UCSD Infectious Disease Specialist, Saima Aslam, MBBS, MS, Baylor College of Medicine Molecular Virologist, Anthony William Maresso, PhD, and Baylor College of Medicine researcher, Austen Terwilliger, PhD, talks about a new bacteria-eating virus that could potentially kill infections.
Interview conducted by Ivanhoe Broadcast News in 2022.
I thought what was interesting is when I was researching this I didn’t realize how many people are really affected by antibacterial resistance viruses.
ASLAM: Yes. So I mean, unfortunately, multi-drug resistant bacteria is a massive problem in the United States and worldwide actually and an important cause of people dying. And within just the COVID pandemic is where we saw a further increase in the rate of drug resistant organisms in particular causing pneumonias and other infections for people that were admitted to the hospital.
Why do you think that is?
ASLAM: I think one of the issues at least for the recent COVID pandemic issue was for patients that were in the hospital with severe COVID lung disease were in the hospital for days and months. When you’re in the ICU setting with multiple catheters going in and out and potentially being on ventilators, et cetera, it really does increase the risk of infections and over time drug resistant infections become more common. We also saw an increase in fungal infections in these patients as well. And some of that may be related to the therapies that we use for these very critically ill patients.
Does it have anything to do with people like Greg who have been on antibiotics for half of his life it seems just becomes harder?
ASLAM: Yes, for sure. So bacteria definitely are very smart and definitely have multiple ways of overcoming antibiotics that we use to kill them. And certainly for patients that are on antibiotics especially for prolonged period of time, they are more likely then to develop really drug resistant organisms that cause infections. And I think he’s personified that.
What is there for you to do to help him?
ASLAM: For patients like him and unfortunately it is a very common problem. Currently we have intravenous antibiotics and unfortunately the pipeline for new and better antibiotics isn’t that great either. But for him and he was on and he was on months and months of IV antibiotics. And that would take care of him being sick but it didn’t get rid of his organisms that lived in his gut or potentially lived within his prostate or for patients either kidney stones and things, the antibiotics don’t penetrate these tissues or stolons well and so that nidus of infection remains. And so resurfaces like in Greg every time he was off antibiotics. A few weeks later his infection would come back.
So was Greg the first person you turned to go into phage?
ASLAM: I’ve actually been treating patients with phage therapy on a compassionate use basis since 2017 here at UCSD for a variety of different indications, but generally in patients that have already gone through multiple causes of antibiotics and have come to the end of the road in terms of further treatment options. So we have treated a few patients before him also.
And I think what’s really nice, you hear a lot about this but I don’t know if you see it a lot in action but it’s incredibly personalized treatment. I mean, you can’t get more personalized.
ASLAM: Yes. So this is the age of precision medicine and for sure with phage therapy right now what we do is take the patient’s actual organisms and find phages that killed that patient’s bacteria. So that we know in vitro or in the lab before we use it that this phage or combination of phages will kill a patient’s bacteria and then we use it in that person. So yes, very precise and personalized therapy.
Is it the goal to get it FDA approved on an overall basis so every case doesn’t have to go and get- meet these requirements?
ASLAM: So there’s a lot of ongoing research at the moment. So this case again was a compassionate use case but I think what we need really are clinical trials in which we can test phage therapy for a variety of different indications against what is our current standard of care or against a placebo to really show that it works. And so we need that- those results then to actually go to the FDA and have it as an approved therapy that patients can use. We can do that again if you want.
Is the hope to get it to clinical trials?
ASLAM: Yeah, so that is the goal. And there are a couple of companies that are working on clinical trials for various indications. But right now I think we still have a while to go before this would be an FDA approved therapy for specific indication. But that’s the goal.
The patients that you treated with phage, have they all had the same results? They’re all basically cured?
ASLAM: So we’ve treated now about 19 patients with phage therapy at UCSD. A few patients died very early so we couldn’t tell if it was a success or not. But among the patients that completed phage and we had appropriate duration of follow-up to assess for success, our success rate is actually close to 80 percent in those patients.
How long have you been a doctor?
ASLAM: Let’s say more than two decades.
So let’s say in two decades have you ever worked with something that you can say 80 percent of the patients are now cured?
ASLAM: No. I think this is amazing, especially for these patients are all, like phage was not their first-line treatment option. This was their end of the road treatment option. And to have that success rate is really encouraging and that’s really what keeps us going and makes us want to do studies that actually show that it work. I do want to add, I mean, there are other cases as well in which phage hasn’t worked well. And I think as we’re doing some of these compassionate use cases we’re learning which indications perhaps are more suited to phage therapy and which perhaps are not. So patient selection I think is important as well as the kind of phage that we’re using and the indication. So I think there’s some combination, there’s different degrees or different pathways leading to a successful outcome for a patient with probably a role played by the patient’s indication, the bacteria, and the phage, so all combined.
