147. Guarding against Gardnerella

Healthy genitals: a good idea? Come listen to our episode on Gardnerella and find out! 

Fellas this includes you, don't skip. 

Transcript

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Jame 0:18

Callum, how are you doing?

Callum 0:20

Great. It's a sunny day. I'm looking out at my tiny, tiny garden. My gardener's out there. I recently hired her. Ella. Oh, hi Gardener Ella.

Jame 0:33

And what a coincidence that is, Callum, because what are we discussing today?

Callum 0:37

We're talking about Gardener Ella.

Jame 0:39

Gardnerella vaginalis and other Gardnerelli as they come up. you know anything about this, pathogen before we...

Callum 0:48

well, not very much. I think by the end of this I'm going to, and you are, dear listener, going to know more about Gardenerella than you ever thought there was to know., Unless you knew more than us already, in which case, please write in and tell us what we get wrong. Jane, what is Gardenerella?

Jame 1:05

Glad you asked, Callum. Gardnerella is a species of gram-negative bacteria discovered in 1955 by American bacteriologist Herman Gardner. There are six species in total. type species is vaginalis, which is the one that everybody else will have heard of. And Callum, we would be remiss if we didn't do a Callum and Jamie alternately read the names of the things at this point.

Callum 1:27

Beenwoodii.

Jame 1:29

Leopoldii.

Callum 1:31

Picetti i.

Jame 1:33

Vagioti.

Callum 1:37

Swedzinski i.

Jame 1:40

That's why I went first, it is a facultative anaerobe, and it is gram variable, in its staining. Callum, tell us about the epidemiology here. Where, where would I find Gardnerella should I want to go looking?

Callum 1:54

this is, something that we don't necessarily try and culture, certainly not my local laboratory, but it is an organism that is found in the vagina and is a commensal organism, And finding it doesn't necessarily mean that you've got a problem, and about fifty percent of the time, it will be there. the, microbiota of the, vagina, is quite complicated, and changes, throughout life., I went to a talk recently about mi- microbiome, and pre and post-menopausal women it changed a lot, so I presume that's pre-pod- pre-menopausal healthy women.

Jame 2:26

yes.

Callum 2:26

Yeah. And why are we talking about Gardnerella?

Jame 2:30

it was the next thing to prep in the series.

Callum 2:32

Well, the, the reason we're talking about it, I guess, is as James said, we're doing all bacteria, and this is the next one on the list. But the reason it's on the list, I guess, is that in humans it's associated with bacterial vaginosis associated being the emphasis, because we know that it can be there and you might not have bacterial vaginosis. So BASH, they've got 2012 guidance on bacterial vaginosis. And they say that the prevalence is about 5% in what they call asymptomatic college students. Come back to that. 12% in antenatal women in the UK and about 30% in women undergoing termination of pregnancy. Which I presume those numbers just come from the studies that have been done in those populations. And the, you know, the microbial diversity of the vagina is really important. You know, lactobacilli are extremely important for lots of things in terms of having a, a healthy microbiome.

Jame 3:24

Yeah, and, actually there's been some recent research on microbial diversity in BV patients versus non-BV, and the presence of three or more Gardnerella species is more commonly associated with bacterial vaginosis. It's seen more in BV patients, about 90% versus 30% of BV negative. So that kind of microbial diversity, this idea that this is polymicrobial I think is well evidenced there. Do you find it anywhere else, Callum?

Callum 3:58

My understanding is it can transiently colonize the, the penis, but I don't think it's that important.

Jame 4:06

Yeah, I don't think so, except as a transmission mechanism.

Callum 4:09

Yeah.

Jame 4:09

What are the talking a little bit more now about bacterial vaginosis itself. So this is not necessarily all applicable just to Gardnerella. But what are the risk factors of bacterial vaginosis?

