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[00:00:07] Angela: Hello and welcome back to communicable the podcast brought to you by CMI communications Esmit's open access journal covering infectious diseases and clinical microbiology. My name is Angela Hutner. I'm an infectious disease doctor at the Geneva university hospital in Switzerland and editor in chief of CMI comms.

I'm joined again by my co host Josh Davis, infectious disease doctor and trialist in Newcastle, Australia, and fellow editor at CMI coms.

[00:00:34] Josh: Hi, Angela. Thanks for having me back to co host again.

[00:00:38] Angela: Glad you're back, Josh. So the topic today is super gonorrhea and other sexually transmitted infections. We're thrilled to have with us two expert guests.

[00:00:47] Angela: The first is Dr. Teodora Alvira Wi. Teodora has been team lead of the Sexually Transmitted Infection Unit in the Department of Global HIV, Hepatitis, and STI Programs at the World Health Organization here in Geneva. Thanks, Teodora. At WHO, she's led the implementation of the Global Health Sector Strategy on STIs from 2022 going to 2030.

[00:01:10] Angela: She's leading the provision of technical support to countries, the development of WHO STI guidelines, addressing antimicrobial resistance and STIs, and facilitating the development of new STI treatment and diagnostics. Teodora, welcome. Thank you.

[00:01:25] Teodora: Thank you so much for having me today. Good morning, good afternoon, or even good evening, wherever you are.

Yeah, we're in a few different time zones. our second guest is Professor Katrina Bradshaw. Katrina's, a clinician, researcher and head of research, translation and mentorship, and of the genital microbiota and microplasma group at Melbourne Sexual Health Center and Monash University. Katrina focuses on translational research to improve treatment and control of STIs, including strategies to optimize reproductive health, antimicrobial resistance and stewardship.

[00:02:00] Josh: Katrina's an N-H-M-R-C Leadership Fellow, a center head for the center to impact antimicrobial resistance at Monash. And finally, a co director of the ARC Research Hub to Combat Antimicrobial Resistance. Welcome to Communicable.

[00:02:15] Catriona: it's a great privilege to be on the podcast and to share this with Tio on her very last day.

[00:02:23] Angela: So I didn't tell our listeners that Teo is actually enjoying her last day on the job at WHO here in Geneva.

[00:02:31] Angela: Teo, perhaps you have a few words.

Teodora: it's good. been working for, WHO for 16 years and almost 30 years on STIs. within the 30 years that I've been working with STIs. We still do not have a low cost point of care test except for syphilis. Hopefully after that there's going to be more that's going to happen with STIs.

[00:02:53] Josh: So, we start these episodes where they get to know you question for our guests and also our hosts. we've tried to make it ID relevant in the past, but today we're going to abandon that and ask a question that's nothing to do with infectious diseases.

Who is your top artist this year on Spotify wrapped or whatever, , platform you use, or if you don't use a platform, what? What vinyl album did you listen to the most? it's a bit complicated for me, because my Spotify account is the account that we use on the home speaker system, so my kids and my family use it, and it's a mixture of my taste and their taste, so my number one was Taylor Swift, as Angela may have guessed.

[00:03:30] Josh: but the rest of the numbers tell the, , dichotomous, bimodal distribution. So we've got Taylor Swift, number one, Bob Dylan, number two, Hozier, number three, and Paul Kelly, who's an Australian singer, number four. How about you, Angela?

[00:03:43] Angela: Oh, yeah. I knew that what I would say would end up likely being very unoriginal and yet it's just authentic.

[00:03:52] Angela: It's also Taylor Swift for me. I knew her, when my kids were little, , we would Dance to her music inside on really bad winter days when we really didn't want to go out.

[00:04:02] Angela: . And then during COVID, my husband and I rediscovered her and we thought, wow, she wasn't just some made up pop star, you know, mass produced.

[00:04:08] Angela: And yeah, and ever since then I've been , a very, strong fan.

[00:04:12] Angela: So anyway, Cat, how about you?

Well, I come from a family, my kids and my husband are very into indie rock, so there's a lot of music going all the time in our household. And there certainly was a, what, what's your top thing on Spotify, rap, I'm a big Angus and Julia Stone fan. So they're an Australian brother, sister pair who are incredibly musical.

[00:04:41] Catriona: And they're just fabulous to watch live. I saw them live this year at this gorgeous venue called the Palais down in St Kilda. And I've just got into Ocean Alley, who I also saw this year, who are a sort of reggae, surf band and it's super relaxing.

[00:04:58] Josh: Okay, there's some good recommendations there for people if they don't know those australian artists

[00:05:03] Josh: How about you last but not least Teo

[00:05:05] Teodora: Just recently we were having all these fun games because we had to do this in my retirement party and because we had Guess This Song i was looking at who's the singer of sex bomb sex bomb You are my sex bomb, and it was Tom Jones. So, 1970 songs, and the Bee Gees, and ABBA.

[00:05:29] Catriona: I was brought up on ABBA. Big time.

Angela: Very cool. So, back to medicine, to today's topic. first question goes to Teo. What exactly is supergonorrhea and in what regions is it wreaking the most havoc?

[00:05:44] Teodora: Well, gonorrhea superbug or supergonorrhea are extremely drug resistant gonorrhea with high levels of resistance to the current recommended treatment for gonorrhea, which is ceftriaxone. most of the superbugs are also resistant to penicillin, to sulfonamides, to tetracyclines, to fluoroquinolones and macrolides, including acitromycin.

[00:06:08] Teodora: The first resistant, , gonorrhea or the superbug that we have found was initially reported in 2009, and this was the HO41 strain, and this was the first strain that was reported in Japan, where you have very high rates of resistance to ceftriaxone.

