00:00 – Professor Malone-Lee: People get better and then they get a flare and it’s extremely distressing, but in fact
00:07 – it’s an expected oscillation.
00:22 – Melissa: For people that are on this long-term treatment, is their progress linear or is it does it tend
00:28 – to be all over the place symptoms wise?
00:32 – Professor Malone-Lee: Originally, I used to think it was all over the place but what we strive to do is to achieve something called
00:41 – damped oscillation. Now damped oscillation means that your symptoms and your disease
00:48 – oscillate but if it’s damped, each peak is less than the last one.
00:56 – And that’s a crucial thing. And nowadays we will produce a damped oscillation
01:03 – in the symptoms and in the urine microscopy and if we can’t see a damped oscillation then
01:12 – we’ll tell the doctor this isn’t going right, we’ve got to alter this.
01:17 – If we do see a damped oscillation we’ll then be able to say to the patient, stick at this by
01:22 – dogged persistence, this is what you want. Now it’s incredibly important to understand that, because
01:28 – people get better and then they get a flare and it’s extremely distressing
01:33 – because they think, oh my god I’m going to get back to all that again and so on and so forth.
01:37 – In fact, it’s an expected oscillation and we understand a lot about damped oscillations. In
01:46 – fact, we can produce chemical reactions that will do damped oscillations in the test tube for us.
01:52 – And it’s an expected phenomena of biology because this is an expected phenomena of chemistry.
02:00 – Where I’m not happy is when it’s not damping, when it’s all over the place. If someone’s all over the place then we’re not doing anything sensible.
02:09 – Melissa: Is it that point where you would change the protocol?
02:12 – Professor Malone-Lee: Yeah definitely.
02:13 – Melissa: And what does that usually mean? More, or just a different antibiotic?
02:17 – Professor Malone-Lee: Well sometimes it means increasing the dose. The way we’ll go is, we try and stick to your original prescription. The principle is try and remain
02:28 – loyal to that. So you’ll try and get past it by altering the dose and getting
02:34 – the dose up. And if that doesn’t deal with it then you’ll change. Now there’s no way of knowing
02:42 – what antibiotic you should be using because there’s no way of knowing what bug is causing this.
02:47 – So we run a protocol that you go from this one, then you go to B, then you go to C.
02:54 – Now in some individuals they notice an effect but it’s incomplete.
03:01 – So we mark that and then we run through the sequence and we may find that we can detect
03:10 – a partial effect in another one and we put them together. Now that classically
03:16 – happens, we do that an awful lot with the beta-lactams. So the beta-lactam will be kephalexin
03:23 – and a penicillin. So there are a portion of our patients who are on a penicillin and a
03:29 – beta-lactam for no other reason than that it gets the dose high enough to have an effect. And
03:35 – similarly, in some patients who’ve got a certain subgroup of infection where they’ll end up on a
03:42 – tetracycline and a macrolide. And once again, that is just to get the dose up sufficiently to have
03:48 – that impact. And why the dose? Well it comes back to the thing – these infections are deep down inside
03:54 – the tissues inside the cells and they’re protected. You just need a concentration to get there.
04:01 – Melissa: Are there patients that present in the first instance in a way that means that you just attack
04:06 – it with a different approach, like with a different type of antibiotic than you normally would?
04:12 – Melissa: Much less nowadays. The reason being, is that we found that our judgments on, we
04:23 – thought we were smart asses and could judge what was the best treatment and we discovered we were
04:30 – so incompetent at that. So nowadays we stick to a rigid protocol. And in fact, oddly enough this
04:39 – morning I got a message from one of the doctors doing the clinic saying, could you look over these
04:43 – notes because I haven’t stuck to the protocol. And the reason was that the patient came in
04:50 – and described a really good effect for one of our first line agents so the doctor went for that one
04:57 – instead of our normal first one and I thought that was a perfect reasonable decision. But one
05:02 – of the things we’ve had to learn is to, and when you’ve been brought up on urine cultures that you
05:09 – know and it’s ingrained into you, they’re telling you what the bug is and they’re telling you what
05:13 – antibiotic you should use, it’s extraordinarily difficult to shake off that conviction. So we
05:21 – do an enormous amount of training in the fact that you, perhaps none of your, you can’t judge
05:28 – what is the right antibiotic to do. You’ve got to do it through a protocol. That’s the way you get there.
05:33 – Melissa: I know with the diagnostic side of things you don’t look for a
05:38 – causative pathogen but in the research that you’re doing do you find that certain organisms seem to
05:43 – be mapped to certain sets of symptoms in patients?
05:47 – Professor Malone-Lee: This is a quite a common question that we’re doing, we are about to embark on a very difficult
05:58 – experiment to crack the problem of causation. Now I happen to know that it’s going to be difficult because of other
06:04 – similar experiments we’ve done are really tough and you’ve got to be extraordinarily
06:08 – disciplined. And you’ve got to work with a large number of patients over a long period of time.
06:14 – And at the end of it we’re hoping that we will get some kind of indication of what’s causing what.
