Why Do Germs Become Resistant to Antibiotics? An MSK Program Is Focused on Avoiding this Problem

Source: Memorial Sloan Kettering - On Cancer
Date: 05/22/2019
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The rapid emergence of drug-resistant microorganisms is “a global crisis that threatens a century of progress in health and achievement,” according to a recent report from the World Health Organization. Increasingly, experts have been sounding the alarm about the evolution of drug resistance. As a result, many common infectious diseases may become untreatable.

The best way to prevent microorganisms from developing resistance is ensuring that antimicrobial drugs are used properly. Memorial Sloan Kettering was one of the first hospitals in New York City to recognize and address this problem. In 2001, MSK established a program to oversee the use of antibiotics and other antimicrobial drugs. It has since served as a model for other cancer centers.

In an interview, Susan Seo, an infectious disease doctor who leads MSK’s Antibiotic Management Program, talks about how MSK is leading the way in ensuring that these drugs are used responsibly.

Why is a cancer hospital focused on antibiotic use?

Infections are a major complication of cancer treatment. We know that preventing and treating them improves patients’ overall health and outcomes.

People with cancer may be more prone to infections because of the underlying disease itself. They may also have weakened immune systems as a result of the therapy they’re receiving to treat the cancer. Subsequently, most people with cancer receive antibiotics at some point during their treatment.

Why is it important to ensure that antibiotics are used properly?

If people take antibiotics when they don’t need them, they may end up with bacteria that can resist those antibiotics. People who have infections due to antibiotic-resistant bacteria can have longer and more serious infections. They may have limited treatment options. And they can die from antibiotic-resistant infections. In addition, people who take a lot of antibiotics can develop side effects. These might include a rash or antibiotic-related diarrhea caused by the bacterium Clostridium difficile. So it’s important that antibiotics are prescribed to people only when they are truly needed.

I think of antibiotics as a precious resource. If we run out of effective antibiotics to treat or prevent infections for people with cancer, then giving chemotherapy or doing surgery becomes very high risk.

What is the role of the Antibiotic Management Program at MSK?

Antibiotic stewardship is a commitment to using antibiotics optimally and safely. My team includes infectious disease–trained clinical pharmacists. Together, we assist doctors and nurses at our hospital in ensuring that antibiotics are prescribed with the appropriate drug, dose, and duration. This allows the drugs to wipe out infections that have been diagnosed and prevent others from occurring. We want to ensure that antibiotics are stopped if there is no evidence of infection.

Members of the program are engaged in teaching our colleagues about antibiotic stewardship because it’s everybody’s responsibility to use antibiotics wisely. In this way, we can preserve them not just for today but for all the generations that come after us.

Can you give an example of how this program has made a difference in patient care?

The problem of antibiotic resistance is due to misuse or overuse of antibiotics. A common example is taking an antibiotic for a viral infection, such as the common cold.  

We recently did a collaborative study with our colleagues on the Lymphoma Service. We wanted to see how many of the people who had cold symptoms were getting antibiotics.

We then developed guidelines that describe the features of common upper respiratory tract infections, the diagnostic workup, and how to manage them. We used the Centers for Disease Control and Prevention’s recommendations for treating upper respiratory tract infections.

We educated doctors and nurses about this issue. The guidelines were posted in the workroom pods. We then looked to see if this made a difference. Happily, we found that the rate of antibiotic prescriptions for upper respiratory tract infections dropped. We recently presented this work at MSK’s Quality Improvement Fair.

My team is now pondering how to build on this work. One focus is keeping this effort going in lymphoma care. We are also thinking about adapting this approach for other outpatient clinics at MSK.