[00:06:27] Teodora: There are also other superbugs that have been reported since then, like the ones we have for France, for example, and then another one In Japan, when you think of, , gonorrhea resistance, you know where the origin is. It's originating in Asia. We have most of the, antibiotic resistance for gonorrhea originating in, areas like, what we have at the moment, for example, Vietnam and Cambodia have very high resistance ceftriaxone, which is the last line, treatment. So overall, most of these also are then spreading to Europe. They're spreading to other countries, globally. It's also because of travel, you know, you go to different countries in, Asia and then you bring this back to European countries and as well as, of course, in, uh, other countries.

[00:07:17] Teodora: Australia. at this point, we see that, Africa is a little bit spared in terms of antimicrobial resistance to the last line treatment. It's probably because their antibiotic use is not as much as , we hope we have. Like in Asia, where, they take it like their pills, you know. When they have something, they take something.

[00:07:38] Teodora: and this affects the antibiotic use, meaning if you have more antibiotic use, the more likely that you're going to be resistant to gonorrhea as well.

Angela: a quick follow up question on that, , are we sure that in Africa there is less resistance or could there be just an issue of detection of reporting?

Teodora: We do have a very rigorous enhanced gonorrhea surveillance program at the moment. And so we have like a built in mechanism to look into sentinel countries and really ensure that we're making a good surveillance systems on the enhanced gonorrhea AMR. For example, in South Africa, we're seeing very Amount of resistance to Aceto Mycin at this point.

[00:08:23] Teodora: other countries have, still very minimal, resistance to subtraction and while comparing it to our Asian sentinel countries like , in Vietnam and in Cambodia. They have reported high resistance to Seine and Suboxone, which are the last line treatment for, gonococcal infection. Similarly, one area is China Korea and Japan, where we have, , reports of high resistance to Ceftriaxone and Cefixime, for example.

[00:08:53] Teodora: But for the, countries in Africa, I mean, we haven't seen resistance to Cefixime and Ceftriaxone. We're seeing some few resistance to Acetromycin. I think it's more an issue of antibiotic use. In Asia, there's more antibiotic use compared to, Africa.

[00:09:11] Teodora: But once it enters the African community, it's going to be a big issue. Because the burden of gonococcal infection in Africa is very high. And at the moment, that resistance strain hasn't really. Penetrated the African, context at this point.

[00:09:28] Teodora: Yeah.

[00:09:29] Angela: Reassuring that there is surveillance going on, , in all continents, but definitely not reassuring, that once it gets in, we know the storybook.

[00:09:38] Josh: A little follow up, clarification, Teo.

[00:09:40] Josh: You mentioned resistance to Keftriaxone and that as the last line antibiotic, but there are other things we can use for that, right? So, as clinicians, if we see a patient who we know or think has Keftriaxone resistant gonorrhea, what are the antibiotic options we can reach for?

[00:09:57] Teodora: There's none. ha ha You know we put it in our recommendation. Use gentamicin, high dose of gentamicin, and, give, 2 grams acitromycin, but it is less effective. Ceftriaxone is still, the best, treatment option for gonorrhea. And so if that's not gonna happen, they use other antibiotics, which are now entrapenem, for example. These are drugs that are already used in a high level hospitalized setting.

[00:10:28] Teodora: But ceftriaxone is the last line treatment. What I can say at this moment is that we have two new drugs, hopefully that are coming up soon. They've gone into clinical trials, and hopefully, In a few years time, we will have new treatment options for gonorrhea. And that's a soliflodacin and cepotidacin.

[00:10:49] Josh: Right. that's undergoing FDA evaluation for UTIs, I think, at the moment, right?

[00:10:55] Catriona: Yeah.

[00:10:55] Teodora: For cepotidacin, it's, I think, an evaluation for UTI is also being done at this point.

[00:11:01] Josh: and while we're on gonorrhea still, just to finish off on this important topic, Teo, can we just step back for a minute and do a quick refresher for our audience on the clinical manifestations and the syndromes we see apart from the genital infections in men and women?

[00:11:18] Josh: What are some of the extra genital manifestations and are these important in this resistance problem?

[00:11:24] Teodora: Yeah, I think they do. I think for men you've mentioned about urethral discharge. You can also have epi or what you call or, and then for women, of course you have the cervicitis. you can also have a cell in and dermatitis and you can have your pelvic inflammatory disease.

[00:11:44] Teodora: of course, in women they can manifest as a vaginal discharge. In men they can manifest as urethral discharge. But in majority of women they can be asymptomatic. in terms of extragenital infections of course you have, Adult infections like proctitis and you can also have pharyngitis , due to oral sex.

And in children you can have, neonatal conjunctivitis, especially if you were born to a mother who has a gonococcal infection. But , Whether the extra genital manifestation plays an important role, I think that's a very important, question, Josh, because you know that in the pharynx, , in our oral flora, you also have other species, like a Neisseria specie, very similar to gonorrhea, because it's Neisseria gonorrhea, and you have other commensal specie in your throat.

[00:12:36] Teodora: And as a result , this Neisseria species can also develop resistance with ceftriaxone, and it's usually a pen A allele, gene that is, being, Modified, because of this resistance and the Neisseria species can develop resistance based on the mutation in the pen, a allele.

[00:12:55] Teodora: And if you have this mutation, and then you have gonorrhea, what happens when you have oral sex, the two mix up the Neisseria species with the resistant gonococcal strain. they can have a horizontal transfer and recombination that can result into resistance strains being transferred to the gonorrhea, microorganism.

[00:13:17] Teodora: And so therefore, the oral, pharyngitis, can really be an important mechanism by which resistance is developed, and as a result of this, of course, you have key populations with very high rates of, sexual activity, with very high rates of oral sex. And as a result, these are where you can develop and transfer and spread, gonococcal resistance .

