[00:00:00] [00:00:07] Angela: Hello and welcome back to Communicable, the podcast brought to you by CMI communications ESCMID's, open access journal, covering infectious diseases and clinical microbiology. My name is Angela Huttner. I'm an infectious disease doctor at the Geneva University Hospital in Switzerland, and editor in chief of CMI comms. [00:00:26] Angela: I'm joined today by my fellow editor, Annie Joseph. Annie is a clinical microbiologist at Nottingham University Hospital's NHS Trust in the United Kingdom. [00:00:37] Annie: Hi Angela. Good morning. [00:00:39] Angela: Today. We are really pleased to have back on communicable Professor Catriona Bradshaw in Melbourne, Australia. Catriona is a clinical researcher and head of research, translation and mentorship at Melbourne Sexual Health Center School of Translational Medicine, Monash University and Alfred Hospital. [00:00:57] Angela: She focuses on translational research to improve treatment and control of sexually transmitted infections, including the development and implementation of resistance and point of care diagnostics, antimicrobial resistance and stewardship in STIs, as well as strategies to optimize reproductive health. Catriona is an N-H-M-R-C Leadership fellow, a center head for the center to impact in antimicrobial resistance at Monash and a co-director of the A RC Research Hub to combat antimicrobial resistance. Cat, welcome back to Communicable. [00:01:32] Catriona: Thank you. It's really great to be here So Cat was our expert guest along with Teodora Wi of WHO back in January when we talked about super gonorrhea and other sexually transmitted infections. And at that time, Cat referred somewhat cryptically to a large randomized trial whose results might change the way we look at the role of men when women get bacterial vaginosis, well, that trial was published just a few weeks later in the New England Journal of Medicine and its results are pretty intriguing. So we've got her back so that we can delve more deeply into this trial to understand what it means, not only for bacterial vaginosis, but maybe for other STIs, and maybe even for UTI, which is something Annie and I are very interested in. [00:02:21] Annie: Oh yes. But first, as our listeners know, we start these episodes with a get to know you question for our guests and also our hosts. So here it is this week, if you hadn't gone into medicine, what field or career did you wish you'd done instead? So I'll start, and for me it's still science, something I've sort of fallen in love with only in the past few years. [00:02:43] Annie: And it's paleo anthropology, so the study of ancient humans and human ancestors. and I think I'd quite like to have been the person digging up Neanderthals and piecing together evolution of humans. How about you, Angela? [00:02:57] Angela: Very cool. . We did have a similar question on an earlier episode that I was also co-hosting. So I've answered this question I think in some other iteration. [00:03:09] Angela: So I have to be consistent. and I am consistent because my answer would still be. travel writer, I don't think I have a very well-formed idea of what that would actually mean because my image and we're talking sort of ideal right? Dream job, my image would be that I would get to travel and to write. [00:03:27] Angela: and That is what I said and what I'm saying now, it's my story and I'm sticking to it. Cat, [00:03:33] Catriona: how funny I think our world sort of intersect. So I was brought up in a household where my father wrote on evolution and we spent a lot of weekends looking for fossils and he was absolutely obsessed with that. [00:03:47] Catriona: So I feel like I lived a lot of that during my childhood, , and I too wanted to be a writer for the Lonely Planet, but actually that came a bit later. My dream job, which my father spent a lot of time talking me out of was to be a marine biologist. , [00:04:04] Catriona: that I might have limited job opportunities. Medicine was a better option. Aw, [00:04:09] Catriona: and that medicine would help me travel the world, which it did actually. So it sort of helped me be a bit of a travel writer. 'cause I spent time in Africa and we traveled a lot. [00:04:19] Angela: it's true that medicine is very varied. You can sort of like a, you know, you can do a lot of different things in the end. [00:04:28] Angela: You just have to work pretty hard to get, get that to be, isn't it? Yeah. Yeah. [00:04:34] Annie: Okay. Then ka Catrina. Before we start talking about the big trial, are you able to give us an overview on what the evidence was saying on the role of sexual partners in bacterial vaginosis bv we'll use from now on, in transmission and recurrence? I. [00:04:50] Catriona: Yeah, so there really is a wealth of published evidence to really show that BV has the profile of an STI. [00:04:59] Catriona: So if we look at incident bv, so acquiring bv, we see that consistently associated with new partners, changes in partners, lack of condom use in numerous observational studies. It's also associated with early age of first sex, and it's rare in women who have not reported sex with others. [00:05:18] Catriona: It is really strongly associated with onset of penile vaginal sex. But we also see in couples with two vaginas, incredibly high concordance for bv. So 80% concordance for bv, so their microbio really align and there's a lot of evidence for that. [00:05:36] Catriona: And in contrast, if we study recurrent bv, it is consistently associated with one dominant risk factor, and that is ongoing exposure to a regular partner. And that pops up in all your treatment trials if you bother to collect that information, and you just cannot adjust it out of analysis. and that can be a male or a female ongoing partner. [00:06:00] Catriona: And obviously that speaks to reinfection because that's exactly what you would see with chlamydia, for instance, if you're not treating a regular partner, because the probability that that regular partner is infected is far higher than the probability that a casual partner in the general community is, infected. [00:06:17] Catriona: We also see these BV bacteria in two anatomical sites in men in both the urethra and the cutaneous penile microbiota, so particularly under the fore skin. And we see them in the male partners of women with BV far more often than in the male partners of women without bv. And a really nice study, a metta in Chicago, but done in western Kenya where she works showed that the penile microbiota, was highly predictive of incident BV in female partners. [00:06:48] Catriona: So collectively we have this really, really overwhelming body of epidemiological and microbiological data that spans actually decades to support the role of sexual partners in both the acquisition and the recurrence of BV. Hmm. are the men in any of these studies ever symptomatic themselves besides obviously, you know, , the usual suspects, but actual bv. [00:07:14] Angela: Yeah. [00:07:14] Catriona: yeah. So they're always described as asymptomatic and there's occasional sort of case reports. But actually you have plenty of men that come to you that complain of a smell Mm-hmm. In [00:07:27] Catriona: uncircumcised men, that same sort of fishy odor. [00:07:32] Catriona: and as in women, there's smellers and non-smellers. So you know, if you've got allergic rhinitis or chronic rhinitis, and genetically some people seem to smell it or not smell now, after 20 years of working in this space, there are mild signs, but I don't think there are