Callum 4:23

Yeah, so vaginal douching, so cleaning out stuff that shouldn't be cleaned out. Receptive cunnilingus. I presume that's because the oral microbiome interferes? Presence of any sexually transmitted infections, so chlamydia, herpes, et cetera. Change of sexual partner. Black race. And smoking and presence of an intrauterine device. So Jame, how do, how does the Gardnerella actually cause a problem?

Jame 5:00

Bit of difficulty finding the details of this actually, but they've got some pathogenic mechanisms. There are type IV pili, um, Stuff here in the pathogenic mechanisms that I don't think we need to really over in detail.

Callum 6:27

Yeah. So lactobacilli, make the pH of the vagina low, and if the pH of the vagina isn't low, then organisms grow more readily, including Gardnerella and then a, a long list of other bacteria that I guess are associated to BV as well.

Jame 6:43

Yeah.

Callum 6:44

Yeah.

Jame 6:44

if you've... The, the normal healthy vagina would have lots and lots of lactobacilli, and the BV vagina would have low levels of lactobacilli and lots of other species, including Gardnerella and Peptostreptococcus, Bacteroides, like other anaerobes, and a bunch of other things that we've,

Callum 7:02

Yeah.

Jame 7:03

Included in the prep notes there.

Callum 7:05

And I guess if like, you know, the, the newer molecular and sequencing techniques, we're getting much more information about some of these organisms that are quite, you know fastidious and difficult to culture. So I imagine that there'll be a lot of you know, new understanding of the, the situation that's going on.

Jame 7:21

Yeah.

Callum 7:21

So yeah, clinical syndrome, so you know, bacterial vaginosis, BV. Other organisms that would be associated with that might include Prevotella, so an anaerobe Mycoplasma hominis and Mobiluncus species, which I've never heard of before

Jame 7:36

No, no, me neither. But these bugs are replacing Lactobacillus and, and this results in an abnormal discharge and an increased association with late miscarriage, preterm birth, premature rupture of membranes, and postpartum endometritis. And the, the main symptom though is this thin white discharge with a fishy odor. There's generally no symptoms of pain, itch, or irritation, so if they are present, then It is likely to be something else and you should go looking for something else. This is mostly dealt with by sexual health clinics and about 50% are asymptomatic. differential of an abnormal vaginal discharge would be candidiasis, trichomoniasis and cervicitis, which again, sexual health clinics are best set up to deal with. And then very rarely with Gardnerella genus, there have been some case reports of discitis and vertebral osteomyelitis, septic arthritis, bacteremia and a retinal vasculitis.

Callum 8:39

This is a very common clinical syndrome as we heard from the prevalence above and, you know, a lot of patients will be seeing their general practitioner

Jame 8:46

about

Callum 8:46

or, you know, community health, healthcare professionals before getting to sexual health. And I think the vaginal douching is quite a social media-driven phenomenon. So certainly this is probably increasingly prevalent.

Jame 9:00

And if people want more details on that, you can see our episode biocide bashing that we did with Natalie Bennett a few months ago. Cal, why don't you take us through the microbiology?

Callum 9:12

Yes. So the main reference for this is the SMI, the syndromes of microbiological investigations number six, infectious syndromes affecting the genitourinary tract. And essentially you know, I guess what we're trying to say is do you or do not have bacterial vaginosis? But we're just gonna talk through a little bit on Gardnerella first. So you might be able to culture this from a vaginal swab and you usually take some vaginal fluid for a, a, a microscopy and gram. The bacteria itself, it's small it's coccobacillary usually about 1 to 1.5 micrometers in diameter. It doesn't form spores, and it's non-motile. It should grow on a normal blood agar quite readily. And they're sort of small convex gray colonies on blood agar. The species ID, so there are commercial PCRs available. But the SMI specifically states you shouldn't be basing a diagnosis of bacterial vaginosis on the detection of Gardnerella by molecular technique like PCR. Because it's, you know, can be there and the patient might, you know, they might not have any symptoms. They might not have actually bacterial vaginosis. So I guess one of the things is about saying what the, the kind of burden of Gardnerella is. In the SMI, they have a diagnostic algorithm, which is in the, the prep notes here. And essentially it's patient presents with discharge or discomfort. And they suggest doing tests for the STIs that we talked about earlier on doing a microscopy for vag- bacterial vaginosis, and then a sort of just a general fungal, bacterial culture. And to diagnose BV, it's not really that based on Gardnerella. There's a couple different criteria. So locally we've-- I've heard of the Amsels and the Nugent criteria, but I haven't heard of this Hay-Ison criteria, which Bash recommend as well. James, do you want to take us through this? That you

