00:00 – Dr. Hsieh: Some patients are prone to UTIs caused by bacteria that don’t grow very well
00:05 – in conventional conditions.
00:20 – Melissa: Let’s move on to the topic of UTI testing, which is one of the biggest topics
00:24 – that we have questions on at Live UTI Free. First of all, do you think
00:28 – the standard urine culture can be used to rule out urinary tract infection?
00:34 – Dr. Hsieh: I think in some patients conventional urine cultures are very helpful and in fact,
00:44 – perhaps the majority of patients. As to why some patients who clearly have UTIs often have negative
00:53 – results on conventional urine cultures is less clear. A few reasons that make sense,
01:00 – one is that some patients are very sensitive to very low colony counts of bacteria in their urine.
01:09 – And then another explanation is that some patients are prone to UTIs caused by bacteria that don’t grow very well in conventional conditions.
01:20 – Melissa: Do you feel like that’s becoming more and more common
01:22 – or is it more that you have other tools now to use so you’re seeing these other organisms?
01:30 – Dr. Hsieh: That’s an excellent question. You know that that refers to the possibility of detection bias.
01:36 – Are we really seeing a shift in UTI biology amongst patients or has this always been the case?
01:44 – You know reading some papers carefully I actually think that
01:53 – there’s always been this important subset of patients who clearly have UTI symptoms and yet
02:00 – their conventional urine cultures are negative. If you look carefully at these papers they’ll say
02:06 – oh, 20% of patients had persistent symptoms despite negative cultures, and it’s glossed over unfortunately.
02:14 – Melissa: Even though that a significant number of patients.
02:16 – Dr. Hsieh: Yes, yes it is.
02:18 – Melissa: Do you think for some people with interstitial cystitis there’s a bacterial component?
02:25 – Dr. Hsieh: Yeah, very controversial and very important topic. I think on both sides there have been some
02:32 – misdiagnoses. I don’t know how many, and by both sides I mean that I do think that some patients
02:41 – told that they have UTIs have actually interstitial cystitis and vice versa. There are
02:46 – definitely patients who have interstitial cystitis who actually have recurrent or persistent UTIs.
02:56 – Alignment with this context, we see that it is a spectrum.
02:56 – Melissa: How would you go about making that distinction in a patient who is somewhere on that spectrum?
03:02 – Dr. Hsieh: It can be difficult and i definitely don’t have all the answers. In some cases
03:07 – I do feel fortunate that I think i’ve been able to sort it out with the patient’s help. So you
03:15 – know, maybe I’ll start by giving the extreme very clear examples. You know I think patients who
03:24 – have consistently positive urine cultures who respond consistently to antibiotics
03:33 – clearly have UTIs and that seems like a very easy case. But believe it or not, I’ve seen a fair number of patients
03:43 – who fit that scenario and yet because of the recurrent nature of their infections have
03:48 – somehow been told by other providers that they have IC which flabbergasts me.
03:56 – The other extreme would be patients who never have positive urine cultures,
04:04 – never respond positively to antibiotics and have waxing and waning symptoms of IC.
04:13 – The classic ones being urinary urgency frequency and pain that improve after voiding.
04:22 – Melissa: What do you think about the theory of embedded infection in the bladder and how that might relate to the failure to respond to antibiotics?
04:30 – Dr. Hsieh: Well, I do think that clearly bacteria have strategies that
04:38 – allow them to persist in the urinary tract or at least reinfect the urinary tract
04:45 – and there’s quite a bit of accumulated data at this point. Both in models of UTI
04:53 – as well as clinical data. So one of the major theories is that patients sometimes have biofilms
05:02 – of bacteria in their bladders. And the biofilm of course is basically a slime
05:10 – that the bacteria can live in to hide out from the immune system and possibly antibiotics as well.
05:16 – Now these biofilms can either be on the surface of the lining of the bladder and they can also be
05:24 – within the cells themselves. The other major theory as to how persistent
05:31 – or at least recurrent UTIs can occur is reseeding from the gut. So there’s
05:39 – actually fairly recent data indicating that many patients prone to recurrent UTIs have a bloom of
05:50 – E. coli in their gut before a UTI episode, which
05:57 – in conjunction with older data showing that many of the E. coli strains found in the gut can also
06:03 – cause UTIs is consistent with the reseeding theory.
06:07 – Melissa: Do you think it’s always reseeding in that case or could it be the bacteria communicating with each other across organs somehow?
06:17 – Dr. Hsieh: Well that’s a very interesting theory. I’ll say that pelvic organs definitely have
06:26 – crosstalk, as it’s referred to. So there may be indirect communication between bacteria across
06:34 – those organs since others have shown that your microbiome, the collection of all your bacteria
06:42 – in your gut, can certainly affect the crosstalk between the gut and the urinary tract.
06:51 – Melissa: People also often refer to their UTI symptoms, and sometimes with positive test results too,
06:56 – coming on with stress. Or like the bacteria just being opportunistic. They can see that something’s
07:01 – going on and they take their opportunity to multiply. Can you explain why that might happen?
07:10 – Dr. Hsieh: Yes, so I have had patients who’ve expressed that this has been their experience.
07:21 – It does make plausible sense that perhaps one could have
07:28 – a milder form of immunosuppression associated with stress. So for example,
07:33 – stress increases cortisol, which is a immunosuppressive steroid.
07:39 – Now it hasn’t been studied to my knowledge but that does not mean it does not occur.