[00:13:42] Angela: How about, these extra, genital infections and development of resistance to antibiotics? Is there something there? is there evidence that, , pharyngeal gonococcal infections, are to blame ?

Teodora: yeah, thank you so much for that question. I mean, it's hypothesized that it's one of the factors. but overall, I think when you say antimicrobial resistance is gonococcal infections. It's really the overuse of antibiotics, you know, the antibiotics that we use for, gonorrhea are something that we use also for other infections.

[00:14:15] Teodora: like, for respiratory infections. Similarly, acetomycin was originally very much commonly used for the treatment of gonococcal infection, but because it's been used also for other infections, as a result, you get these high rates of resistance gonorrhea, based on this use of azithromycin.

[00:14:36] Teodora: So really it's the overuse of an antibiotic overall that makes, it, a challenge to really also look at monofocal infection overall and monofocal AMR developing

[00:14:48] Angela: so often the same answer Yeah. For, many of our resistant, infections. Indeed. Yeah. Yeah.

[00:14:54] Teodora: I think also in STIs, we don't have the right diagnostic tools. You know, we base our treatment on syndromic approach. A woman has a vaginal discharge, a woman has a urethral discharge, we presume that they have a gonococcal infection. we give treatment for gonorrhea.

[00:15:11] Teodora: Every time, anywhere, when we suspect that you have a gonococcal infection, even if you are not diagnosed to have a gonorrhea infection, and as a result , there's still an overuse of antibiotics, because of the lack of low cost diagnosis. It's imprecise because we use syndromic approach.

[00:15:29] Angela: Yeah. We take out our big bazooka and we just mow everything down.

[00:15:35] Angela: Thank you so much. Turning to you, Kat. now it's your turn. So when clinicians think of gonorrhea. We always kind of reflexively think of chlamydia as well. So can you update our audience on chlamydia trachomatous infections?

[00:15:48] Angela: Are these spiking just like gonorrhea? What does chlamydia have in common with gonorrhea ? And what doesn't it?

Catriona: Yeah. Thanks, Angela. I mean obviously it's got a lot in common with gonorrhea. It's a bacterial STI and it's transmitted in all the same ways that gonorrhea is, although it is less transmissible through oral sex. So we do see the pharynx as a major driver of transmission of gonorrhea and less so for chlamydia and even less so for mycoplasma genitalia, my favorite topic.

[00:16:21] Catriona: And it's a cause of all the same syndromes and clinical presentations as gonorrhea. And I like to really describe a cascade of symptomatology when it comes to chlamydia, gonorrhea and MGEN. So all of them are capable of causing asymptomatic infections, but gonorrhea really tends to be a much more aggressive infection.

[00:16:43] Catriona: It's associated with more marked symptomatology and has the potential to really present. quite severely, particularly in women, but also, you know, in men. MGM, Mycoplasma genitalium is far more indolent, and Chlamydia just sort of sits somewhere in the middle. we also know that, symptoms are driven by host responses, and the same infection in one person can be highly symptomatic and asymptomatic in another.

[00:17:10] Catriona: But I think you can say, as Teo, just commented, we've got to read that chlamydia is far more often asymptomatic than symptomatic and I don't really like to put a figure on it because they vary and I don't really think they're very evidence based. But chlamydia causes cervicitis, it causes pelvic inflammatory disease, so endometritis, alpingitis.

[00:17:32] Catriona: tubo ovarian abscesses, tubo factor infertility in women, urethritis and epididymal orchitis in men. We know it's a significant cause of proctitis as is gonorrhea and uncommonly associated with sexually , acquired reactive arthritis. in terms of, epidemiology, Like gonorrhea, the highest burden of chlamydia is in populations with young, sexually active people.

[00:18:00] Catriona: Young women particularly, up to the age of 25, and gay and bisexual men. Geographically, chlamydia, like all STIs, we see disproportionately affecting low income countries and regions, so sub Saharan Africa, South and Southeast Asia, Latin America really have some of the highest incident rates of STIs like chlamydia.

Many regions are experiencing the same patterns that we see with gonorrhea with rapid rises over the last decade or so. We see this sort of. Really interesting trough. I was just looking at some data from our service during COVID. It's mirrored in all the global data sets. and then we see really record high notifications from 2022 onwards and really steep rises in gay and bisexual men.

[00:18:49] Catriona: And I think you asked me about antibiotic resistance and chlamydia and this is our really easy STI treatment for chlamydia is so straightforward compared to gonorrhea and certainly compared to mycoplasma genitalium. Because fortunately, we still don't experience treatment limiting AMR for chlamydia.

[00:19:13] Catriona: So we can use azithromycin still without macrolide resistance. But we do know that it is less effective than doxycycline at the rectal site. So doxy really retains high efficacy across all sites. It's a cheap, generic drug. And I think we're really lucky with Chlamydia because the drugs that are most effective, generic, well tolerated, really generally affordable and widely available, globally.

[00:19:42] Catriona: So that's my sort of cook's tour of the easiest STI to deal with.

[00:19:47] Angela: does anyone know why chlamydia is not able to become easily resistant to azithro or doxy for that matter.

[00:19:57] Catriona: Yeah, I mean, I'm not a chlamydia person, [00:20:00] so that's my first disclosure. it's got a really interesting cellular cycle. it may have a more stable genome that's less prone to, mutations. We know, for instance, mycoplasma genitaliums, highly error prone, flax DNA repair mechanisms. We know with gonorrhea that we see an enormous amount of Exchange of genetic material, particularly at sites like the pharynx, and we don't tend to see that with chlamydia, but to give you a really highly evidence based answer, we do need to ask a chlamydia expert.

Josh: I'm just reflecting as we're talking about this, that, most I. D. physicians know that secretly our favorite antibiotic is doxycycline.

