Victor Nizet, Professor at UCSD in Pediatrics at the School of Pharmacy, talks about a drug that brings cholesterol levels to such a low point they prevent some heart diseases talks about two already approved drugs that may be able to save the lives of some sepsis patients.
Interview conducted by Ivanhoe Broadcast News in February 2022.
What is sepsis?
NIZET: Well, sepsis is one of the most dangerous syndromes known in medicine. It is an uncontrolled inflammatory response to a severe bacterial infection that is spreading through your body. Some estimates suggest that up to 20 percent of human mortality might be attributable to sepsis. Certain vulnerable groups are particularly affected, such as those at the extremes of age, the very young and the very old, or patients who have underlying medical problems like cancer or diabetes or those that have been hospitalized for surgery or other complex procedures. Sepsis can be a complication that they develop during their complex medical care. Sepsis also has a devastating toll in the developing world, where poverty and lack of access to medical care are widespread.
You’ve covered a little bit of it, but what causes that injury?
NIZET: So, sepsis occurs when you have a bacterial infection that could start in different places in your body, perhaps as a pneumonia in your lungs, a urinary tract infection, or the infection of a wound on your skin. Then the bacteria spread deeper, ultimately entering the bloodstream. This can be accompanied by a very strong and sometimes overwhelming response of your immune system, where the uncontrolled inflammation from the response is causing a lot of harm to the body and its functions. Truly, every organ system in the body can be adversely affected by sepsis. You can have difficulty breathing and exchanging oxygen across your lungs. Your heart can fail. Your kidneys can lose the ability to filter the toxins in your body, and you can stop urinating, and your liver can be dysfunctional, which can lead to a risk of bleeding.
You’ve covered a little bit of this, but let’s just sort of hit the nail on the head. What are the signs and symptoms?
NIZET: Well, initially, at the earliest stages, sepsis has symptoms like any other severe infection. You might have fever, extreme fatigue. You can have mental confusion, pain in different parts of your body and then symptoms related to wherever the initiating infection occurred. For example, cough with pneumonia, pain urinating if it’s a urinary tract infection, and so on. I guess concern should be raised whenever you have an infection that normally would begin to resolve, and you don’t see it resolving but getting more and more severe. Septic patients may have nausea and really, really feel unwell to the point that it frightens them, and that’s, of course, when we’re very, very concerned as physicians, because it can progress so quickly.
Can it be fatal?
NIZET: Yes. Unfortunately, sepsis has very high mortality. Even in the face of antibiotic treatment and ICU care, mortality rates in severe sepsis are 30 percent or higher in patients that have underlying medical problems like the very elderly or those with immunocompromised systems, and unfortunately, there is no current approved treatment that is specific for sepsis. Essentially, what we’re in the hospital doing is trying to treat the infection with antibiotics and support the function different organs. Sepsis patients are typically admitted to the intensive care unit where they can be monitored very closely, and they receive medicines to support their blood pressure, which may drop low, to support their cardiac function. In severe cases, they may have blood factors and plasma replenished in their body. They can go on dialysis for their kidney failure, and they can go on mechanical ventilation for the lung failure.
Go ahead into so tell me about your study.
NIZET: So, we were studying patients who have one of the most common causes of sepsis, which is a bloodstream infection with the bacteria Staphylococcus aureus, or “staph”. Staph is one of the most important human pathogens, and it’s often resistant to antibiotics, which makes it more difficult to treat. You may have heard of MRSA which stands for methicillin-resistant Staphylococcus aureus, which is even harder to treat because it forces us to use second line antibiotics. The mortality rate for staph bloodstream infections and sepsis remains about 20 percent, even with all the advances we’ve had in antibiotics and ICU care. So, we’re very interested in understanding it better and in developing new treatments that may be able to work alongside antibiotics and together with all the ICU support help led to better outcomes in staph sepsis. We looked in the blood of patients at the very earliest point in infection, right when they were admitted to the hospital, the same blood culture in which the staph bacteria were originally identified, studying their white blood cell counts and other characteristics. We found a surprising finding that in patients who ultimately had the worst outcome, those that died, that their blood platelet count was very low. This correlated more strongly to the outcome of the infection than any changes in their white blood cell count. Platelets are very important cells in our body that have a central role in blood clotting. Doctors and scientists have been studying platelet biology for many decades, and there are a lot of drugs that we give to patients to control their platelet activity. For example, if you’ve had a heart attack or a stroke, abnormal blood clotting is a key feature of these dangerous conditions. We recommend drugs that affect platelet biology to make the risk of clotting and stroke or heart attack recurrence lower—these might include a baby aspirin or many other more sophisticated drugs.