07:46 – Melissa: I think it’s quite interesting the number of people who report this as a sequence of events and it would be great if we could do some research.
07:59 – Dr. Hsieh: Yeah, I will say anecdotally it also seems clear that stress in general magnifies urinary symptoms. How that works mechanistically
08:09 – I’m not certain. That being said, I do think that many stressed out patients focus more on their
08:18 – urinary symptoms in general and perhaps there’s a vicious cycle occurring in that situation.
08:24 – Melissa: I would say it’s quite difficult not to focus on bladder symptoms especially given the
08:30 – brain is wired to tell you something’s going on there, very difficult to forget.
08:34 – Dr. Hsieh: Of course.
08:36 – Melissa: You’ve spoken a lot about using urinary microbiome testing as well to provide
08:41 – more insight sometimes for patients where they test negative on culture. Do you often use
08:47 – multiple types of testing alongside culture or is it always something you do independently?
08:53 – Dr. Hsieh: When I first see a patient I will tend to send off what are called
09:01 – enhanced quantitative urine cultures, in conjunction with microbiome testing,
09:08 – which is essentially detection of bacterial DNA in the urine. The reason I do that is there are
09:18 – a fair number of patients in my experience who may have negative conventional urine cultures but
09:25 – still positive cultures when you do what are called enhanced quantitative urine cultures.
09:31 – In those patients, the enhanced quantitative urine cultures I think are are actually
09:40 – more accepted by the medical community than the microbiome testing because ultimately it’s still
09:48 – growth-based. Now there’s also another important segment of at least my patient population where
09:56 – even enhanced quantitative cultures are negative.
10:00 – In which case I tend to rely more on microbiome testing. That being said, I think microbiome testing
10:09 – for clinical use is still relatively unestablished and we we don’t know the optimal ways to
10:22 – interpret these results and which patients would most benefit from this type of testing.
10:29 – Melissa: Do you see differences in patient outcomes across those different types of tests?
10:36 – Dr. Hsieh: I do, and another interesting observation is that the tests often disagree,
10:46 – It’s not overly surprising because the technology that underlies each of these testing platforms
10:55 – is different but it adds an extra layer of challenge in terms of interpretation
11:01 – of results when you have to reconcile differing findings across tests.
11:07 – Melissa: Do you only tend to treat things that are known pathogens, or sometimes you have to go outside that because of what you find?
11:16 – Dr. Hsieh: Certainly known pathogens, especially E. coli in a symptomatic patient I will try to treat.
11:24 – But you are correct. Many times, especially on microbiome testing, more unusual organisms
11:31 – that are poorly characterized in general and may or may not be your pathogens, do appear.
11:38 – And then it becomes especially challenging. The dilemma is whether or not treatment should be directed against these organisms as well.
11:48 – Melissa: Have you had any cases where a very unusual organism has come back on a test and treatment has resulted in improvement in symptoms?
11:58 – Dr. Hsieh: You know most of the time when patients have unusual organisms on their microbiome testing
12:05 – they usually also have more conventional uropathogens, and I tried to treat those
12:13 – patients with antibiotics that would cover both the better known bacteria as well as the
12:23 – unconventional potential pathogens.
12:25 – Melissa: So it would be hard to differentiate what caused the symptom relief in that case?
12:32 – Dr. Hsieh: It can be. Antibiotics very rarely can target only a single bacteria.
12:38 – Melissa: One of the questions that comes up quite a bit around the microbiome testing that’s based on DNA sequencing is about the DNA itself.
12:46 – So on one hand we’re often told that DNA begins to break down quite quickly once an organism is no
12:52 – longer alive, but on the other we’re told that they can sequence DNA from fossils that are millions of years old. So what is the correct answer here for
13:02 – urine samples. Are the DNA alive or are they dead, or can you just not tell?
13:09 – Dr. Hsieh: That’s a very important question. The underlying assumption with microbiome testing is that
13:18 – any bacterial DNA we detect is important but presumably only live bacteria will cause urinary
13:29 – symptoms associated with the UTI. So I think current testing platforms do not distinguish
13:40 – between DNA from live versus dead bacteria which is a major limitation. Other fields in microbiology
13:49 – have shown that DNA from live versus dead bacteria do make a difference in various contexts.
13:59 – Melissa: Okay, and are you able to talk about the research that you’re doing in this area?
14:07 – Dr. Hsieh: Yes. So a number of years ago another urologist’s interest in the microbiome questioned whether
14:18 – the DNA that we’re detecting is from live or dead bacteria and thus if it’s clinically important.
14:27 – And that really stuck in my head. So we’re currently, in my laboratory, trying to develop
14:34 – methods to distinguish between DNA from live versus dead bacteria in urine samples and hope to do a clinical study very soon.
14:46 – Melissa: What’s the timeline on that do you think?
14:50 – Dr. Hsieh: We are actually poised to start testing clinical samples hopefully in the next few months.
14:58 – Melissa: That’s interesting. And the results from this research, is that kind of a few years away or sooner?
15:06 – Dr. Hsieh: Hopefully within a year we’ll have published.
15:08 – But you know the cogs of academia turn slowly. I will
15:16 – upload it first as a pre-print so that the findings are publicly available. Of course,
15:24 – findings uploaded to pre-print are not peer-reviewed and should be taken with a grain of salt.
15:32 – Melissa: We’ll be looking out for that research, definitely.