any intraurethral symptoms associated convincingly yet with BV as a syndrome, but possibly with some specific bacteria. But we really need to look more in that space. I'd never thought about symptomatic men with bv associated bacteria. [00:08:07] Catriona: it's subtle, It's not sort of something that people generally race in, but, some men are very fastidious about their hygiene and very disturbed by then. [00:08:16] Catriona: There's a lot of over washing that goes on and, and this and that. [00:08:20] Annie: I was gonna ask a bit more on the microbiology side of things. So Gardnerella, which is one that everybody kind of remembers, but what about the other BV associated bacteria? [00:08:30] Annie: Are there there others there in the mix that we should know about? [00:08:33] Catriona: Yeah, I mean this is so frustrating, this condition because we love in medicine to distill everything down to one infectious etiologic agent that is present in someone with disease and absent in someone without disease. And we can't do that for bv. [00:08:52] Catriona: What we really actually don't know if BV from the outset is initiated by a single founder organism with Gardnerella vaginalis being the sort of favorite the moment. And Does that come in through a transmission event? and does that set up camp displace, lactobacilli and bring its friends in? [00:09:14] Catriona: we know that there's these synergistic relationships between bacteria and people have tried to look at this and whether there's a sequence of events. And Christina Muny, has published, you know, beautiful hypothetical models on this with G Vag coming in, setting up camp and secreting amino acids and inviting Preva in. [00:09:35] Catriona: And these guys, Gardnerella Vais, has quite certain strains. We now have about 13 different strains. So we're talking about a pathogenic subtype within it, not just all GA. But good adherence characteristics, good biofilm forming characteristics, secreting amino acids that Prevotella likes, and, inviting in [00:10:00] the other friends and so we have organisms like and, mega sphera and other fastidious BV associated bacteria. [00:10:10] Angela: which many of us wouldn't have heard of because these are not pathogenic. right. Well, [00:10:15] Catriona: they're all part of, if you go back to looking at sequencing data, they are all organisms that are very much part of a suboptimal microbiota or community state type, however you wanna define it, and that suboptimal community state type correlates quite nicely with Nugent, bv and correlates quite nicely in epidemiological studies with bad outcomes like increased risk of acquiring STIs and HIV and obstetrics sequalae, et cetera. [00:10:50] Angela: Should we actually take a moment here to ask you what is Nugent? Bv Can you tell us what the Nugent score is? [00:10:58] Catriona: not only do we not have a clear single infectious course, we are stuck with slightly suboptimal diagnostic tests. Although I, as time goes on, I, I'm not sure how suboptimal they are. [00:11:08] Catriona: They actually. Capture the clinical syndrome quite well, particularly amsel's criteria so the Amsel method, really relies on four characteristics. [00:11:19] Catriona: One is the presence of this discharge, which is like really quite a milky sort of discharge. It's not that thick curdy, cheesy thrush, light discharge. It's quite thin. I often say to students and trainee doctors, it's almost like the vulvas just sat in a saucer of milk. You get this sort of glistening, almost translucent discharge on the outside things. [00:11:44] Catriona: You're a bit sort of shiny, a little bit. Opalescent, pop the speculum in, and you might add this sort of giant puddle in that posterior. phonics and, that's, the effect of exfoliation of vaginal epithelial cells, [00:11:59] Angela: and in the manuscript you say it's got to be homogenous, right? [00:12:03] Angela: I think you use the adjective, and [00:12:05] Catriona: that's, that's the, that's the definition. Yeah. Look, the reality is it can be hard, particularly as a non-expert, but also it's really, really not a very precise thing. So. I think it's the only one [00:12:18] Angela: of those criteria that is not entirely objective, right? It's a subject. [00:12:23] Catriona: It's not, and also women have often cleaned out the discharge. They're embarrassed. It's not there when you see them. Mm-hmm. So, yes, you know, it's a, it's the problem criterion. now when you lose your optimal lactobacilli, you actually lose your lactic acid and you get an elevation in your vaginal pH. [00:12:45] Catriona: And so that goes up. So we all know that healthy vaginal pH is usually less than four and over 4.5. But quite frankly, 4.5 is not normal. Is your alkaline pH that reflects this sort of loss of this lactobacillus dominant environment. So that's one of the criteria that is an absolutely essential tool for clinicians. [00:13:10] Catriona: No one should examine a woman without pH paper at 0.5 increments You've got speculum, mean swab, roll it. The minute you can see it's alkaline. It's either gonna be tric or bb. You know? Yes, it can be blood and it can be se and it can be mucus, but frankly, it rarely is any of those things. If it's blood, it's very obvious. [00:13:30] Catriona: It's blood. it ruins your pH anyway, so, that's your second, your third and fourth rely on access to a microscope. Mm-hmm. And so your third criterion is the positive amine test. Now this was developed with a drop of vaginal secretions, popped under a, cover slide off. [00:13:52] Catriona: It goes to the lab people look at the wet prep, flick the cover slip off and put a drop of potassium hydroxide on it. And that liberates these volatile amines. And so that you then say you can smell them. Well, if you can smell that smell on clinical examination, that's a positive Amen. Test. You don't need to be doing a tiny drop of vaginal secretions that's half dried out by the time it's got to the lab [00:14:17] Catriona: I mean, you write positive w test if you can smell it. And then the fourth, which is the most specific. are clue cells now clue cells are exfoliated epithelial cells from the vaginal walls that are coated in biofilm. so that you see, you know, these classic epithelial cells just coated in these gram variable cocci baccili , supposedly obscuring the borders of the epi cells and making up more than 20% of your epi cells. [00:14:48] Catriona: so all of these definitions have been sort of used and you can somewhat loosely interpret to a degree because this is not a normal state. The normal vaginal microscopy doesn't look anything like this at all. You've got this beautiful acidic pH, you've got these scant bacteria, you've got these lovely pink epi cells, you see a few purple gram-positive rods floating around that are your lactose. [00:15:13] Catriona: And that's healthy and everything else that isn't very healthy. [00:15:17] Angela: to the trained eye, it's easy. Yeah, [00:15:19] Catriona: it really is. It really, the answers that easy, And I say to people, you know, without a microscope, what you can do is record the discharge, the smell, and the pH. So you could at least, if you have three out of three. [00:15:34] Catriona: It's gonna be bv, right? and you could get into a bit more of a mess in a , high trike prevalence environment. We don't work in a high trike prevalence environment, but that's where it can get a bit trickier. the Nugent score or the Nugent method, and in the UK they use ice and hay a little bit more. [00:15:52] Catriona: