Clinical Education Initiative MENINGOCOCCAL URETHRITIS. Speaker: Marguerite Urban, MD

Transcription

1 Clinical Education Initiative MENINGOCOCCAL URETHRITIS Speaker: Marguerite Urban, MD 9/27/2017

2 Meningococcal Urethritis [video transcript] [Intro music] 00:00:10 OK. So I have no disclosures 00:00:14 and the objectives today are to describe some recent outbreaks that have been reported in the literature of meningococcal urethritis and described the treatment and I've put up here. This is a urethral smear with PMN shown here and intracellular gram negative diplococci which is a typically a urethral smear we think of as being gonorrhea but meningococcus could look like this as well. 00:00:46 So in background I should just say if you search this and you do sort of a pub med literature search you'll find a smattering of reports but would quickly get back into like the 1960s that that you're looking at reports. But if you look in the last year you get reports and in fact I even checked this morning because they're coming up so frequently that that we're seeing new reports come out. So in background Neisseria Meningitidis is an exclusive human pathogen as I as I just mentioned it is a gram negative Diplococcus and is typically classified by serogroups is characterized by these capsular antigens. There are 13 total and most human disease are caused by the ones we're familiar with serogroups A,B,C,Y, and W135. It's the organism can be carried in the nasopharynx and occasionally will result in an invasive meningococcal disease and typically that manifests as meningitis or bacteremia. And we now have vaccines available for. A,C,Y, W135 and a separate vaccine that's now available for serogroup B. There are however some meningococcus organisms that don't express any capsular antigen. 00:02:13 If you look at studies in the past you can find documented rates of Nasopharyngeal carriage of somewhere in the 25 to 40 percent range for young people. And these studies are typically done either in military recruits settings or in dormitories in colleges and universities so generally about the same age range and in group housing type situations where we sometimes see invasive meningococcal outbreaks. There have also been studies done in STD clinics particularly in men who have sex with men and they've had similar high carriage rates in nasopharynx typically between 25 and 40 percent it there are known risk factors for developing invasive disease. And if you take board test particularly id board test this is always on there that if you have a terminal complement deficiency you have an increased risk of invasive Neisseria infection. There are some newer monoclonal,new modulators particularly, I always mess this up, eculizumab. OK. Which is Solaris is the trade name, I believe. AIDS has now been declared a risk factor for invasive meningococcal disease. Most household contact to a known case. Smoking has also been associated and some of these risk factors do inform how we choose to vaccinate and give antibiotic prophylaxis to invasive disease. And until 2016 there were very sporadic case reports of meningococcal urethritis generally in men. The prevalence estimates of urethral carriage for 1

3 meningococcus has been less than 1 percent in the 0.1 percent to 0.7 percent range before these recent reports. 00:04:13 So the first report that came out was in June This was in the MMWR and it was entitle "Increases in Neisseria Meningitidis Associated Urethritis Cases Among Men" had two sentinel clinics one in Columbus, Ohio and the other in Oakland County, Michigan. Both of these clinics participate in the CDC's Gonococcal Isolate Surveillance Project and as part of that project the first 25 male GC urethritis cases each month of culture and antibiotic susceptibility testing as part of the guest project and their procedures are that there is a urethral swab done for gram stain GC cultural susceptibility are done. And urine is obtained nat testing. In Columbus, in background, from January through November of 2014, all of their gram stain positive, so they were gram negative intracellular diplococci like that first year I showed you. They were also positive by both culture and nucleic acid amplification test for gonorrhea. Then in December of 2014, they had two cases that were gram stain positive. But the culture grew Meningococcus and that was ultimately confirmed by a PCR. And then over the next 10 months or nine months, January through December of 2015, they had an additional 52 cases of Meningococcus causing urethritis. The second site, Oakland County in Michigan, in background, had two cases of meningococcal arthritis in In 2014, they were able to identify eight cases. And in 2015, they had 15 cases. 00:06:00 So the CDC did an analysis on 52 of these isolates that were sent in from Ohio and 12 isolates that were sent in from Oakland County in Michigan. They report on the demographics in this MMWR and they were quite similar between the two locations. So in Columbus, 85 percent of the cases were African- American. They were all reported to be heterosexual. Ninety eight percent of them had symptoms. 52 percent had prior gonorrhea and 19 percent were also infected with chlamydia. 90 percent were treated with a recommended regimen for gonorrhea at the time of their visit with Ceftriaxone and Azithro. And the remainder received for the most parts Ceftriaxone and doxycycline. I think one case received Azithromycin only. In the Michigan cases, again it was similar. 00:06: percent were African-American, 93 percent were heterosexual, 93 percent had symptoms, 33 percent had a prior episode of gonorrhea. There was no typo no co-infection with chlamydia and 87 percent were treated with the recommended regimen. 00:07:16 Their median age was 30 with an interquartile 25 to 75 percent range of 24 to percent of the cases in Columbus reported oral sex although they don't detail if it's insertive oral or receptive oral sex. And 93 percent of the cases in Oakland County also reported oral sex. They had similar numbers of sexual partners two plus partners. And in Columbus they had 10 percent who reported some out-ofstate travel in the prior five days. The CDC did their analysis they were all non-groupable so they didn't fall into those A, B, C, Y or W135 categories they were non-groupable. And they were able to do some 2