Researchers Identify a Bacterial Species That Could Protect against Hospital-Acquired Infections

Source: Memorial Sloan Kettering - On Cancer
Date: 08/21/2019
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Hospital-acquired infections are a major threat, especially for people whose immune systems may be compromised because of cancer treatment. In recent years, researchers have been studying fecal microbiota transplants as a way to treat this serious complication. These transplants involve collecting stool from a healthy donor and delivering it into the intestine of the patient. The beneficial microorganisms from the transplant restore the balance of healthy bacteria in the gut.

Little is known, however, about which species of bacteria offer protection against harmful pathogens or exactly how they provide this benefit. A new study from Memorial Sloan Kettering is reporting the first evidence of a bacterial species that appears to maintain the balance of healthy microbes by killing dangerous ones. The findings also suggest how it mounts this attack. The research was reported August 21 in Nature.

“A lot of work is being done to figure out how harmful pathogens are able to colonize the human body,” says first author Sohn Kim, an MD-PhD student in the Tri-Institutional MD-PhD Program of MSK, Weill Cornell Medicine, and The Rockefeller University. “This project provides important new information about the bacteria that keep them in check.”

Focus on a Deadly Infection

The study focused on a particularly threatening hospital-acquired infection called vancomycin-resistant Enterococcus (VRE). VRE sickens about 20,000 people in the United States every year, according to the Centers for Disease Control and Prevention, and kills up to 10% of them. Earlier work led by former MSK graduate student Silvia Caballero, a co-author on the current study, showed that a mixture of four bacterial strains protect lab mice from VRE. These strains are normally found in the gastrointestinal tracts of healthy people.

The new study built on this earlier work by conducting a series of experiments to isolate one of these four bacterial strains: Blautia producta. “The next step was to determine the mechanism by which Blautia producta mediates protection against VRE,” Dr. Kim says. It turned out that a protein produced by Blautia producta is able to kill VRE even when the bacterial cells themselves aren’t present. Further study revealed that this protein is a lantibiotic, a type of antibiotic that is manufactured by microorganisms.

“If you think of Blautia producta as a member of the microbiota that helps maintain order within the gut, this lantibiotic is what it uses to do that,” says MSK infectious diseases expert Ying Taur, a co-author on the study. “This study really helps further our understanding of how all this works and provides important new insight.”

Evaluating the Effects of a Bacterial Product

The researchers did a number of additional studies. These included sequencing the gene that codes for the lantibiotic and performing RNA sequencing to determine when the gene is expressed.

They also tested the lantibiotic against about 150 strains of intestinal bacteria, to gain a sense of its spectrum of activity. This part of the research was significant because a major side effect of the antibiotics that doctors prescribe is that they can wipe out these healthy strains.

The team found that Blautia producta and the lantibiotic did not damage healthy strains. In fact, when they reviewed their library of samples collected from healthy donors, the researchers learned that about half of them already had Blautia producta and this lantibiotic product.

“It’s remarkable how precise this product is at targeting harmful microbes while sparing healthy ones,” Dr. Taur notes. “This is something we do not know how to do with any antibiotics that we have now. Our antibiotics are very clunky in comparison to the precision of what these bacteria do.”

Moving Forward with More Research

More work is needed before this approach can be tested in people with VRE infections. Drs. Kim and Taur say they haven’t even determined how a treatment would be best administered or whether they would use Blautia producta or the isolated lantibiotic. The treatment could possibly be given as a pill, or the findings from this study could be used to develop a more specialized type of fecal microbiota transplant. They plan to study various approaches in mouse models.

“Previously, studies have shown that Blautia is associated with better outcomes in people who have developed graft-versus-host disease (GVHD) after having a bone marrow transplant with donor cells,” says study co-author Marcel van den Brink, Head of MSK’s Division of Hematologic Malignancies. “In addition, we have recently found that Enterococcus is associated with increased incidence of GVHD. These findings offer exciting opportunities to control GVHD and improve outcomes for people having transplants.”

“There are a lot of things we still don’t know, but we have learned so much from this study,” Dr. Taur concludes. “It was really an amazing piece of detective work.”