All of these are scoring methods that effectively score that pathogenic process of loss of lactobacilli. So for the Nugent method, zero to three of those lovely pink epithelial cells with no gram variable, coco bacilli, lactose. and then your four to six is this intermediate state where you're starting to lose your lactose, but, and you've got some gram variables, coco bacilli, but you still see a few lactose floating around. [00:16:22] Catriona: So. That keeps you in this four to six range. Now, in our clinical service, 50% or more of women who have intermediate flora microbiota by the Nugent method, they actually have BV by Amsel. Mm-hmm. So for us, we use Amsel and we ask. for 20 years, we've asked our lab to report both and our clinicians to report both. [00:16:46] Catriona: So we do both. And we define bv, which a lot of people now do in trials as three to four AMSL criteria with a Nugent score of four to 10. So you don't have anyone accidentally sitting in there with a zero to three. and you can really audit, review the slides if you think they're out of whack with each other. [00:17:06] Catriona: And, uh, you might find that people are mis calling. And so this relies on a lot of expertise with microscopy, which is a dying art in the world of private medicine, but even in busy hospitals. but it is so wonderful. I mean, we have this at our service. It enables us to, within 10 minutes, say BV trike, candidiasis. [00:17:32] Catriona: Normal. Everything looks normal. This is physiological. it's truly fantastic. and so seven to 10 then is like full blown, no lactose, and you get into the higher thing if you have this little curved rods. Mm-hmm. Which were [00:17:47] Catriona: thought to be mobile and are now considered to be, I think BVB one or something. [00:17:51] Catriona: But anyway. it really requires expertise to recognize these and to understand normal and to be able to differentiate these morpho types. one of the things that we are planning to do in plenty of ages is the difficult, tricky slides where we have a mismatch between our microscopists to sequence the damn things to look at what's going on and see whether there's an abundance of some species that's causing problems. [00:18:18] Angela: Oh, that'll be a good one [00:18:20] Annie: I think it's so interesting that there's a condition still, like in 2025, that we rely so heavily on manual microscopy and like the expertise of the microscopist. it's amazing, really. [00:18:32] Annie: I'll tell you a [00:18:33] Annie: side story is that my office is just like off the main micro laboratory. And we had a little move around of things and the genital bench ended up right outside my office for a few months and I could hear the microscopist going. [00:18:46] Annie: Oh, lovely. Oh lovely. Another lovely one. And, and training the, the more genius staff. And there was this, there was this guy who must have been, oh, blessing, he looked like he was on work experience. He was maybe 18, 19. And one of our really senior scientists was like talking him through the vaginal microscopy. [00:19:04] Annie: And he was saying, you see this one, this one's just beautiful. The vagina was a beautiful flower And this poor kid, he looked like he wanted to die on the spot. So funny. [00:19:15] Catriona: We need more people like her. Yeah. I mean, it's interesting. I'm really glad we're having this discussion before we even start talking about your trial, because Clearly in Melbourne it's different and apparently also in Nottingham, but in my center, bv, everything sort of, let's say down there is not dealt with by infectious disease doctors that goes to the gynecologists. we do UTI, that's, you know, where I come in and my center, and below that it is not, infectious disease people. So I'm not sure our, listeners are. Entirely familiar with Amsel's criteria, with the Nugent scoring system or any other scoring system for that matter. [00:19:53] Angela: for vaginal. it's good we're, hopefully laying the groundwork. So, without getting into the results just [00:20:00] yet, Cat, can you briefly summarize your trial's design for our listeners? [00:20:04] Catriona: Yeah. So the purpose or aim if the trial was to determine if concurrent oral metronidazole given with topical Clindamycin cream, both twice daily for seven days to male partners of women who were receiving first line therapy for bv. Compared to our current global standard of care, female treatment only reduced the risk of recurrence in the 12 weeks after randomization. [00:20:28] Catriona: So it was a randomized controlled trial, it was not placebo controlled, and we can go into the reasons for that. women were eligible if they were 18 years or older, had symptomatic BV with three to four AMS LS criteria and a unit score of four to 10, which now everyone understands, had a regular partner, male partner for eight weeks and no other partners. [00:20:52] Catriona: And then they could refer their male partner if he was also over 18. He didn't have other concurrent partners, no allergies to either antibiotics for him because he was the one that was being randomized. and he needed to be able to enroll within a week of his female partner. So you can already start to see how difficult this study is to get the man at the right time with the woman and get everyone to agree to do this study, to be randomized and to be followed for 12 weeks, during a COVID pandemic. [00:21:27] Catriona: The intervention was specifically designed to clear BV bacteria from the urethral site. So this was the purpose behind the oral metronidazole and to clear the BV bacteria from the cutaneous penile site. . And particularly under the for skin. And so this was the reason for the topical clindamycin. [00:21:44] Catriona: And we chose Clindamycin because of its efficacy against BV bacteria in the vagina in vaginal studies and also for evidence in our pilots. 'cause we did two pilots before we proceeded with the trial to look at acceptability, tolerability and clearance of BV bacteria in men. weekly for a month, but also monthly for three months. [00:22:09] Catriona: Now the control arm received global standard of care. and that is female only treatment. And I, know I'm using the words female and male in this just for simplicity, but you go to our website, we talk about people with penises and people with vaginas. It's just a little hard to sort of say that, in the recording. [00:22:27] Catriona: but that, I mean that in an inclusive way. and couples were randomized to partner treatment or global practice. And randomization at the study sites occurred also by IUD use and circumcision status. 