In general, can you say these patients are better than these, like can you give me an idea?
ASLAM: Things that we’ve had really good success with so far and again, these are just a few cases are patients with drug resistant recurrent urinary tract infections. There have been some cases in particular at other centers in addition to one from ours of prosthetic joint infection treated with phage. There’s interest in using it for pneumonias, in particular with drug resistant organisms. One indication that I was really interested in and we’re still trying to figure out how to make it work better are left ventricular assist devices, it’s a heart pump that unfortunately can get infected with drug resistant organisms. And so we’ve treated several of those patients here. In one it was a great success but in two others it did not work out. So I think that they’re still in the area of learning trying to figure out how to make it work better.
Now, after this, is there a fear they’re returning again or?
ASLAM: I think it’s possible. It’s been six months and I feel like if that original organism was still there it should have come back because for him he would have recurrences every few weeks. Whenever we stopped antibiotics within a couple of weeks he’d be back on antibiotics. So now it’s been six months. So I think if he did get it again it probably would be a new infection rather than the previous one that then recurred.
Why is stronger bacteria forming? Did COVID contribute to that too?
MARESSO: No. I mean, there may have been some I think it’s going to take years to figure if the pandemic contributes to the problem. But this is something that’s been developing since the 1950s, which was the golden era of antibiotic making. Where all the major classes from that period to the ’80s of antibiotics that we use to treat patients were generated. Basically, the more you expose bacteria to these drugs, the more likely they’re evolving to evolve or adapt or change to get around them. And then those ones that survive, they start to populate the environment and that’s what infects people. So we don’t really have many new antibiotics being approved or developed every year by pharmaceutical companies. They’ve really gotten out of this industry and moved a lot of their efforts to like cancer or cardiovascular disease or diabetes. But this infectious disease problem remains and is getting worse since so you’ll get patients that don’t have any really antibiotic option to treat their bacterial infection. Some of these bacteria can chronically colonize that’s phrase we use, are live on us or in us. And they were perpetually cause a problem. It may not get so serious. Sometimes it’ll be debilitating. But eradication or the elimination of the infecting organism with current drugs is sometimes not attainable. So then what are the options for these? How do you help these people who both can be life-threatening or it can be chronically infected and living with these conditions. There’s really no other alternatives for them except what we’ve made here, what we’ve done here and that’s why I think this is in the newsworthy 2 and in Austin as well as because we’re specifically making a type of virus called a phage, which only infects bacteria against their bacterial string. And Austin is really pioneered the process for how to do that safely and effectively and then get it approved by the FDA. And then we shipped to the treating clinician and then they will use the personalized medicine that we made if you wanted to describe it like that against their infecting Bactrim for treatment. And that’s what Simon did in this case, that’s what Dr. Osman did. So we make it we do a lot of the science of it. And Dr. Osman and her group are the experts on the treatment.
Now, are these people, like Greg, is he considered cured now, after this two-week session?
MARESSO: I would ask that same question to Dr. Austen because the clinicians have various degrees of success that they will actually break it down into. It’s not uncommon to have complete eradication or complete elimination of accepting that term after treatment like this, I think in his case, he’s no longer symptomatic and no longer has detectable presence of bacteria. So that might be considered a complete cure, but I think only time will tell long-term if anything really truly has gone if something doesn’t come back.
What is phage?
TERWILLIGER: Phage is short for bacteriophage. These are the viruses that specifically infect and kill bacteria only. They are not going to infect human cells, and they have been doing this literally for billions of years. They are basically the earth’s first enemy of bacteria. It’s pretty much how nature keeps a check on bacterial world worldwide. These are found everywhere, all bodies of water. You can find them in the ground even, and they’re part of our microbiome as well. People understand more and more what the microbiome is now. They typically maybe think of it as just the bacteria on and inside of our bodies, but it includes viruses as well, and phage are going to follow their bacterial host. So these phage are on and inside the body all the time, so we’re used to seeing in dealing with phage.
How do you figure out like which phase to use for which problem?
TERWILLIGER: Yeah, phage can be very specific for the bacterial host that they infect and kill. Part of this process, and really one of the first steps is getting a clinical isolate from the clinical lab sent to us so that we can test all the phages that we have on hand, whether they’re capable of infecting and killing that patient’s strain. And if we determine that this phage or strong and good killers of that patient’s bacterial isolate, those viruses, the phage are then considered good candidates for treatment.
Your colleague said this is personalized medicine. This is about as personalized as it gets for these people.
TERWILLIGER: Yeah this is not a blanket treatment. You can’t take the same phage and treat every single person with the same type of infection. The phage must always be matched with the clinical isolate from the patient.
How many people do you think are living out there like Greg, when I talked to him. Have you met Greg?