06:22 – To date we have not, we absolutely have not been able to link certain symptom clusters
06:29 – with certain microbes. Some patients, I once had a very entertaining patient,
06:37 – used to describe her different symptoms in terms of naming them after a microbe of some kind.
06:44 – She was absolutely convinced. Anyway it’s fine, that’s what she wanted. Now I’ll give
06:49 – you something. We are extremely suspicious that a certain cluster of patients suffer from what
06:58 – are called obligate intracellular microbial infections. So that is mycoplasma, ureaplasma,
07:06 – legionella molecules and what’s the famous one in that, chlamydia. But we’re only
07:17 – suspicious of that because of their propensity to respond to a certain antibiotic class, namely
07:25 – tetracyclines and macrolides. We haven’t caught the bugs inflagrante yet and we haven’t fingered
07:30 – them. What we can say is so we have exonerated chlamydia, but I often get approached by people
07:37 – saying I have a ureaplasma and really my response is well I should hope so. We can find ureaplasma
07:43 – as often in normal controls as in patients. So it’s a perfectly normal bug to find.
07:50 – Melissa: In certain cases could it be causing an issue for people though? Theoretically?
07:55 – Professor Malone-Lee: Theoretically yes. But I don’t think, I think people have got to be honest and not know.
08:01 – I mean if you look at, there’s a venn diagram once in the book that illustrates the fact that
08:08 – if you take these species isolated in the bladder and compare them with patients with
08:16 – these symptoms who have not been on an antibiotic, patients who have been on an antibiotic,
08:22 – and normal controls, there’s a 90 to 95 percent overlap. And you know if you’re seeing…
08:30 – We isolate ureaplasma using genetic methods as often in the normal controls as in the patients.
08:37 – So one of the things I will say, I think that the urine infections
08:42 – are probably being caused by bugs that were, you know, are present in the normal microbiome.
08:49 – But we’re going to have to pin it down and in fact you see the trouble is, you
08:53 – get a species like E. coli, but there are all sorts of subspecies in there and the 16s
09:03 – ribosomal genomics that people are using do not do not achieve the the degree of subspecies
09:10 – analysis that’s necessary to pin it down. But to say what’s causing it, it’s going to go…
09:20 – Not only is the clinical method difficult, but in fact the laboratory microscopy
09:25 – and the basic laboratory methods that are fiendishly difficult to pull off.
09:33 – Melissa: How close are you to doing that research?
09:39 – Professor Malone-Lee: We’re getting going and Harry, who’s head of our basic science program, he’s hammered out the
09:47 – basic science methods. But it’s incredible. It’s like sort of cracking the enigma code but we’ve done well.
09:52 – We got it and we’ve got good equipment and we’re about to launch off with a cohort of patients
09:58 – that we will follow longitudinally through. And fortunately we’ve built up such large numbers coming
10:03 – through the clinical service nowadays that we will be able to populate that quite successfully.
10:09 – Melissa: What’s the timeframe for that study?
10:12 – Professor Malone-Lee: I’m not really sure. I think that we will be reviewing results every couple of years.
10:18 – Melissa: I want to ask a couple of practical questions about your approach.
10:21 – Do you use the same treatment protocol for male and female patients?
10:25 – Professor Malone-Lee: We start them off the same. All of that was because I was being a smart ass with the men and
10:35 – I thought okay, we’ll start them off on the standard chronic prostatitis program. And
10:41 – to my embarrassment, we then discovered… In fact I was dealing with a man this morning who has responded
10:48 – superbly to our ordinary regimen for the women. So once again I learned from that. The cluster
10:56 – analysis, when we look at our data in aggregate and do these Bayesian cluster analyses we can
11:02 – see the men grouping. Some of the men grouping and tending to group around the tetracyclines and
11:08 – macrolides which is no surprise. That’s the way we approach the treatment of chronic prostatitis. But
11:15 – one of the things that fascinates me in this is that when we got our men on treatment they
11:20 – tend not to get Acute epididymo-orchitis and they’re on a tetracycline and/or a macrolide.
11:29 – Now we treat acute epididymo-orchitis with Augmentin, you know the broad spectrum penicillin.
11:35 – So that’s a bit of a head scratcher for me. So I’m quite interested in looking at that in time.
11:42 – Melissa: Have you done any studies with male cohorts or has it mostly being with female?
11:46 – Professor Malone-Lee: Well most of it’s been for females because all the doctors who come in to do PhDs with me are gynecologists.
11:55 – But we’re about to start working with – the part of the program that we’ve got ahead of
12:02 – us now is going to have a very very important group of men. And it really is because of –
12:11 – it’s helped a great deal that urologists are starting to stop
12:17 – seeing us as as sort of wild mavericks and so on and so forth,
12:21 – so that the patients are coming through. I mean one of the problems was that in the dark days,
12:27 – you know, you had units and primary care who had rules that under
12:33 – no circumstances are their patients to be referred to that unit. Now it’s reversed and
12:41 – it’s quite the opposite. It’s happening, but that held us back, particularly with men.