[00:20:46] Josh: and I think probably sexual health specialists as well, probably feel the same. That was a bit of a bliggett. Unnecessary side comment, but we're going to move on to another pathogen now, Treponema pallidum, and back to you, Theo. So let's talk about syphilis, for a minute. is syphilis also experiencing a resurgence?

[00:21:05] Josh: And if so, in whom and where? And then the other thing for us to think about is the resistance question as well, syphilis seems to still be susceptible to penicillin and same sort of question that Angela asked, why is that?

[00:21:18] Teodora: Josh, I think there's really now a resurgence of syphilis.

[00:21:22] Teodora: In the early days, even in , high income countries, we thought we've eradicated syphilis. And now it's back to h aunt You know, for example, that in 2020, our estimate for syphilis was about 7 million syphilis acquired every year, and we just did our new estimate, and now it's about 8 cases every year.

[00:21:45] Teodora: So there's really increase in syphilis rates, not only in low and middle income countries, but also in high income countries. Additionally, we are also seeing a rise in congenital syphilis because now you, also are increasing maternal syphilis that increases the rates of congenital syphilis globally.

[00:22:06] Teodora: , most of the reports that we receive when it comes to syphilis, it's coming from men having sex with men. Among, sex worker, but also among pregnant women. So when you're already seeing reports of syphilis in pregnant women, this is meaning to say it's part of the general population issue.

[00:22:26] Teodora: And as you have more syphilis rates in pregnant women, you also see higher rates in, congenital syphilis. But very importantly, it's also good to know that we still treat syphilis with benzathine oil. Penicillin. So it's still the drug of choice. The big challenge with benzathine penicillin is not resistance.

there are shortage in some countries. it's a very cheap drug some manufacturers would not like to produce this drug because it's cheap. It doesn't give them any profit. Also at the moment, what the big challenge that we are seeing is that there's no quality assured.

[00:23:03] Teodora: Active product ingredient, for benzine penicillin, and this is what we're working on, to look at quality assured products for benzine, penicillin on the side of the healthcare provider. The big challenge is really when you are a primary healthcare physician, you would like to inject benzo, penicillin, you know, it's painful and you're always so scared of an anaphylactic shock.

[00:23:29] Teodora: therefore, even if you have a treatment for syphilis, there are many challenges in the administration of benzathine penicillin. So what other alternatives? And Jos, if you're an STI the next alternative is really doxycycline. Again, using Chlamydia, we use doxycycline. For syphilis, you can use doxycycline.

[00:23:51] Teodora: The big thing here is the compliance issue, because you have to take these two alternatives. 14 days to 30 days, as an indication for syphilis. Initially, we've also, recommended acitromycin. The big challenge with acitromycin is that we are also seeing resistance. So there have been reported resistance, to acitromycin for, treponema pallidum.

[00:24:14] Teodora: So, at the moment, this is not, a treatment of choice for syphilis, but also, acitromycin doesn't cross the placental barrier, so therefore, acitromycin as well as erythromycin, would not be useful for maternal syphilis because it will not prevent you from having congenital syphilis. So, if you're a pregnant woman having syphilis, the best, treatment would still be benzathine Penicillin, no other alternative as possible.

[00:24:46] Teodora: When you're allergic, that can be a problem.

[00:24:49] Josh: Thanks, Teo. That's nice and clear. shall we move on, Angela, to our next and hit parade of STIs?

[00:24:57] Angela: so next question is for Cat. Changing gears again, moving to a different STI. Much of your research focus is on mycoplasma genitalium, which is also considered an STI superbug that we don't always hear as much about it.

[00:25:12] Angela: So can you describe this organism to us? What does it do clinically? How should it be dealt with?

[00:25:17] Catriona: you know, Mgen is really our first STI for which treatment limiting AMR is a major issue. We've truly run out of drugs and clinicians on a daily basis commonly encounter untreatable Mgen infections, everywhere. So it's an infection without a cell wall, so that rules out beta lactams immediately, and that limits our toolbox.

[00:25:42] Catriona: and we're really stuck with antibiotics that either inhibit protein synthesis or DNA replication, and so , we're really limited to some macrolides, some extended spectrum fluoroquinolones, some limited tetracyclines and a strepto gramin. we don't have a lot to begin with and, it's rapid acquisition of AMR is resulting in loss of those drugs that we have in our limited armamentarium

[00:26:08] Catriona: so M-gen's capable causing all the same syndromes as chlamydia. And again, like chlamydia, it's often asymptomatic. and it's a really often quite an indolent infection with low level symptoms. And I really think increasingly that this contributes to some of the views out there that it's not a pathogen, that it's not important, because it's tends to be a bit more of a divisive STI.

[00:26:35] Catriona: there's really no debate about the evidence showing an association with urethritis in men. It's got a really good odds, cervicitis in women. But where we start to see debate is its association with PID and, you know, recent meta analysis that came out of our group. Really tried to drill down and look at this very carefully because any studies that look at PID are inherently problematic because PID is a terribly difficult diagnosis to sort of standardize.

[00:27:06] Catriona: but really, pull data from all available studies up to 2023 gives us a odds of around 1.7. So that's just slightly down from the previous estimates that we're sitting around to. So it's a modest but significant association and you see it in about one in 10 women with PID across all the published studies.

[00:27:26] Catriona: So yes, there's a less strong association with PID than we see for chlamydia, a less established one, but it is associated with PID and any practicing clinician will tell you they have seen plenty of cases. And we're also seeing our traditional pathogens, chlamydia and gonorrhea, quite interestingly contributing a bit less to PID in high income settings.

the other area that's a bit controversial is, it's associated with spontaneous abort and preterm birth by meta analysis. But there are a lot less studies of MG in pregnancy. a recent study in PNG that I was involved in found an association really interestingly with low birth weight was quite modest, but it adjusted for a really broad range of confounders.