Putting female mosquitoes on human diet drugs could reduce spread of disease

Source: Cell Press
Date: 02/07/2019
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Unlike humans, who usually get hungry again only a few hours after eating, a female mosquito that has fed on human blood will lose her appetite for several days. Because movement of female mosquitoes from human to human–male mosquitoes do not consume blood–is the means by which mosquito-borne infections are passed along, researchers have theorized that reducing the frequency with which female mosquitoes feed is one way to lessen the spread of disease.

In a study publishing February 7 in the journal Cell, researchers report that they have identified drugs that can reduce mosquito hunger for blood. These compounds act on the hormone pathways that signal to a female mosquito that she’s full.

“We’re starting to run out of ideas for ways to deal with insects that spread diseases, and this is a completely new way to think about insect control,” says senior author Leslie Vosshall, a Howard Hughes Medical Institute investigator and head of the Laboratory of Neurogenetics and Behavior at Rockefeller University. “Insecticides are failing because of resistance, we haven’t come up with a way to make better repellents, and we don’t yet have vaccines that work well enough against most mosquito-borne diseases to be useful.”

The new research used Aedes aegypti mosquitoes, which spread pathogenic viruses including yellow fever, dengue, Zika, and chikungunya. Female Ae. aegypti feed on human blood to nourish their growing eggs. Because a female Ae. aegypti mosquito has several broods over the course of her lifetime, she requires multiple meals. This cycling behavior results in a number of opportunities to pass an infectious virus from one human to another.

But after consuming a meal that doubles her body weight, the female mosquito loses the drive to eat again for at least four days. Vosshall’s lab hypothesized that certain neuropeptide hormones were responsible for a mosquito’s attraction to humans and that feeding turned these pathways off. “We know these pathways are important in hunger in humans. Because they are evolutionarily conserved, we made the decision to use human diet drugs to see if they would suppress the appetite of the mosquitoes,” she explains. “Finding that the pathways work the same way in the mosquitoes gave us the confidence to move ahead with this research.”

Her lab identified a receptor called neuropeptide Y-like receptor 7 (NPYLR7) as the one that signals to the female mosquito whether or not she’s hungry. They then performed high-throughput screening in tissue culture cells of more than 265,000 compounds to determine which ones would activate the NPYLR7 receptor.

Once they identified the best candidates, they tested 24 of them, in the mosquitoes and found that compound 18 worked best. The drug was capable of inhibiting biting and feeding behaviors when the mosquitoes were introduced to the scent of a human or a source of warm blood. “When they’re hungry, these mosquitoes are super motivated. They fly toward the scent of a human the same way that we might approach a chocolate cake,” Vosshall says. “But after they were given the drug, they lost interest.”

More work must be done before a compound can be developed for mosquito control. Researchers need to further understand the basic biology of the receptor and how it might best be exploited. In addition, future studies would need to focus on how to best get the drugs to the mosquitoes. One idea is a feeder that would attract the females to come and drink the drug rather than drinking blood.

Vosshall notes that if the techniques prove effective, they are likely to work with other kinds of mosquitoes, such as those that spread malaria, as well as other arthropods that feed on human blood, including the ticks that spread Lyme disease.

“Another benefit to this approach is that the effects of the drug are not permanent,” she concludes. “It reduces the appetite for a few days, which will also naturally reduce reproduction, but it doesn’t attempt to eradicate mosquitoes, an approach that could have many other unintended consequences.”


This research was supported an Advanced Grant from the Robertson Therapeutic Development Fund, the National Institutes of Health, a Rockefeller University Women & Science Fellowship, an APS Postdoctoral Fellowship in Biological Science from the American Philosophical Society, and the Howard Hughes Medical Institute.

Cell, Duvall et al: “Novel small molecule agonists of an Aedes aegypti neuropeptide Y receptor block mosquito biting behavior.” https://www.cell.com/cell/fulltext/S0092-8674(18)31587-3