'cause these are two big risk factors. and as I said, the primary outcome was BV recurrence. That was within 12 weeks. [00:22:47] Catriona: So we had to try and keep these couples in for three months, and that was also defined as three to four Amsel's criteria and a Nugent score of four to 10. And so we looked at cumulative recurrence rates. And time to recurrence by arm hazard ratios by cost regression. And we stratified all that data by IUDs and circumcision status. [00:23:07] Catriona: And we had a range of secondary outcomes, Nugent outcomes, microbiota outcomes, which I won't go into. And we aim to recruit 342 couples. but we built in an interim analysis to be undertaken by an independent data safety monitoring board once we got to 150 couples. And that had a really conservative stopping rule, so it could be stopped if the p value was less than 0.0001. [00:23:35] Catriona: and it was stopped. [00:23:37] Angela: I guess you probably were not expecting that, [00:23:41] Catriona: it was a relief. I mean, to be honest, we had really prepared for this trial for so long because when I said we were going to do it, first of all, I avoided doing this trial for a very long time. [00:23:54] Catriona: I knew partners were driving recurrence. It was in every clinical trial I did. Any treatment you give to women, they failed. And ongoing partner was driving that failure. But , the seven trials that had failed, six of them had failed due to significant limitations. And these were done in the eighties and nineties. [00:24:15] Catriona: the seventh failed probably because it only used oral Metronidazole because it was beautifully done and it addressed all the limitations of the previous studies. Yeah. So it really was a case of this is ridiculous, we have to do this trial and prove this because the failure of the other trials was that The six first trials was subject to systematic review in around 2012 by VPR Metto who did the other penile microbio study. And that showed it was associated with incident bv, and she showed that these trials failed due to really significant limitations like lack of sample size calculations. Unusual therapies, this, that and the other. [00:25:00] Catriona: And also they fail probably 'cause it's really hard to get men to do these studies. it's really hard to get people to close their relationships. Remember you're recruiting in STD clinic populations. Yeah. You're also recruiting women who are highly motivated. And why are they motivated? 'cause they're desperate. [00:25:18] Catriona: So 90% of women in our studies had highly recurrent bv. 80% had an uncircumcised partner, and then 30% had IUDs. And IUDs, particularly copper IUDs are this huge risk factor for bv. So you are set up to fail. You get people who are desperate, who have multiple risk factors where you feel, oh my God, is this one week intervention to men? [00:25:45] Catriona: Is this actually gonna work in this population? You need to be doing it. In women who come in for the first time with bv, acute BV never had it before. Brand new partner, we see them in clinic all the time. I've got this awful thing, I don't know what it is. I hooked up with a guy last week and surprise, surprise, incubation periods, three to four days, which it is for bacterial sdi. [00:26:06] Catriona: And so it's very obvious in clinical practice that this is very strongly associated with exposure to a new partner. For the first episode or an acute episode, and that's a group you really wanna give partner treatment to before they have an entrenched biofilm. So what I can say is the fact that it worked in this population, frankly means it's gonna work even better in women with less entrenched bv. [00:26:33] Angela: for you, it was sort of the trial that you knew you had to do, but you really didn't want to. You didn't want to. Yeah. But thank goodness you did it and you did it so well. Like this time, you know, you chose the right intervention. your couples stayed together long enough to get the outcomes data, et cetera. So on a practical note, how long did it take you to secure funding for the trial? and was it particularly hard to recruit or wasn't it hard to recruit in, in the setting it was conducted in? [00:27:02] Catriona: Yes. so, you know, as I had the opportunity to talk about this already in detail, we really carefully built this body of evidence over a really long time and embarked on pilot studies. [00:27:14] Catriona: So by the time we went to apply for funding for the trial, we had some really strong evidence. And so we applied to the National Health and Medical Research Council, which is like the MRC in the UK and the N NIH in the us we got it second time round, so that was pretty good. [00:27:31] Catriona: That's good. but it doesn't mean that we hadn't had years of applying for funding for all the preceding staff. And often hadn't got it at all because it is, in Australia, we only have a population of 25 million and your grants get reviewed by generalists. So you have a really unusual grant system where people review your grants who know nothing at all about it. [00:27:56] Catriona: They've never heard of bv. Mm-hmm. And [00:27:59] Catriona: you know, I will review grants and I will be moving from, cardiology to rheumatology to psychiatry, you know, it's ridiculous. [00:28:09] Angela: And I really do wonder because you know, when we try to do urinary tract infection research, you know, a lower UTI really doesn't kill you and BV doesn't kill anybody. [00:28:20] Angela: Right? I can imagine for somebody it sort of does by [00:28:22] Catriona: HIV, but, but you're right. You know, you fair enough compet against fair. Yeah. Long [00:28:26] Angela: term. Sure, but a generalist may not appreciate that right away and might say, Hey, you know, there's limited. Funding here. [00:28:33] Angela: I've gotta give it to the bigger killers. Right. that's [00:28:36] Catriona: exactly what happens, and it's really depressing to start a grant with an extensive definition of what you're actually studying. That's the bit I have absolutely hated. You know, I will sit here writing my grants. My husband works on malaria. [00:28:51] Catriona: He doesn't have to tell people what malaria is. It's done and dusted in one sentence, gives me discussing it. You know, it's not a single cause and it does this and it does that. This goes up, this goes down, you know, it's, it's really difficult to get funding. and yet it's just amplified by the fact that it is yes, a female condition. [00:29:11] Catriona: Then when you say, what does it do? Oh, well, I smell in an odor. Well, it does a lot more than that because it sets you up for really awful, sexual and reproductive health, seally, but none of that's very immediate or very obvious. So it's hard. Yeah, so recruitment was really hard. There were whole lot of considerations and agonizing over designing this study, how long do you follow couples for? [00:29:39] Catriona: You gotta follow them for long enough to get your outcome, but not too long enough for other people to have. Additional concurrent partners disclosed or undisclosed and breaking up from their relationships, which also happened. Yeah. we just wanted to follow everyone for a month and we probably could have, but you know, I wanted to prove a [00:30:00] sustained effect of this intervention. [00:30:01] Catriona: But you can't follow people forever. It's really onerous doing it. Mm-hmm. So we settled in the end on three months being the sweet spot. [00:30:10] Catriona: but we had to counsel, we wanted couples that were going to stay together. So if you recruit people who have just hooked up, break up, particularly when you have that conversation about bv. [00:30:23] Catriona: So we learn pretty quickly how to have. Conversations about sharing good bacteria and bad bacteria. And that's what happens when humans share drinks and they shake hands and they kiss and then they have sex. you know, just normal living, humans living on a planet with bacteria and viruses. [00:30:42] Catriona: This is a dynamic process. So you have to be able to have that conversation in a sensitive, non-stigmatizing, inclusive way. You have to try and get couples at a point where they're invested in their relationship and it isn't too much of a discussion to have. [00:30:59] Catriona: So that. One or both of them walk away and then you want them to actually be able to be together. To top it off, you have to say, we don't