[00:28:14] Catriona: I think it's safe to say it's preferable not to have MG in pregnancy, but we don't have , the data to really support screening in pregnancy. And we actually don't have the data to support screening for MGN anyway, pregnant or not pregnant. and that's really fundamentally because we're in a situation where our treatments are often not highly effective.

[00:28:37] Catriona: And some of the agents that we need to use may be associated. with worse health outcomes occasionally than the condition itself. So the balance, the equipoise, the screening really hasn't been achieved, for MGen. And quite interestingly, we're starting to pull back with screening recommendations anyway, even for chlamydia and gonorrhea, because they don't seem to have made significant impacts on prevalence and incidence.

[00:29:04] Catriona: We can see that screening is driving up antibiotic consumption, driving up AMR. So again, when we start talking about cascades, we've got MG at the bottom where we're really, there's no dispute, no guidelines recommend screening, but we're starting to get a bit less keen on screening for even our other STIs and trying to revisit the evidence, behind this.

[00:29:29] Angela: actually was not aware that there is reflection right now on pulling back on screening, even for gonococcus, chlamydia. Do you two want to comment?

[00:29:39] Catriona: In MSM (men who have sex with men).

[00:29:40] Catriona: Yeah, so I think what we see, and in fact this data is coming out particularly from Northern Europe, is that there've been, you know, guidelines recommending very frequent screening in gay and bisexual men, begonorrhea and chlamydia.

[00:29:58] Catriona: And this has been [00:30:00] really quite rigorously enforced in conjunction with PrEP so, people diligently come back every three months. They get their prep. They get their checkups and some really nice work that's come out of Belgium and Chris Kenyon's group has really shown that, antibiotic consumption rates in these individuals are 50 times that of the general population.

[00:30:24] Catriona: And that AMR is much higher. In these populations. So we've got very direct correlations between screening frequency, antibiotic use, and AMR.

[00:30:35] Angela: I'm assuming and meanwhile, you're not making a dent in the actual prevalence of these organisms. Yeah. That's what, yeah.

[00:30:42] Catriona: We're not.

[00:30:43] Teodora: I think this is a very big debate. Cat, you were part of our WHO guideline development group, looking into whether we need to screen or not to screen. Well, of course, this one study that Chris Kenyon was saying was that you really didn't make any difference in terms prevalence.

[00:31:01] Teodora: Similarly, we've also seen some of the studies among, adolescent women. of course, they are the first person that we need to be screening for chlamydia, for example. Because they are the people who would then develop PID or infertility in the future.

[00:31:16] Teodora: they also haven't seen the prevalence decrease of chlamydial infection, for example. But when you look at screening, you need to have a screening strategy. And when you say it's a screening strategy, you need to have a good coverage to really make a good difference in terms of prevalence and incidence a certain disease. Infection. And most of this, your coverage hasn't really made a difference.

[00:31:39] Teodora: What we can say with screening is that they can make a difference individually. You can have individuals be prevented from having infertility or not. And again, Kat, think the antibiotic consumption is an issue, but in low and middle income countries. They take antibiotics, as if they're taking antibiotics already.

[00:32:01] Teodora: And so having a screening strategy could even prevent them and lower the rates of, antibiotic use because now you have a test to say that when you're tested, then that's the time you get treated. Similarly, again, we're here now maybe looking at doxepam. Would you rather screen? Or would you just be taking in Doxypep every time you have unsafe sex?

[00:32:24] Teodora: So there's still so much controversy related to that. I know that it's always a big challenge, for all of us to really make recommendations globally.

[00:32:34] Catriona: Yeah, and I agree, Teo. It's very population specific. So I think what we're talking about is, women are a very different population to men.

[00:32:46] Catriona: They have the uterus. They're at risk of death. PID, they're at risk of serious complications. So, screening recommendations need to be very population specific in terms of, the high income, low income resources, access, you know, to services. Male versus female, et cetera. So I think it's very specifically in the high income gay and bisexual men that we've seen some of this work coming out and you can't generalize that at all to other populations.

[00:33:21] Catriona: but I think for MGen anyway, at least it's not controversial. and I think it's, interesting, you know, it's quite a hard concept to get across to patients because, my clinic's full of people with like a person genitalium or bacterial vaginosis most days. and, so, I get sent to the patients that are really hard to treat with Mycoplasma genitalium, and they've often been really diligent with their STD screening, and they're really distressed and upset, as to why did they not have this test earlier? They've been seeing their doctor regularly for their STI checkups and how have they only just found out about it now?

How long have they had it? why didn't we test them earlier? it's, difficult. For patients as well as clinicians, sometimes to synthesize the evidence and to be able to provide that, coherent, digestible fashion, in a clinical consultation for people,

[00:34:18] Angela: it's really interesting because it seems like some of these organisms, their so-called virulence factor is actually their ability to kind of blend in, coexist with our immune system, invite some immune tolerance, let's say, do these low level infections, such that we in the medical community often really kind of, dismiss some of these organisms and their pathogenicity.

[00:34:43] Catriona: you know, , it's good to talk to people about the role of the host response, because some of us mount very vigorous responses to things, other people don't, and it's a battle between the bug and the host. And if you get your balance just right, you clear it and you don't get sick. If you're a hyper responder, you might die from, a cytokine storm and an over response.

[00:35:05] Catriona: And if you're an under responsor, the bug kills you. So, it is a really, Important concept to get across, I think, to people, dealing with MGen, I think, is really becoming increasingly fraught and challenging, for clinicians, obviously access to testing varies globally, and we've worked with Teo closely on diagnostic manual and on guidelines, we have had.

[00:35:31] Catriona: A number of conversations over the years about really the need for regional and global surveillance. So more coordinated surveillance efforts for MGEN that include AMR markers. potentially integrating that with the existing surveillance networks. but we have really big differences in macrolide and quinolone resistance, between regions.