Jame 10:57

Yeah, let's do Amsels 'cause it's easier. So at least three of four criteria need to be present for the diagnosis to be confirmed, and those four symptoms are white homogenous discharge, cells on microscopy of wet mount, a vaginal pH of greater than 4.5, and the release of a fishy odor on adding alkali, which is 10% potassium hydroxide to the sample. And the Hay-Ison criteria are a bit different 'cause they're actually looking at the preponderance they're, they seem to be pathological criteria,

Callum 11:37

Yeah. And the clue cells just for a quick reminder, are vaginal epithelial cells which are sort of surrounded, like, by bacteria. So the cells look kind of a hazy stippled appearance under the microscope. It's a bit of an art to do that. I think UK NEQAS do the e-external quality assurance scheme in UK. They, they run some questions about this, and it was interesting looking at results of that recently from our lab because I think we look for clue cells, but not necessarily every lab does, and there was quite a variance in results. So I think the, the lab techniques for this are probably gonna change in the next five years to be a more molecular based, you know, you're gonna get a profile of your microbiome and move towards more saying like, "Okay, actually, you've got too much Gardnerella and you've got not enough lactobacillus, so we're gonna, we're gonna treat."

Jame 12:20

Yeah. Okay. This next bit we've got is about treating bacterial vaginosis,

Callum 12:26

Oh,

Jame 12:35

a good hard think about what to do. But let's talk about treating BV in general. So

Callum 12:43

sorry, the thing on RefHelp about it.

Jame 13:33

from treatment before 20 weeks of

Callum 13:35

Hmm. Hmm.

Jame 13:36

So remember, it's associated with preterm labor, so we want to try and reduce the risk of that happening. And what we'd use to treat it, you would give oral metronidazole, and there's two regimens really. You can give two grams stat, or you can give four hundred milligrams twice daily for five to seven days. So quite a wide range there. And I wonder actually if g- taking two grams stat, you know, that's only five metronidazole tablets a oner, might just be a bit more convenient. Be interesting to know what sexual health clinics tend to advise if they do the stat dose or the five to seven-day dose. And there are some topical or gels that you can use. There's metronidazole naught point seven five percent gel applied once daily for five days, and there's clindamycin two percent cream, which you can give once daily for seven days. That is much more expensive than the metronidazole gel, however. And in terms of other things that you could use, you, if you can get your hands on it, you can give oral tinidazole, two grams stat, and you can also use clindamycin three hundred milligrams twice daily for seven days. So quite a low dose of clinda only given twice daily, so not what we would normally do, but that's what's in the BASH twenty twelve guidance.

Callum 14:47

Just on the stat versus seven days, our local guidance say that the longer duration course is associated with a lower rate of relapse. But I guess you're balancing that against the,

Jame 14:59

Potentially.

Callum 14:59

convenience of it.

Jame 15:00

have a 70 to 80% cure rate at the four-week mark. But let's now talk about something new, which is not mentioned in the BASH 2012 guidance, which is treating the partner.

Callum 15:12

Yes. I, I think in our local guidance we have a statement about, potentially treating the partner with topical and, and systemic therapy. But it specifically says it's not routinely done, just if it's recurrent.

Jame 15:25

I in the future probably routinely be done after the first, say the first recurrence,

Callum 15:32

Yeah.