actually know whether this works. [00:31:12] Catriona: So this is a scientific hypothesis and we're going to randomize you. So you dunno what you're gonna get until the computer tells us. Yeah. And if you get randomized, the control group and she experiences recurrence will give you compassionate access to partner treatment. Well, we had plenty of patients who know this is sexually transmitted. [00:31:35] Catriona: And then they get randomized to the control group. Great. Yeah, [00:31:38] Catriona: so they're devastated. It was difficult for so, so many reasons. so we have a website that we call BV in Focus that we've designed to provide all the information for healthcare professionals, consumers. And we've got videos on there from couples who agreed to talk about their experience and Wonderful. It was really lovely. I was talking about all the reasons why the trial was horrid to do. [00:32:04] Catriona: but the people in the trial, they were spectacular. They were really supportive. And a lot of people, we did qualitative studies after this with participants men talked about this, making them closer to their partners and women talking about it being closer, creating a bonding experience. [00:32:22] Catriona: Because we also tried to synchronize treatment and talk about not having unprotected sex till you'd finished the treatment. So they did actually discuss this. It had to be a partnership really for this to work. Otherwise, it's gonna undermine the intervention just like it would be for chlamydia. There's no point in one person taking chlamydia treatment the other then having unprotected sex with their partner and their partner taking treatment a month later. [00:32:44] Catriona: Of course, they're just gonna have been reinfected. so this had to be a shared, responsibility really, [00:32:50] Angela: So Cat, again, before we get into the results, which we obviously are really excited to hear, on a note here, you explained in the paper that the reason that the trial could not be blinded and you know, truly placebo controlled was that you said a placebo cream wasn't used because you. had a concern that the application of any topical cream, whether you know anti-microbial or not, could alter the composition of the penile microbiome. [00:33:18] Angela: Did reviewers still give you a hard time for that, or did they think that the way you defined BV recurrence with these AMSEL criteria and the Nugent score, was that enough for them to accept an open label intervention? [00:33:32] Catriona: Yeah, so that was another challenge thinking about doing the study. [00:33:36] Catriona: So that was at least a year of thinking about that. Would I dare do a study that wasn't double-blinded placebo controlled. Now the problem with that, the placebo was not only any potential chemical effect, but the mechanical effect of rubbing cream on the penis twice daily for seven days. [00:33:59] Catriona: Well, it's like cleaning vigorously. It's gonna take off the BV bacteria. if you're doing this sort of twice a day, you're gonna alter your endpoint. So it is gonna have an effect. Whether it's small or large is unknown. But this study, remember we are doing the eighth partner treatment trial. If this fails, that's the nail in the coffin. [00:34:24] Catriona: People had already taken the previous trials as evidence. That BV was not sexually transmitted. Wow. It wasn't taken as evidence that the trials didn't work. It was taken as evidence that BV is not an STI that was written in every major guideline in every country. And so we had this one opportunity to see if this was gonna work. [00:34:47] Catriona: And we have this, you know, gold standard design of the double blinded placebo controlled trial with men popping a, placebo pill twice a day and a cream. And that's what I wanted to do, but I'd had an experience with a vaginal placebo that had really put me off, really made me worry about the influence of that placebo on the vaginal microbio. [00:35:08] Catriona: And I just wasn't prepared to take that risk. So I did discuss it with people randomly at conferences and my team. Agonized over placebo. Duration of follow up. What was the end point? You know, should we drag everyone back in? It would be so easy to do a Nugent endpoint so that if we get people who can't come back, we've still got their slides 'cause we self collected slides are just as good. [00:35:35] Catriona: But I know, gotta get them back in. So there are all these little decisions, which of course everybody has when they're designing a trial, but they get you bogged for months because you know that if you make the wrong decision that could sink your trial. [00:35:49] Catriona: so we explained that the New England Journal gives you 2,700 words. There's no room for explanation for anything at all. I've never struggled to write something. It was like bare bones results, bare bones everything. No room for interpretation in the discussion. [00:36:10] Catriona: So I couldn't write a little essay on the placebo, which I wanted to do. One reviewer, there were five asked, I think, but people accepted it. they were fine. I think it was reviewed really beautifully, by people who really understood the field. And I think quite frankly, you see those Kaplan-Meier survival curves with a small number of people and you go, oh, that's not a marginal effect. Yeah. [00:36:33] Catriona: So I think the data fortunately, weren't marginal. and so that helped. [00:36:39] Angela: So , now, can you spill the beans? Can you tell us the results? at that interim analysis where the DSMB, the Data Safety Monitoring Board is looking at these first 150 couples, what did they find? [00:36:53] Catriona: there was a very, very significant difference between the groups. [00:36:56] Catriona: I could tell you our final analysis. but yes, a very big difference. It was, you know, group A versus group B. So one was better, one was worse. but really there was a really quite large effect size. So we're talking about a hazard ratio of about 0.36 to 0.38. You know, depending on whether you've got your modified intention to treat, or your protocol, P value was less than 0.0001. [00:37:21] Catriona: I think what is really important is it was very robust to any missing data, whether we imputed it as all cured or failed, it was very robust across the stratified groups as well. So when we looked at it, we saw an effect within the presence of IUDs. In the presence of lack of circumcision, we had smaller numbers of men who were circumcised and we looked particularly at IUD type, so we had smaller numbers with a copper IUD. [00:37:54] Catriona: But what we did conclusively show is this intervention works with uncircumcised partners who are your big risk with a big load under their foreskin. And it works in women with an IUD, although women with an IUD are overrepresented in women who experience treatment failure. The other thing that was very important was, in our pilot study, so we had 50 couples in our pilot studies, and we always have adherence around 92, 90 3% self-reported. But, you know, high rates of adherence reported. In men, we had about, I think it was like mid eighties, a hundred percent adherence to oral metro and about mid seventies to topical clindamycin, a hundred percent adherence to topical clindamycin. So, you know, all 14 doses. [00:38:47] Catriona: So those are the pilots. Well, when it came to the trial, it adherence to Clindamycin was a lot lower than Metronidazole. Men were clearly remembering to take their tablets, but they're rushing out