That's going back to the same theme. It's clearly driven by antibiotic use and consumption because exactly the same areas that have the highest resistance For gonorrhea, have the highest resistance levels for MGN. So, you know, we'll talk about Asia, the Asia Pacific region, where we've got macrolide resistance exceeding 50%, but in gay men, more than 80%.

[00:36:17] Catriona: Quinolone resistance is so much higher in our region. where Josh and I are, where we've got, more than 20 percent of our mGen infections have really relevant Par C mutations, and these are all concentrated within our macrolide resistant infections. So then we end up with these dual class resistant infections that we can't cure with macrolides, we can't cure with quinolones, and it just leaves us with really few effective options.

[00:36:45] Catriona: And so for MGen, it's your prototype of an STI, where you really do need to use resistance assays at diagnosis and resistance guided strategies, because that helps you as a clinician to try and select the best drug that's likely to achieve the highest level of cure, terminate the infection, prevent repeated cycles of infection and ongoing transmission and a decade ago now, we developed the first resistance guided strategy for MGN using macrolide resistance markers that served us well.

But, you know, in our service, we've had to now introduce some key quinolone targets in the last 12 months to try and improve our use of agents like moxifloxacin because we're now losing that as well. So, just like we heard from Tio with gonorrhea, we urgently need new drugs. We need new classes of antibiotics.

[00:37:36] Catriona: We've repurposed some, like chrysanthomycin and minocycline, and we're always experimenting in our service with combination therapies. but getting companies and not for profit organizations interested in Mgen is far more challenging than it is for gonorrhea. And It's really still very much a low priority on the global funding scale.

[00:37:57] Josh: To make matters worse, there's been a world shortage of pristinomycin, or at least outside France lately, so it's very hard.

[00:38:05] Catriona: Totally. But citrofloxacin too, Josh, so export ban on pristinomycin because it's only produced by one company in France, export bans on citrofloxacin produced by two companies in Japan.

[00:38:17] Catriona: You try and source it from China and it's. Seven times the cost of the Japanese companies. So, you know, we're really operating in infectious diseases at a really interesting time because we've got this really endless supply chain issue with all sorts of drugs that, I mean, I understand pristinomycin, but whoever thought benzathine penicillin.

[00:38:39] Catriona: Metronidazole it happened to. You know, it's just sort of going in and out. Gentamicin right

[00:38:45] Josh: now in Australia as well. Gentamicin,

[00:38:46] Catriona: right. Of course, then we had the saline issue as well. So it is a bit, a wild time.

Josh: maybe Just to reframe, in case our listeners are worried that there's no more STIs, we've talked about gonorrhea, chlamydia, syphilis, and mycoplasma genitalia, but don't worry, there's more. So, cat, You recently completed a multi center male partner treatment trial for women with bacterial vaginosis. Can you just first tell us a bit about bacterial vaginosis, because it's a bit More complicated than the other single pathogen things we've been talking about. And, also tell us a bit about the trial.

so bacterial vaginosis is what we call a dysbiosis. it is a disturbance of the vaginal microbiome where you, lose your optimal, lactobacillus species. And you see this. increase in diversity and load of facultative, and anaerobic organisms. So it's a polymicrobial infection that has been presented for many, many years as an imbalance of your bacteria.

[00:39:54] Catriona: it affects one in three women globally. and it's far more common in Sub Saharan Africa. So in excess of [00:40:00] 50 percent of women in Sub Saharan Africa. And it's associated with really nasty complications. So it increases your risk of every bacterial STI and viral STIs, herpes and HPV.

[00:40:15] Catriona: it increases your risk of pelvic inflammatory disease, post mortem preterm weight. and it not only increases your risk of acquiring HIV as a woman, but if you are co infected with BV and HIV of transmitting to male partners. So it is safe to say it is not an optimal state to be in for a number of parameters.

[00:40:41] Catriona: So I started working in this field 20 years ago a first cohort study to really show that our current treatments weren't working.

[00:40:49] Catriona: recommended treatments directed solely at women, were associated recurrence rates. So more than 50 percent of women got their BV back within three to six months. But in that cohort, the factor that really stood out was the women at highest risk of recurrence had an ongoing male partner, so a regular partner.

[00:41:13] Catriona: But when you looked at the epidemiology of BV, it became really clear that it had the profile of an STI.

[00:41:22] Catriona: You don't find it in women who have not had sex with others. It's associated with penile vaginal sex, lack of condom use. It's associated with new partners, higher numbers of lifetime partners. And if you study, women with female partners, so the LGBT community, we see Unbelievably high concordance rates for BV, so 80%.

[00:41:44] Catriona: and it's also got an incubation period that's really typical of bacterial STIs, so 3-5 days.

Josh: Can I interrupt, Cat, just to clarify, I didn't understand that. So women who have sex with women, high concordance rates, what do you mean?

[00:41:57] Catriona: so the prevalence rate in, women who have sex with women is really high.

[00:42:03] Catriona: often a lot higher in studies. than heterosexual women. And this was often used as evidence that it wasn't an STI. but in fact, what you see is if you study couples, you have very high concordance in these couples. So 80 percent will have concordance. for their vaginal microbiota by nutrient score.

[00:42:23] Catriona: And in fact, if you start doing sequencing, you see, you know, sharing of GVAG strains and lactobacillus species. a no brainer if you're in infectious diseases. When people have sex, they exchange bacteria, good and bad bacteria. So, if a partner has BV, if an index has BV, her partner 80 percent probability that a partner has BV.

[00:42:45] Catriona: so we did some really fascinating studies in this population where we followed, women for two years. We showed that if you didn't have BV at the beginning, that the only women that acquired BV, during 24 months had a new female partner. and that women in monogamous relationships who did not have BV at the beginning didn't have BV at the end.