Given that the platelets were lowered in the patients with sepsis, we wondered if platelets had a special role in immunity against the bacteria. So, we took normal volunteers and isolated blood and separated the different cells in the blood. We found to our surprise that platelets in the blood were able to kill staph better than the white blood cells. So that was a very interesting observation, and that was the initiation of our study.
Wow. That is fascinating. This was all done here?
NIZET: Right. All done here at UC San Diego with some collaborators also at the University of Wisconsin and Scripps Research Institute.
Explain the battle between bacteria and platelets.
NIZET: So, it’s interesting. When you get an infection with staph bacteria your platelet count, the number of platelets circulating in your blood, tends to go down. We were able to show that in animals as well. If we infected mice with staph bacteria, their platelet count went down. We also found that it was a particular toxin that is made by the bacteria called the alpha toxin that was responsible for damaging the platelets and causing their levels to go down. So, it seems like there’s a battle going on in your blood. The staph is trying to eliminate the platelets with this toxin while your platelets are trying to eliminate the staph. The platelets make various anti-microbial molecules, sort of natural antibiotics, that help kill the staph. So, most of the time when a few staph bacteria enter our blood, the platelet counts are stable, and we can control the infection with the assistance of the platelets. In a few unlucky patients, and these are the ones that had the terrible outcomes in sepsis, their platelet count collapsed. At that point, they’ve lost one of their key defenses against staph, and they’re very, very susceptible to overwhelming infection and sepsis.
I’m just learning this for the first time, so it’s fascinating for me. So traditionally, how is this treated?
NIZET: So normally in treating sepsis, we use antibiotics to try to eliminate the bacteria, as well as the ICU support of the different organ systems, which is really buying time for the antibiotics to work. However, we don’t really have any drugs that are successful at controlling the abnormal inflammation that occurs in sepsis. By learning the specific tricks that bacteria use to gain advantage in the body, we might have new opportunities for therapy. So, in this case, we discovered a key role that platelets were a super important cell for protecting you against staph, which made us wonder—what if we looked at different medicines that affect platelet biology, such as drugs that are used in patients who recently had a heart attack or a stroke to reduce the risk of blood clotting? Well, we found that one common platelet medicine, they’re known as P2Y12 inhibitors, an example being Ticagrelor or Brilinta, its trade name, that is taken safely by millions of individuals, affected platelet biology in a way that benefited its interaction with staph. The Ticagrelor protected the platelets from the damaging effects of the staph toxin and also helped the platelets kill the bacteria. When we gave mice the doses of Ticagrelor that you would normally give in a human adjusted for the tiny weight of a mouse, we found that it protected them against lethal staph infection even in the absence of antibiotics. We also learned that another medicine, which is used to treat influenza, it’s called Oseltamivir, trade name Tamiflu – had an effect to alter the surface of the platelet in a way that the platelet lifespan in the blood was increased. And that helped the animals be more protected against staph infection. So, understanding this new role of platelets in defending against staph gave us the opportunity to repurpose or find a new use for two drugs that are already approved by the FDA that are already used in clinical medicine that doctors are familiar with to potentially improve patient outcomes in sepsis, one of the most dangerous and lethal medical conditions.
This concept of therapeutic drug repurposing is very appealing because it takes years and years and millions and millions of dollars, if not more than a billion dollars, to bring an entirely new drug from discovery in the lab, through the human clinical trials, to distribution and marketing, so it’s widely available for patients. By probing that pathogenesis of these diseases, understanding new aspects of the biology allows us the opportunity to maybe repurpose some of our existing medicines, which could help patients right away since clinical trials can now be envisioned in which you just take patients who are experiencing the disease, in this case sepsis, allow them to have the current best standard of care, or that same best standard of care plus the new repurposed drug, and see if there is an added benefit of the treatment. We hope our research can inspire some of these clinical trials. We’ve already seen in some individual cases in patients, including one that we recently published, that giving the antiplatelet drug Ticagrelor allowed the patient’s staph bacteremia to clear very rapidly and help in the cure of his bloodstream infection.
