Can you give a brief overview of the pathogenesis of Nontuberculous Mycobacteria (NTM) lung infections?
The first thing that is important to stress is that this is an area that we actually know very little about. What we generally think, rather than know, is that NTM has a lot in common with pulmonary tuberculosis. The bacteria mostly enter the airways by inhalation.
The bacteria come from environmental sources and are widely present in our environment. They are very hydrophobic, which means they don't like to stay in wet environments; they prefer to be aerosolized and then are blown into the air. We inhale them and they end up in our airways, where normally they would be thrown out again by what are called our cilia, the small hairy tentacles inside our airways that help us to clear sputum and lung slime, along with these bacteria.
In some people, this process is apparently insufficient to clear these organisms. Then, if the mycobacteria survive and actually reach the lower airways, they are engulfed by macrophages which are part of our innate immune system. The mycobacteria are supposed to be taken hostage and killed by these macrophages. The fact that this disease exists is a showcase of the fact that this killing apparently does not always succeed.
This disease can only exist because there are insufficiencies in either the killing of these microorganisms by macrophages or an insufficient ejection of these microorganisms by the cilia, the small hairs inside the airways.
We know this because the few patients in whom we have found actual immune defects all have diseases that interfere with those two mechanisms: the killing by macrophages or clearance by a normal lung structure or architecture. When the lung architecture is destroyed by COPD, or emphysema, for example, or in the case of bronchiectasis, then these bacteria stand a chance of surviving the normal transport back to the outside world by cilia.
In what ways is NTM lung infection different to TB?
The biggest difference with these infections is that they tend to affect a completely different group of people. Pulmonary tuberculosis can really affect anyone and all humans are susceptible in various degrees to tuberculosis. The NTM lung infections, on the other hand, affect very specific groups of people, which may include people with underlying lung disease such as people with COPD, cystic fibrosis or bronchiectasis.
There's also a group of patients that get NTM pulmonary disease without any of those apparent risk factors. We think that in those patients, there are subtle deficiencies of their innate immune system which could, again, be either in the cilia transport, which is something that many groups are currently investigating, or in macrophage function.
We now know from genetic research that many patients who have this so-called nodular bronchiectatic disease, which is sometimes called Lady Windermere syndrome actually have subtle deficiencies in the structures that normally eject these mycobacteria and make sure that we don't get infected.
How much is known about the localization of mycobacteria during NTM infection?
Actually very little. It’s not that easy to investigate where they are because you would need to look into lung tissues, which you would only be able to do, for example, when you operate on patients, which is not very commonly done, or you would need autopsy specimens, which, of course, are also very rare. We actually know very little about the exact localization.
The other problem is that NTM pulmonary disease comes in two very distinct types or manifestations. One used to be called the Lady Windermere syndrome, which is the nodular bronchiectatic NTM pulmonary disease. There is some data on where the mycobacteria are localized in that disease.
Then there is the group of patients who have pre-existing pulmonary diseases such as COPD who get a fibrocavitary NTM pulmonary disease. That resembles pulmonary tuberculosis, with big holes in the lung and a lot of pus. For those patients, we actually know even less about exactly where the mycobacteria are because very few pathology studies have been done in that group.
From the patients with bronchiectatic disease, we know that if you look in those bronchiectatic bronchi or in those dilated airways, you find a lot of these mycobacteria basically just hanging around and not clearly engulfed by macrophages. A lot of them just lay loose in those bronchiectatic airways where there are deficient cilia beatings or they cannot be taken out and coughed up to prevent infection.
We know that there's a lot of them in those airways, but those patients also have small lesions inside the lung tissues, which is the nodular part. They are small nodes that are button-like lesions in the lung. That's also where the mycobacteria are located and, in there, they are more often engulfed in macrophages.
What are the main challenges in getting IV drugs to bugs in NTM lung infections?
The challenges are two-fold. The first challenge is literally getting IV drugs to reach the bacteria. For some of the IV drugs in frequent use, we know that they have difficulty entering macrophages. The bacteria are engulfed by macrophages which we hope would kill them, but we know that they often persist and are inside those cells of our immune system. A lot of the IV drugs that we use have a lot of difficulty entering those cells.
The other bacteria are, as I said, often inside the airways. We also know that for some of the IV drugs, it's hard for them to actually get to that level and get into the fluid that lines our airways, where the mycobacteria also accumulate. There is a physical and chemical difficulty in terms of those drugs reaching the bacteria where they are in the lung.
The other challenge is that a lot of these drugs, even if they are able to kill mycobacteria, take a long time to do so. Even if the drug is quite good at reaching the mycobacteria, they have to stick around there for a long time. That means patients have to be on those drugs for a long time, which causes a lot of practical problems.