[00:43:07] Catriona: So this was all done, you know, 15 or so years ago. We did trials in young university students and showed as long as they all did anonymous questionnaires where they didn't have to talk to a clinician. There was no BV in women who'd not had sex with anyone else. A tiny little bit in women who'd engaged in non coital activities and all the BV was in women who engaged in penile vaginal sex.

[00:43:31] Catriona: So we had a very substantial body of data from our studies and other people's studies. The problem was there have been a considerable number of partner treatment trials. that failed. And this was taken as evidence that BV is not an STI, rather than evidence that the trials had limitations, which many of them did.

[00:43:56] Catriona: They were done a long time ago in design, very significant design issues, underpowered, et cetera. But a really important thing was they all used oral therapy in men. So they just evaluated oral therapy. Around the time of the Rakai studies, you remember the big HIV male circumcision studies?

[00:44:15] Catriona: There were three in Sub-Saharan Africa. There was a really lovely post-hoc analysis in 2009 of the Rakai study in Uganda that actually showed that, the female partners of men who were randomized to male circumcision had a very dramatic reduction in incident bv. It was really striking and it was fitting with what I was seeing and thinking about.

[00:44:38] Catriona: then sequencing and advanced molecular testing really started to show us that males had these BV bacteria that we find in women, not just in the urethra, but also in the skin of the penis, particularly under the foreskin. So the role of the foreskin, and penile cutaneous and urethral carriage started to sort of become quite apparent.

[00:45:00] Catriona: So, I wondered whether evaluating a topical antimicrobial at the same time as an oral antimicrobial would help clear this cutaneous carriage of BV bacteria. The oral antibiotic would really help clear that urethral carriage. So we would try this combination approach. So we combined the two antibiotics that we use in women commonly, a clindamycin cream and an oral metronidazole, So we use these daily, we use them in fact twice daily in men. So We asked men to apply this clindamycin cream from the tip of the penis, right down the shaft, twice daily for seven days and to take oral metronidazole. We did a couple of pilots, we did acceptability, tolerability, it was unbelievably well tolerated.

[00:45:51] Catriona: We did sequencing of the urethral and cutaneous microbiome. We saw this incredible rapid clearance of these bugs in men at day eight that was sustained out to three months. So it gave us the confidence to apply for funding to do a large RCT. and the long and the short of the whole thing is, of this very long journey, is that, we saw an Incredibly significant reduction in BV recurrence in women, more than a 60 percent reduction out to three months.

[00:46:26] Catriona: The trial was stopped prematurely at a planned interim analysis by the Data Safety Monitoring Board. We had a hazard ratio of 0. 3, P value of less than 0. 0001, And this was in a population of women that had a really high burden of risk factors. We were set up to fail. These were motivated women, sick of their BV, failed everything.

[00:46:51] Catriona: 80 percent had recurrent BV. 30 percent had an IUD, which is a real risk factor, for acquisition and persistence of BV. 80 percent of them were uncircumcised, but this intervention worked really dramatically in this population, and so we now have, for the first time, relatively cheap, I hesitate to say this, because clindamycin cream is not cheap in a low income country.

[00:47:19] Catriona: but a really acceptable, very short duration intervention that greatly improves cure for women. You know, I do want to say that the pathogenesis of is really probably, multifaceted. So we are dealing with prevention of recurrence that we have shown is largely due to reinfection from sex partners.

[00:47:44] Catriona: But you have a group of women with persistence, perhaps due to the host factors we were talking about, due to an IUD. so we've taken a very exciting first step that will have really major, implications for our guidelines and for women, but it's not the end of the story by any means.

[00:48:02] Josh: that's really interesting. I hadn't heard about that trial. can I just ask two brief follow on? One is, where was it published in case people want to read more about it? And the second is, is it in guidelines yet? And if not, why not?

[00:48:14] Catriona: It's under embargo, Josh. So we can't. So it may or

[00:48:20] Josh: may not be published at some time soon.

[00:48:23] Catriona: Oh, it will be . And we are working with guideline committees, currently. Okay. the world as well as our own. what is really, important is we've built a beautiful website. When we're allowed to release all of this, it will have downloadable instructions for consumers, clinicians, pharmacists, everything can be adapted to the local setting.

[00:48:46] Catriona: It'll be a one stop shop people can go to to get information because You know, it's not necessarily that easy to prescribe clindamycin cream that's packaged with vaginal applicators, to men. And so it's really important that we get the right messages through to pharmacists and we're working with pharmacists to disseminate all of these.

[00:49:07] Josh: I mean, it's hot off the press. You heard it first here saying my communications unless you heard it at a conference. You heard it first here.

[00:49:15] Angela: So the trial was stopped prematurely, and that's a good thing. However, did you guys decide to continue observationally following these participants just to see how long out you get this effect?

[00:49:28] Catriona: Yeah, so we're doing implementation studies at the moment.

[00:49:33] Catriona: , one of the fundamental reasons why a lot of the other trials failed and why these trials are so hard to do, why people just raise their eyebrows when I finally plucked up the confidence to do this, is you tend to do it in an STD clinic setting. And so what do you need for this to work?

[00:49:49] Catriona: You need closed monogamous relationships because you're treating a partner and that's not going to work if you've got concurrent partnerships. They're going to just introduce bugs. it's a [00:50:00] precarious balance. If someone is in a long term relationship, and you treat them, and they don't enter new relationships, then we would expect this to work.

[00:50:11] Catriona: But a lot of our population is in relatively transient relationships. But I can say, anecdotally, we've got people that have come back to us, contacted us, they've got pregnant and they've been bv free for two years and they've got some really happy couples. But it really does all depend on that individual context because of course intervention is only going to work in a closed relationship for that couple.