TERWILLIGER: No, part of this process is to de-identify any information, so there’s a separation between the patient and until we get to a point like this where they’re fine with being recognized and noticed. That is a very important part of this process to maintain privacy of patients when needed. So no, I have not seen or metric yet.
How many people do you think are out there?
TERWILLIGER: This is the first time I’m hearing something like that and it is wonderful. It’s great, and really inspires me and people that work in the lab to see that we can have this effect on people’s lives. But getting to your question, this is a very common problem. There are 10,000 of people at any one point in time that are suffering from these types of infections. More specifically, chronic but stable, multi-drug resistant infection. These are people that are caught in cycles of infection. They will go to a hospital for treatment. They are given some antibiotic drugs. They have some level of clearance, maybe get better for several weeks to a few months, but then they get re-infected with that same strain or version of it and they’re back in the hospital, and the cycle just keeps on going. The more antibiotics that you give and treat to a patient, the more likely that that infection is going to become multi-drug resistant, that it’s not susceptible to the to the antibiotic drugs that we have. The doctors and the patients slowly but surely run out of options, and that is when they start looking for other options and they come to us possibly looking for phage therapy.
Is this therapy open?
TERWILLIGER: Yes, it is a very long and difficult process. I will say obviously, for some of the reasons we had previously mentioned that this is personalized medicine. So it takes a lot of time and care to identify the phages first. And we may also have to manufacturer the phages in that patient strain to which brings in a whole other bunch of regulatory questions that we could get into if you had wanted. But the main thing is there’s no standard pipeline for phage therapy in the United States right now. It’s all done through this mechanism called an IND or an investigational new drug. What that basically means is that each personalized phage cocktail is its own separate new drug. The FDA is going to look at, and they are going to consider each cocktail as- as a different drug, so there’s a long regulatory process involved in that. Just to get, to treatment. We would like to see, what the phage therapy field would probably like to see is that in the United States and the world over to move towards a more quality-by-design approach similar to what we do when making the flu vaccine each season. That each flu vaccine each year doesn’t have to go through Phase 2 trials prior to being approved for use because the process by which it’s made was approved. There’s nothing like that for phage therapy currently in the States. One of the few places that are working in this manner are Belgium.
How long was that process? Is it a year process?
TERWILLIGER: You would think that that is a simple question, but it’s not. So I’m going to try to summarize this as best as I can. There are several different routes to treatment that take a varying length of time. I’ll start with the shortest one. You have a patient in very dire need, meaning that if they don’t get treatment in a span of a few weeks to a month, there’s a very good chance that they are going to pass. We receive a clinical isolate from the lab. We have pre characterize and purify phage on stock that we test against that patient strain that we know are virulent against that patient strain. We say, great, let’s make a cocktail with these phages. We can ship them off to the patient. With that timeline, you can go from receiving the patient’s clinical isolate to sending that cocktail in two weeks. That is the shortest timeline. What is more likely to happen and what we tend to focus on are again, these chronic words stable cases. So these patients aren’t necessarily at risk of passing anytime soon. So we have some months that we can work with. It takes that amount of time to purify new and novel phages, to sequence those new and novel phages as well to ensure that there aren’t any factors in their genome that we wouldn’t want to give to the patient. So any bacterial virulence factors or toxins or antibiotic resistance genes and elements. If those are in the phage genome, you certainly don’t want to be treating the patient with that phage. So all of that process takes a decent bit of time. And more often than not, most of the cases we get it’s about six months to treatment, but it really can take anywhere from six months to a full year plus just depending on how any number of factors fall.
Do you have anything else you want to talk about?
TERWILLIGER: I think I would want to add, if I can put in a segment on the logic of hunting for phages and how we found these phages, which I think is a pretty cool story. So it is a really cool process how we hunt for and search for these phages. The logic is pretty straightforward. Wherever there’s some bacteria, you’re going to find a phage that infects that bacteria. And a lot of these infections, these cases we deal with are coming from what are known as gram-negative enteric bacteria. These are E coli, klebsiella, Pseudomonas, things of that nature, because they are enteric, meaning gut. They’re going to be in our stomachs and our intestines, and they are going to pass through into sewage. And so we hunt for these phage in waste water, in sewage from cities. You can very easily pull out phage from waste water. So one of the phages that was used in this cocktail was pulled from wastewater. The two other phages, HP3 and HP3.1, we looked for a different source of E. coli in birds. Birds are known to harbor a lot of these infectious E. coli strains. And so I was not a part of this, but a group prior went phage hunting, looking at duck and goose poop in Hermann Park, which is just right near Baylor College of Medicine, here and here in Houston. And so from the duck and goose poop, we found this HP3 phage that has worked really well for us and in this case was a virulent against the patient’s strain.
END OF INTERVIEW
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