Jame 15:32

they've got

Callum 15:33

Okay

Jame 15:33

a stable sexual partner. the evidence of this trial, which was published in NEJM last year, is really impressive. And actually, the entirety of episode 29 of the Communicable Podcast, which is of course our rival podcast from CMI Communications goes into this trial in extensive detail. It's about an hour and something, but it's, it's totally worth a listen actually. It was, it was great.

Callum 15:59

Hour-long podcast episode. That's far too long. I would never listen to a podcast that does an hour-long episode. It's terrible.

Jame 16:05

know. I know. Can you imagine? is starting to drag on a bit as well, actually.

Callum 16:11

Yeah.

Jame 16:11

you want to tell us a bit about the trial?

Callum 16:14

Yes, So the PICO, so the population was 81 couples assigned to the intervention versus 83 assigned to placebo. And intervention was essentially comparing treating male partners with metronidazole for seven days and also topical clindamycin cream, which is very expensive, to the glans penis and the upper shaft and also under the foreskin if they were uncircumcised, and that was for seven days as well. And the comparator was just placebo pills. But there was no placebo cream. So I guess it's not completely blinded. Well, it can't be blinded.

Jame 16:49

cream that doesn't have anything in it, but they didn't want to kind of mess with that, so they thought better to leave it alone.

Callum 16:56

And then the outcome essentially the primary outcome they were looking at was recurrence of bacterial vaginosis, and that was defined by either at, at least... Sorry the both, the presence of at least three Amsel criteria and a Nugent score of four to 10 within 12 weeks. So using those same criteria that we mentioned earlier on. The secondary outcomes they were looking at was early recurrence within four weeks and then some other scores, and also some vaginal microbiota outcomes. And what were the results?

Jame 17:27

The results were that it was stopped early for benefit. BV recurrence at 12 weeks was in the active treatment group versus 63% in the control group, and the mean time to recurrence was much longer in the active treatment group, 74 days versus 55 days in the control group. So an overwhelming success and kind of confirms what people were suspecting for many years actually, which is that BV is a sexually transmitted infection. just not that you're transmitting one pathogen, you're transferring a colony of pathogens and increasing the likelihood that you're going to disrupt the vaginal microbiome and result in symptoms. It's a really cool trial and a really nice kind of evidence that treating the partner is important in BV. And I think Bash, they're gonna update this guidance eventually, going to recommend partner treatment at that point. Maybe with the caveats that you said.

Callum 18:29

Yeah, 'cause I guess it's interesting that we're, you know, using this quite, you know, the systemic metronidazole angle. Like, ideally, if I was to design the optimal treatment for this, I'd want something that,

Jame 18:40

Yeah.

Callum 18:48

Necessarily disrupting my gut microbiota. We're talking about dysbiosis and, you know, you know, and C. diff as well,

Jame 18:56

Hmm.

Callum 18:57

with fecal microbiota transplant. You know, we're saying there's a dysbiosis, an imbalance of the bacteria in a certain biological niche, and the treatment is to kill the bacteria and give more antibiotics. Like, it doesn't really make sense, does it? So

Jame 19:09

not

Callum 19:25

I, I'm not sure exactly the, the evidence base behind all of those,

Jame 19:29

faced

Callum 19:29

Although I'm sure Tash, if she's listening, will be eagerly writing in to tell us.

Jame 19:34

I'm sure she'll be screaming at her podcast app

Callum 19:38

So, you know, I g- I guess the, the future is exciting in this field

Jame 19:44

A couple more bits. So in terms of breakpoints and resistance mechanisms, so we don't have any

Callum 19:49

Right.

Jame 20:09

so.

Callum 20:09

Should other frees don't really matter, do they? Don't

Jame 20:58

reference. And that, Callum, is that. I think. for further reading, uh, the BASH 2012 guidance, particularly if uh, working in the UK. And I hate to say it from our nemesis podcast, episode 29 of the Communicable episode, if you don't want to read the paper itself that it's based on, would be, good further reading, for this. And at the end of that, you will know more about Gardnerella than you ever needed To know.