I’m sure there’s a lot of professionals that are glad it’s an option outside of further antibiotics.
NIZET: Right. Despite the medical importance of sepsis and hundreds of clinical trials and the attention of research groups all around the world, you’re going to be very surprised to learn that there is no single approved drug specific for sepsis, and part of it is it’s just so complex. There are dozens of different bacteria that can cause sepsis. Every patient is unique in the predisposing medical conditions that put them at risk for sepsis. There are literally dozens, if not hundreds, of molecules that are being made by your immune system that cause the hyper inflammation. So, going in and targeting just one molecule or antibiotics alone is often not enough to reverse the entire situation. So, we need to go in and understand the complex physiology and come up with new ideas, new insights. And in this case, we’re doing what is known as reverse translational research. Often you hear about bench to bedside research. The scientists in the lab discover something exciting in a test tube. They move to the mouse experiments and ultimately to the clinical trials over a period of several years. Here we have an opposite idea. We’re studying the patients, looking for little signals that give us a clue about what’s going on. Then we bring that back to the laboratory. So, bedside to bench, to test to see if the clinical association reveals a new mechanism. Then we flesh it out through experiments that establish a proof of concept for a new drug idea. That could be something that requires discovery and development of an entirely new drug. In this particular case, it offered an opportunity for the drug repurposing. So the bottom line of our study was two different drugs already approved by the FDA, one that is used to improve platelet function in patients who are prone to clotting, such as those that had heart attacks or strokes, and another that is used to treat patients with severe influenza to shorten the duration of that infection actually have a benefit in the case of staph bloodstream infection to prevent staph injury to platelets, to prolong the lifespan and raise the platelet counts in the blood during staph infection, allowing the platelets to kill the staph, the surprising new property of platelets that was observed in this study. These drugs might therefore be what is known as an adjunctive or supplemental therapy to our current management of sepsis. Hopefully, these discoveries can improve patient outcomes. In this case, the findings might be specific for staph infection and other bacteria that are sensitive to platelets, but similar research that is ongoing at UCSD is looking at different organisms that cause sepsis. What is their unique signature? Are there any interesting aspects of biology that they change in our body in which we could support the patient, support the healthy function of their cells so that they are more effective in combating sepsis?
Right now, we have kind of a one-sided approach to treating severe infections – chemicals that kill the bacteria. Antibiotics is the name you know them by. And most of these were discovered in the laboratory for their ability to kill bacteria. Antibiotics are one of the most important drug classes in medicine, of course. They’ve saved countless lives over the years. They do have some costs. You select for resistance among the bacteria, and antibiotic resistance is an ever-increasing problem. Also, they do some damage to our microbiome. Our microbiome, the healthy bacteria in our body, are very important for our metabolism. They help make vitamins in our body. They instruct our immune system. So over prescription of antibiotics would be a major problem. So, looking for new ideas in which we try to assist in the clearance of infection by boosting the immune system I think is a very important future idea for medicine. We have a lot of drugs in medicine who act to reduce the activity of the immune system, anti-inflammatory medicines. You might take them for asthma or arthritis or multiple sclerosis, but remember, there are a bunch of molecular brakes and accelerators that are controlling immune system activity, and those very same pathways could be pushed in the other way to increase immune cell activity. If even for a very short period when the patient is at the most critical stage of the infection, maybe we could support immunity and combine that with antibiotics to achieve better results. In this research, we did it by supporting the platelets, which are so important for staph. I think you should reflect on cancer chemotherapy. There has been a revolution in the last 20 years or so of increasing immune treatments for cancer with dramatically improved outcomes in a lot of cancers such as melanoma and certain types of leukemia. Patients who have the therapy that boost the immune system can clear the cancer cells. I think we could achieve that for a few bacterial infections, and that would be an advantage to future generations.
END OF INTERVIEW
This information is intended for additional research purposes only. It is not to be used as a prescription or advice from Ivanhoe Broadcast News, Inc. or any medical professional interviewed. Ivanhoe Broadcast News, Inc. assumes no responsibility for the depth or accuracy of physician statements. Procedures or medicines apply to different people and medical factors; always consult your physician on medical matters.
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