the door to work and they didn't remember to put their cream on. And so in fact, only 50% of men took all of their topical clindamycin doses. [00:39:08] Catriona: So, we saw stronger effects in our pilots. So Lenka A. Vodstrcil the epidemiologist in my group and the first author on the paper. she conclusively showed that the lowest recurrence rates in women. Were in women whose partners were a hundred percent adherent, so a hundred percent adherent to both medications. [00:39:28] Catriona: So they had a recurrence rate of like 1.3 per person years. the control group's 4.1. and so, you know, it's a no brainer if you take it, it works, [00:39:40] Angela: you had to show it. [00:39:42] Catriona: You really have to take your medication. And so we have these things that erode the intervention. And so that is poor adherence, particularly in men, particularly to topical clindamycin. [00:39:53] Catriona: So we have to work on that. And that can be related to the messaging, right? We were very. Balanced about this. We [00:40:00] told people we didn't know if it was gonna work. So now we tell people it works, but you've gotta take all of it. if you don't, it won't work. So that's a very different message . [00:40:08] Catriona: And we also say, if you've missed the morning, just keep going. So you've taken a full 14 doses. I do wonder whether it is so sensitive to adherence, whether in fact men need a bit more drug. I think women probably need a bit more drug too. I think this is a biofilm disease where longer durations of therapy are probably needed for women and perhaps for some men. [00:40:31] Catriona: And I think we are lucky to have seen that effect, but I wonder if more drug would be helpful. we also know that, some people had unprotected sex during treatment. Not a lot, but some did. and some people reported concurrent partnerships. So we said to people, we have to treat a closed couple unit. [00:40:51] Catriona: We didn't use the word monogamy. We have to treat a closed couple unit where [00:40:56] Catriona: everyone's treated. In this, sexual relationship. So if there are other partners that are untreated, they're just gonna reintroduce those bacteria and cause failure, which will then mean we think it doesn't work. If you are having other partners, your questionnaires are confidential, please document it in your questionnaires, They're not shared with partners. And then we know why something hasn't worked. So there were disclosed and undisclosed concurrent partnerships as well. So you can sort of see, I'm grateful that we got the effect size that we did 'cause there were a whole lot of things that were operating to sort of undermine it. [00:41:34] Catriona: but yeah, so that's, those are really the data. It's quite a simple study, but not simple to do. Yeah, [00:41:41] Annie: in terms of kind of real life applicability as well, I mean, those things are all gonna matter in real life, aren't they? In terms of, you know, the men forgetting to put the cream on and, you know, the undisclosed partnerships. [00:41:53] Annie: And I think the effect size is so big that it's, nice to know that despite potentially those real world things that are going to happen in terms of compliance with medications and things, there is still really that effect size to be seen. I think as well, what you were saying about the, what you say now versus what you could say in the trial in terms of being neutral Yeah. [00:42:12] Annie: About whether it's gonna work. it could be quite a powerful message, couldn't it, in terms of those. Couple partnerships to be like, we know this really works, but you have to do it every day. I can imagine, you know, the partner being like, do the cream, do the cream. You know, I don't wanna get this again, use all the cream and reminding each other and, and doing that as kind of like a, you know, treatment together and to get the best outcome, rather than it being solely reliant on the, you know, the woman as it is at the moment to, fix her problem. [00:42:40] Catriona: Yeah. I mean, a theme that comes out of this trial, but also the quality of studies are that, you know, women are most affected psychologically and in their relationships when they've had recurrent BV and endless cycles of antibiotics and endless visits to doctors. for the women that experienced cure and their partners who experienced that previous journey with them, they would say things like, A week of inconvenience is nothing compared to what we went through before this. [00:43:11] Catriona: and it is only a week. I didn't know about you, but I treat mycoplasma genitalia and we are really, you know, in between a rock and a hard place with that. And we are doing a lot longer regimens for people. And, bv this is not a weird concept. the fact that partner treatment reduces recurrence, proves reinfection is driving the majority, not all, but the majority of recurrence, or perhaps we should call it treatment. [00:43:38] Catriona: Failure. and that proves BV sexually transmitted. So then we treat it like that and we discuss it like that. I think it's really time to stop with this opaque language. I think we are doing women a great disservice now to call it an imbalance of their bacteria. Sends them off down rabbit holes, trying to restore their imbalance with yogurt and vinegar, douches and you know, all sorts of home therapies because there's something wrong with them and they're out of whack. [00:44:07] Catriona: And it's a transmission event that has resulted in bv. If they have ongoing bv, that is another matter. We've proven that reinfection is driving a lot of recurrence. But we are looking at the women who experienced treatment failure. Now we know some of the reasons are the men didn't finish their treatment the women didn't finish the treatment. [00:44:31] Catriona: They had unprotected sex treatment. There were other partners, et cetera. But there's a group of women there who still have BV at day eight. And day eight was the day after they finished treatment and they had not resumed sex, and we call them the persisters. So I think the great thing about this trial is it has helped us understand the pathogenesis of treatment failure. [00:44:52] Catriona: We now understand reinfection driving recurrence. So now we've got our persister group . IUD users are overrepresented in that group. That's a bit of a no brainer, you know, biofilm, foreign body, et cetera. So now we can start to direct our strategies at those women. [00:45:09] Catriona: Do we need longer durations of therapy for them? Do we need to remove their IUD. [00:45:13] Catriona: treat cure, treat their partner, then they're gonna have it back in. So there's gonna be a group of women that need more aggressive therapy, and that's fine. [00:45:21] Catriona: I feel like we were treating everyone the same way. Very unsatisfactorily with multiple rounds of antibiotics directed at women. We can now cure a large group of them, and now we're left with a residual group that we can develop evidence-based strategies to cure them too, so we can achieve, you know, cure for all women. [00:45:40] Annie: we've talked a little bit about the women who hadn't responded by day eight and persistent BV despite sort of standard of care treatment. [00:45:49] Annie: can you tell us a little bit about potential, sort of future treatment possibilities, that may be on the horizon or in studies around microbiota replacement or live biotherapeutic products that potentially show, show some promise for these women? [00:46:05] Catriona: Yeah, first