Being on an IV drug for a long time is an absolute nightmare and it really disrupts normal life. In addition, of course, there’s a big toxicity problem. If you are on these drugs for one or two days, there are not usually a lot of side effect issues, but you can imagine if you're on these drugs for four, five, six months… then you'll run into a lot of side effect problems, some of which are really severe.
The challenge is to get there physically or chemically: to have the drug reach the site where the bug is and then stay around there long enough to kill all of the bacteria. It means you have to give the drug for a long time and there are a lot of problems with side effects.
How can these barriers be overcome?
There are a couple of strategies that could be applied. One obvious strategy is not using the IV drugs, but if you know the bacteria are in the lung, trying to get something into the lung. That's why various groups are showing a lot of interest at the moment in looking at drugs that could be given by inhalation, which could overcome chemical and physical barriers.
Other strategies are also currently being researched. One of them is the addition of other drugs, not necessarily antibiotics, but other drugs which can function like a Trojan Horse, for example, to help the antibiotic actually reach the lung or help it enter the macrophage.
The other possibility is optimizing drug dosing. A lot of these IV drugs and, in fact, for all of the drugs, we use doses that we have extrapolated from treating other diseases, not necessarily by mycobacteria and not necessarily in the lung. The other way to look at this would be to examine the effects of a higher dose or a change in the way the drug is dosed.
For example, giving it two times a day instead of once or increasing the dose could be very helpful in terms of bringing more relevant concentrations into the sites where the infection takes place, so in the airways, the macrophages, and in the lung tissues. Various groups are working on this to see whether we are giving the right drugs and whether we are giving them at the right doses.
Could altering the dose impact side effects?
Yes. That's always the very nasty trade-off. It's logical for antibiotics to become more effective if you increase the dose, but it's also logical for many of those drugs to have more side effects when you increase the dose.
Some side effects are not what we call dose-dependent; they are what we call idiosyncratic. They either happen or don't happen, irrespective of the dose or frequency you use, but yes, obviously, a lot of side effects are dose-dependent.
If we say a higher dose would be better, it would also mean there's a bigger chance of very severe side effects. You might end up using, for example, a higher dose for a shorter duration of time.
What additional hurdles do oral drugs present over IV drugs?
There's the obvious physical and chemical issue that a drug has to pass across our bowel. It has to be taken up from the gut and enter the bloodstream and then, of course, we have livers and kidneys ready to say, "Okay. Wow, this is something toxic. This is something we need to get out of the bloodstream and convert into something that is less toxic and that we can get rid of, either by putting it in the urine so it can leave the body through that route or bringing it into feces so it can leave the body by that route."
A lot of the drug that you give by the oral route does not even enter the bloodstream, so it cannot be transported to the site of infection because it just stays in the gut and is not actively taken up.
Another part is then converted, either by the liver or kidneys, and excreted, so it can never reach the site of infection. You lose a lot of the drug by natural defence mechanisms. Therefore, it's harder for drugs to make it all the way from the gut to the site of infection.
That, again, needs to be overcome by looking at dosing and sometimes even checking how much of the drug has actually reached the bloodstream, which we do for some drugs to make sure that patients are exposed to adequate concentrations.
There is a lot more uncertainty about how much actually is going to be effective for a patient and a lot more variability, because not all people taking these drugs are alike and there's a lot of variability in how much of these antibiotics is taken up from the gut. There's also variability in how much of it is quickly detoxified and excreted. It's less predictable what the actual exposures will be.
What advantages could inhaled-drugs for NTM infections offer?
I think there are two important advantages. One we are looking at is effectiveness. You can probably give some drugs by inhalation and reach very high concentrations inside the airways and lung tissues, so the bacteria will be exposed to higher concentrations of the drug. For many drugs, that would make it more likely they would kill these bacteria and probably be more effective.
The other advantage would be that, if well designed and applied to the right drugs, the drug probably will stay in the airway and diffuse into the lung tissue but it will not, to a large extent, reach the bloodstream, meaning there's no what we call systemic exposure. The drug is in the lungs and in the airways, but it doesn't reach other organs, so there's no chance for it to do any damage.
Therefore, the side effects will probably be less severe although, of course, giving a drug by inhalation means that there's high exposure of the airways to the drug, which could lead to specific side effects. The drug might hurt the airways and lead to its own side effect there locally, but systemic side effects and the damage done to other organs is likely to be very limited if you can use antibiotics by inhalation.
How difficult is it to get the concentrations right?
Well, that depends. As a microbiologist, I look at this from the bacterial perspective and getting the concentration right means how to make sure that you get enough antibiotic to the bacteria to effectively kill them.
That is difficult because for many antibiotics, we just don't know how much of them you need to actually kill the bacteria. That's the core business of my research group and what we do. We define how much antibiotic is really needed to kill these organisms. From that perspective, it's difficult to get the concentrations right.