[00:50:35] Angela: thanks for that comment, which actually makes my next question a little bit too, simplistic. this question was pre planned and it's for both of you. What do you think has been, until now, the most effective measure to reduce the spread of STIs? where should resources be focused?

Teodora: You know, the STIs is very common. You have one million STIs every day. and many people have sex. Every day. Of course, it's important to know how we should be preventing sexually transmitted infections.

[00:51:05] Teodora: we know what works. We know what is the public health, strategy for, reducing STIs. First of all, it's prevention. it's the condom. If you want to have sex with someone that's casual, for example. And you need to do, your early diagnosis and treatment. Provide effective treatment.

[00:51:24] Teodora: And treat your partners. So that's a very important public health strategy. Prevent, test, and treat. But what is very a big challenge in sexually transmitted infection is really the stigma and discrimination, related to sexually transmitted infection. If you have an STI, you're always stigmatized because of STIs, and as a result, This lingers on, and if you don't get treated, then the transmission chain is not broken. So, where should we focus our resources? provide, quality STI services .

[00:51:58] Teodora: We need to train physicians, train, our health providers. To know how to do a good sexual history, for example, how to talk about sexually transmitted infection. I mean, people will be so scared to say, I have an STI. But if you are a person that they can approach, they can tell you everything.

[00:52:17] Teodora: And that would be very important for the management of your sexually transmitted infection. Of course, we need to reduce stigma and discrimination. And talking about sex is so important in a positive way.

[00:52:31] Teodora: Sex is for pleasure. It's for your well being. And you need to protect yourself, related to, these things. Where else should we put our resources is in innovation. We still do not have a lot of good point of care tests that are low instead of a pregnancy test, How I wish to have a dipstick to say, oh my God, , I have gonorrhea. Oh my God, I So, having that innovation for a local test would be very helpful. And now, as Kat was saying, how do we do with microplasma genitalium? How can we have more tests related to that and related to treatment? So, those are the most important things that I would say.

[00:53:11] Teodora: Sexual health in a positive way and making sure that we provide the quality STI service.

Catriona: I was waiting for Teo really to say that A big focus of WHO has also been.

[00:53:23] Catriona: Integration of STI services into existing health services. So this all goes back to the fact that they're marginalized, stigmatized, underfunded. and so, trying to integrate it into the broader provision of healthcare has been a really big focus. And then providing guidelines that are actually relevant and usable.

[00:53:49] Catriona: To these settings, because, you know, clearly the highest burden of STIs is in low income countries, in the regions we've just talked about in Africa and Asia and Latin America. And this is driven by many socioeconomic factors, you know, poverty, poor access to health care, low awareness of services.

[00:54:07] Catriona: sexual health and, you know, lack of screening and lack of access to drugs and everything culminates in making these regions and countries within these regions far more susceptible. then well resource settings. And then we add to that, that we see the highest burden in young people in these settings and marginalized LGBT communities.

[00:54:28] Catriona: So we definitely need to focus our efforts. In these regions, and we need to try and address these drivers, which is complex because it all relates to money and political and stakeholder engagement. it also goes to, not just integration and bringing these services into the broader focus.

[00:54:47] Catriona: Fold of the more acceptable sort of healthcare, services, but, it's education in schools, you know, and empowerment and education of women, which is enormously powerful when it comes to, not only looking after their own health, but the health of their children and their families. So it's a really big complex job that Teo spent the last 16 years trying to do.

[00:55:13] Josh: And that might be a good time to move on to just our final question for both of you, . Each of you want to leave as a message with our listeners.

[00:55:22] Josh: So Cat, you first.

[00:55:24] Catriona: BV is the new STI, a new kid on the block. So when you think BV, please don't solely focus on women. Vaginas don't occur in a vacuum most of the time. There are partners involved. So please. Think about BV, both the acquisition and recurrence as a sexually transmitted event and consider partners in your treatment.

[00:55:52] Catriona: we're currently doing studies of the LGBT community as well. So while we've got one successful male partner treatment trial, we don't want to leave anyone behind.

[00:56:01] Josh: Excellent. That's a good one for people to remember. And, last word to you, Teo.

[00:56:05] Teodora: I think my last word is that there's A lot of STIs. When you eat, you get infections when you drink, you breathe, you get infections and as infectious disease people, you treat them like any other infection.

[00:56:19] Teodora: Well, like sex, you can also get an infection. And we urge you as an infectious disease physicians and all the physicians. Treat sexually transmitted diseases as any other infection. And always ensure that there's no stigma and discrimination. Treat them with respect. And make sure that you provide people centered care. Thank you so much.

[00:56:43] Angela: Thank you so much, Teo, and Cat, we really appreciate your being here, Teodora Alvira Wi at WHO here in Geneva, her very last day, and Catriona Bradshaw at Monash University in Melbourne, Australia. What we did not do is we did not touch the question of doxycycline as PrEP, , we are leaving that, for a future episode, when.

[00:57:07] Angela: Guidelines, statements, have, been finalized. We will come back to that. We know it's a pressing question. We thank you for listening to Communicable, the CMI Comms podcast. This episode was hosted by Josh Davis in Newcastle, Australia, and Angela Hutner in Geneva, Switzerland.

[00:57:24] Angela: Editors at CMI comms open access journal. It was edited and produced by Dr. Katie Hostetler Oy and peer reviewed by Dr. Ariana Zaria from Mother Teresa University Hospital in Tirana, 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.

[00:57:46] Angela: And any literature we've discussed today can be found in the show notes. You can subscribe to communicable wherever you get your podcasts, or you can find it on Eskimo's website for the CMI comms journal. Thanks for listening and helping CMI comms and Eskimo move the conversation in ID and clinical microbiology further along.