of all there's been a lot of, Probiotics looked at over time and it's been fairly clear through systematic review that there've been fairly significant limitations with the trials and the products until lectin V came along, and that is truly a vaginal species Lactobacillus Crispus. Craig Cohen led the studies in, Western Kenya on that, product, and women were treated. [00:46:34] Catriona: I think this is the key. There's been no convincing evidence that any, sort of live by therapeutic works well on its own. It really is very much about using it as an adjunctive agent to antibiotics. So using antibiotics to clear your bacteria and then come in. So he did that, with a intermittent, regimen and he effect size over 12 weeks was about 30%. [00:47:01] Catriona: It was really good. Mm-hmm. this was in all women though. This was not in women with just a regular partner, so it was all comers. interestingly, the lactobacillus probiotic. Sustained colonization was really affected by unprotected sex. So I think that's a really important thing. The key to doing these things is it's money and expensive, and that product has to be manufactured, it is not something you can just buy like Clindamycin cream and re-badge. You've actually gotta get funding for the manufacturing of it. I really think there's a real role for the right life biotherapeutic following an effective antimicrobial regimen. And as I alluded to before, I'm not convinced that we have landed on exactly the right duration of therapy for our, primary regimen necessarily either yet. I think it's, it's something that we need to all be open to and consider. in terms of things like vaginal microbit transplant, where Caroline Mitchell from Boston works on that. and that is a really interesting concept. I think there were four cases reported originally from a study in Israel. [00:48:12] Catriona: and that follows very much along the lines of, it's not just the bugs, but giving it as a package is gonna be more effective. and that's had variable success. It's a really important area to be working in. And I think Caroline's view is that scale up would always be a problem. Yeah. Yeah. and that it is an important proof of concept. Life Biotherapeutics come into is really this sort of adjunctive supportive role to help women achieve an optimal microbiome in a sustained way. 'cause often when you treat with, antibiotics, you don't see lactus Cris come back quickly. [00:48:50] Catriona: You often see ins. There People talk about it being unstable and transitional, and women withins can transition to BV and more easily. lots of people are focusing on ins at the moment to understand what does it do, what is it doing there, how important is it to get rid of it, or is it a problem if you have it? [00:49:11] Catriona: and so I think there's, space for that too. [00:49:14] Annie: actually there's some really nice parallels with c Diff and the fecal microbe to transplant. Other conditions that traditionally have been that kind of, maybe it's dysbiosis and you need to replace not just one thing, but a whole, niche of organisms. [00:49:30] Angela: So we have [00:49:30] Annie: touched on quite a few of the applicability and, challenges of implementing these studies, findings in practice around partner adherence, and, keeping the couple relationship, what are the other challenges you think? [00:49:45] Annie: Might limit the applicability of this study's findings. I specifically wondered what you thought about ethnicity maybe, and how that, may play a role, in bv. Yeah. There's been a lot of debate about ethnicity and BV hasn't [00:50:00] there, ethnicity can get tangled up with Practices like vaginal cleansing and douching practices that are obviously not great for your lactobacilli. They don't necessarily give you bv, but they might set you up to you know, have a less. effective host defense system. but we also have examples, very much of ethnic associations that are related to really terrible access to healthcare. [00:50:25] Catriona: You know, in some countries particularly, so people who are most affected come from certain ethnic groups where there's no access to healthcare for them. So they have a whole lot of things, lots of STIs, as well as BV and other things. so I touched on this before, but I think that first of all, if this study worked in this population who were really set up to recur, I feel confident. [00:50:53] Catriona: That the intervention works, but you do, like you do for all s STIs, you know, if you have open relationships and people are getting exposed, you know you are going to not derive the same benefit as you would in a closed, monogamous relationship. One of the questions I think is, so we are using our samples not only to start to look for the cause of bv, but we're also using our samples to see is there a predictive penile microbiome profile for BV recurrence? [00:51:22] Catriona: Are there BV bacteria that predict recurrence? Then you can develop a test, then you can test men. Then you, the world's first True prevention strategy to prevent women from acquiring, BV to begin with. Not just prevent recurrence, but prevent acquisition. So obviously that's like a very big thing and that comes with all the issues around antibiotic use and stewardship and this and that. [00:51:44] Catriona: But we don't actually know what the prevalence of these bugs are in the general population in men. So, you know, we know that chlamydia is sitting at around one or 2%. we measure all of these things and we report them. So we know your probability of encountering that you casually go out and have sex with someone is one or 2%. well what is it for bv? It's a lot higher for absolute sure. so when we talk about the challenges in the applicability of our study findings and ethnicity, it's gonna depend really on behaviors in population. So sexual behaviors, relationship behaviors. Carriage prevalence, all of these sorts of things. [00:52:25] Catriona: So we need to do these studies. I think what this tells you is in high income, well-resourced urban setting with people with reasonable health literacy, this intervention works. Yeah. [00:52:39] Catriona: I think that we need to reproduce this in different populations, and yes, it will have different effects for all of the reasons we've discussed today. [00:52:49] Catriona: because, you're gonna have a whole lot of different societal factors operating. but as I said, I think the other thing about it is, you know, you've really gotta be open about BV and use clear language so women and men understand. [00:53:02] Angela: Okay , this is my antibiotic steward hat. Have you, in this trial you had, the time, let's say to look at. Resistance outcomes, what could be unintended consequences. [00:53:14] Angela: Exactly. Do you know? Particularly [00:53:15] Catriona: with Clindamycin? Yeah, [00:53:17] Angela: yeah, yeah. are you gonna be looking in that, . Yeah, we [00:53:19] Catriona: can. well, I think actually for Clindamycin it does just depend, you know, we obviously have missed the boat for all the traditional sort of culture based, cultivation based studies and mics. [00:53:31] Catriona: So we would really have to look, at markers of resistance. And we know metronidazole really isn't associated with significant resistance issues for, the BV bacteria. There's some intrinsic resistance. Clindamycin is a much worse sort of agent. to be using. So I think it is really important. [00:53:50] Catriona: I mean, particularly if you start to think about scaling up of testing and