If you look at it from a more pharmacological perspective, and ask how to use pharmacokinetics to get the right drug concentration in this patient, of course, the lungs and the airways are not that variable between different people.
You know that if you have a person of a certain size and you give them a certain amount of antibiotic by inhalation, you can assess how much antibiotic will hit each, say, square centimeter of airway. In that sense, it might be easier to get the concentration right.
The other thing that drug producers need to work out is where the drug lands, which is done by design of the drug or its carrier. You need to make sure that it does not just end up in your mouth after inhalation, but actually goes into the deepest airways and really hits the lung rather than just the mouth or throat.
In that sense, it's also difficult to get the concentrations right. That is something that I think can be overcome by design of the drug and the carrier.
What do you think the future holds for therapies for NTM lung infections?
These are interesting times for NTM. There are a couple of companies looking into repurposing existing drugs for NTM lung infections. Many of those have taken on the route of inhaled antibiotic use. I think there's going to be a lot of development in that area, with people looking at inhaled therapies for these infections using repurposed existing drugs.
What I am a little more worried about is that this pertains to a small number of antibiotics. We still need new drugs, especially oral drugs because they are easy for patients to use and can be effective.
We now treat these infections with a lot of drugs of, I would say, dubious efficacy, and we really need new oral as well as inhaled drugs to seriously treat these infections. Looking at oral drugs coming out specifically for NTM lung infections, I think there's very little movement.
There are some agents currently under evaluation, including in my own lab, but I fear that we're still far away from the magical cure of these infections. Even though there are a couple of very interesting options now becoming available and entering clinical studies, we need a lot more.
I really hope that more people will follow the example of the few companies that are now actively looking into NTM lung infections as an interesting disease to work on and to design therapies for. I really hope that will bring us some more new antibiotics. I would prefer new ones over repurposing old ones, to really combat this disease. I think that is something where there's still a lot more attention needed.
What are your future research plans?
The core business of my research group is looking at pharmacodynamics and how we can best dose a drug so we can get the maximum effect, minimal toxicity and therefore minimal side effects. What we try to do is optimize the dosing of drugs that we are currently using and to optimize combinations, because we know that some combinations of antibiotics are synergistic. They are helpful to each other, so their combined effect is larger than simply the combination of their individual effects.
Some of them can work as Trojan Horses for the others. So, we are building smarter combination regimens and, at the same time, try to introduce new drugs that are in current development.
We are trying to persuade pharmaceutical companies to assess the efficacy of these drugs against NTM which is not, as you can imagine, within the standard set of things that pharmaceutical companies do when they have a potential new antibiotic.
They don't typically look at NTM, so that's something that we try to persuade them to do, as well as having us look at what would be the best dose for NTM and what could be a smart combination. We are building new regimens of the smartest combinations of antibiotics in the best possible dose to be most effective and least toxic to patients.
The other side is that we're also looking at the bacteria to see how they respond to antibiotics because this is something that we know very little about. What is the first line defence of the bacteria against exposure to these antibiotics?
We strongly feel that if we can perhaps add a drug to the regimen that can distort this defence mechanism, that we can probably be much more effective, without having to increase doses of antibiotics and generate more side effects. That's something that we are currently studying intensively.
Where can readers find more information?
One thing that I really like is that if readers want more information on the various issues of NTM pulmonary disease, ranging from the immunology through to which drugs are used, what the toxicities are and what the disease looks like, there's actually a great series of lectures available on YouTube called the Bucksbaum lecture.
It's a series of lectures for patients and their relatives, with all the world's experts on NTM disease really covering all aspects of the disease such as where patients get it from, how they respond to it immunologically, what the best treatment is and why, what the different forms of the disease are and which types of patients they affect. It’s a really interesting series of lectures.
About Dr Jakko van Ingen
Jakko van Ingen, MD, PhD, is a Consultant Clinical Microbiologist and head of mycobacteriology at the Radboud University Medical Center in Nijmegen, the Netherlands.
After Medical School at Radboud University in Nijmegen, he combined work as an MD in the department of Pulmonary Diseases and mycobacterial disease reference clinic with research.
For his research on NTM, he was awarded a PhD with honors from Radboud University, a rare award in the Netherlands.
After a brief post-doc period at with Professors Charles Daley, Michael Iseman and Leonid Heifets at National Jewish Health in Denver, Colorado, he returned to the Netherlands to specialize in clinical microbiology at Radboud University Medical Center.
After this 5 year training, he was appointed head of the mycobacteriology department, which became the national NTM reference lab under his leadership.
Jakko van Ingen has published >120 articles in peer reviewed scientific journals and 10 book chapters on NTM disease and has won several (inter)national awards for this work.