(E) It is simple on the surface, though in reality decades of research and clinical experience have led up to this moment and made this kind of system possible – documenting the failure of traditional antibiotic susceptibility methods, understanding the complex interactions between species that can affect antibiotic susceptibility, developing laboratory growth media that can handle multiple bacteria at once, and much more…
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