developing a diagnostic test, et cetera. So Cat, going back to the trial and all the work you had to do for it, it was honestly very obviously a highly successful trial. But you know, there's always something you might wanna do differently afterwards. Was there anything in this case that you would've done differently? Looking back. [00:54:16] Catriona: Not doing a trial during a COVID pandemic would be one. Providing more material to assist women with discussing BV with partners, I think from the very outset is really important. . Really hammer home adherence to men. I would say hammer it home to women, but women are motivated 'cause they're symptomatic . I'd like to say I do a pile of things differently, but with the funds available and all the constraints of a randomized control trial, where you have to be balanced and tell patients you dunno if it's gonna work. You always go, gee, I wish I had more. We've got lovely microbio samples, but gee, I wish I had samples for AMR. But you also have to just go, I can't over collect [00:54:57] Catriona: think about how you're gonna use it in analysis. If you're not gonna use it in analysis, don't put it in. It's not fair. so we keep questionnaires quite short. We keep sampling, you know, to the minimum important samples so that we are not over collecting and overburdening our patients, which contributes to dropout and loss to follow up. So Cat, we've heard a lot about bv. If you had, you know, the million, million dollars, maybe lots of millions, how would you spend that money? [00:55:28] Annie: To answer the big unanswered question in bv. [00:55:31] Catriona: Well, I think if we just distill it down to one big unanswered question, we still dunno what the cause is, the exact cause. You know, that's ridiculous, isn't it? We don't know if it's caused by a single pathogen or a polymicrobial consortium from the outset that displays optimal lactose reflect, depletion occurs first, enabling overgrowth of BV bacteria. [00:55:53] Catriona: And most of us are starting to feel it's a pathogenic strain of Gardnerella Veis., That's transmitted. We we're gonna be using our samples from our trial to really try and understand causation. see if there is a predictive of penile microbiome or penile bv. Bacteria that are predictive of recurrence in women, which then really helps to address that sort of whole causation, issue. [00:56:17] Catriona: So that's the one big unanswered question. 'cause once you've done that, you can then develop better targeted diagnostics, which we know are lacking more targeted therapeutic agents as well. You can develop tests for men that enable you to test, treat, eradicate, prevent BV women that you can truly impact the global burden of bv. [00:56:38] Catriona: You can prevent pregnancy sequela, [00:56:41] Catriona: you can develop vaccines. So this is like just for me, the starting point really. for other recurrent infections in women, even those , that are still not considered to be sexually transmitted. [00:56:53] Angela: I have a certain amount of women patients who get recurrent UTI, who tell me, , with this partner I get. UTIs And with my ex, I didn't, or vice versa. And I have been asked by some patients, could you please treat my partner too? But that's completely uncharted territory for U uti. I, what do you think about that? [00:57:14] Catriona: I agree with your patients wholeheartedly. And I think, you know, obviously in medicine we are supposed to do, our randomized control trials and all of these things and we are not supposed to function. Based on anecdotes, but the worst thing you can do is ignore what your patients tell you because it's their lived experience. [00:57:36] Catriona: I've heard the same thing. I am completely on board. It's something we are very much planning to do because I think it's doing women a great disservice, telling them repeatedly, really with lack of evidence that it's actually your own bacteria that are giving you a UTI and it's just the mechanical action of sex that causes them to migrate up a short urethra into your bladder. [00:58:05] Catriona: We were all taught that we are still telling patients that just like we told them, BV wasn't sexually transmitted. I actually think that it's time to overturn that myth. So if you wanna do a study, we are on board 'cause we are planning to as well. Oh. So we can do a multi-site. [00:58:22] Angela: My patients would love that. [00:58:24] Angela: Yeah. I think you're right. We owe this to them, and it's completely understudied and [00:58:28] Angela: we need to do it. Yeah. [00:58:29] Angela: do you have any last message or messages for our listeners? [00:58:33] Catriona: Yeah, look, I think this is a big paradigm shift in knowledge and in clinical practice that is a little bit overwhelming, particularly for, primary healthcare providers, but for everyone in their busy practice. [00:58:46] Catriona: So we put a lot of effort in the last six months into designing a lot of information around helping consumers, discuss BV with their partners. and information for clinicians. information for pharmacists. And we've put all of this on our BV in focus website a lot of this is downloadable. [00:59:07] Catriona: And it's there to enable people to confidently discuss their evidence and the intervention with their patients and to give people information. And it includes things like a letter for pharmacists. That you can print out with your prescription so that the pharmacist doesn't go, what the hell have I just been given a vaginal clindamycin script to a man? so we are trying to mitigate all the issues and once we've changed guidelines , then we can start lobbying the pharmaceutical company behind the product so that we could have a product that was just Clindamycin cream and doesn't say vaginal with six applicators on it in a box. [00:59:52] Catriona: And one last message. Don't forget the condom, condoms prevent [01:00:00] transmission of bv. We published a meta-analysis in 2008 showing that. I know they're not very fashionable. But they are very cheap and they have very broad reaching effects against s STIs, of which BV is one of them. [01:00:16] Catriona: and it is something you can do. To prevent acquisition or catching it, but also to prevent recurrence as well, if that's something. [01:00:25] Angela: Yes, very good point. [01:00:26] Annie: Yeah. We need to make condoms cool again. [01:00:28] Annie: We do, [01:00:29] Catriona: we do. In our pandemic of STIs. They're just going upwards at the moment. Cat, thank you so much again. Catriona Bradshaw at Monash University in Melbourne, Australia. and thank you for listening to communicable the CMI Comms podcast. this episode was hosted by Annie Joseph in Nottingham, uk. [01:00:48] Angela: And me, Angela Huttner in Geneva, Switzerland, editors at CMI, comms ESCMID's Open Access Journal. It was edited and produced by Dr. Katie Hostetler, oy and peer. Reviewed by Dr. Ariana Zeria from Mother Teresa University Hospital in Tara Albania. Theme music was composed and conducted by Joseph McDade. This episode will be citable with a written summary referenced by A DOI in the next eight weeks, and all the literature we've discussed today, as well as the websites that Kat has mentioned can be found in the show notes. [01:01:20] Angela: You can subscribe to Communicable wherever you get your podcasts, or you can find it on ESCMID's website for the CMI COMMS Journal. Thanks for listening and helping CMI, comms and ESCMID move the conversation in ID and clinical microbiology further along.