4 specific genetic testing and they were identified as sequence type 11 which is part of the known clonal complex. 00:08:14 So this was a brief report and they concluded that I think I have the wrong thing on the top there. They concluded that the cases of your arthritis were caused by this clonal type sequence type 11 occurring in heterosexual men in Ohio and Michigan. They recommended using the standard antibiotic regimen for the treatment of gonorrhea. Ceftriaxone plus Azithromycin until more data are available, it was recommended to continue to treat sexual partners in the same manner as if they had been exposed to gonorrhea. Even though this was meningococcus and they asked that if there were increases in meningococcal urethritis above baseline that you report that to the CDC and they established a address shown here: nmurethritis@cdc.gov. 00:09:15 So shortly thereafter there's another report this comes out of Indiana entitled as you can see here, "Neisseria Meningitidis ST11 Complex Associated with non-gonococcal urethritis 2015 to This was fifty nine men who were involved in GC treatment trials from 2014 to Their age range was 29 to 61 and to be enrolled in the trial you had to have a purulent urethral discharge with more than 10 white cells for high power field and gram negative intracellular diplococci on gram stain. So, they were looking for real gonorrhea to do these treatment evaluations. And they found that there were four out of these 59 that were negative for gonorrhea on nat and ultimately were confirmed by culture to actually be Neisseria Meningitis. All four of those cases had both vaginal and oral exposure. One of them also had meningococcus isolated from a pharyngeal culture. They were all treated and cured with the experimental agent which isn't identified in this report. And two of the isolates had susceptibility testing and they were all pansensitive so sensitive to Ampicillin, Ceftriaxone, Levofloxacin Meropenem and Chloramphenicol. They did hold genome sequencing for those two isolates and they were consistent with that same sequence type 11 reported in the MMWR report. And they did some further phylogenetic analysis and they linked that sequence type back to a serogroup C that was first isolated in the United Kingdom in :11:02 So they were intrigued by that. And they went ahead and did a retrospective review looking for possible cases in their setting and they were able to identify groups that were gram stain positive. So they looked like they had gonorrhea on gram stain and ultimately had nat testing that was negative for gonorrhea. And they looked back for the prior four years. You can see here in 2013, they had approximately a 3 percent rate of this gram stain positive not negative. In 2014, only 1.4 percent and then a bump up in 2015 to six point nine percent. And by the first nine months in 2016, up to almost 10 percent. So sort of a similar trend to what was seen in Columbus. 00:11:55 These are the characteristics that they reported in their groups they looked at both 2015 and 2016 and you'll see here this also was a more African-American population. Seventy eight percent in 2015 and 90 3

5 percent in They were largely heterosexual, 92 percent in 2015 and 96 percent in And they reported here more detail about their sexual practices. So 89 percent insertive vaginal intercourse, 2015, 90 percent in Ninety five percent insertive oral intercourse in 2015, 88 percent in percent receptive oral intercourse and 66 percent in And you see the remainder there. 00:12:48 They looked at symptoms and they were largely very symptomatic, 100 percent had both discharge in dysuria. In 2015, 98 percent in 2016 they had similar rates of exchanging sex for money or drugs, which were quite low. They had similar rates of drug use in the prior 60 days which excluded both alcohol and IDU and approximately 50 percent in both groups. These were not statistically significant. They were all treated with fairly standard regimens for gonorrhea and appeared to all be cured. They had, interestingly in 2015 and 2016, 16 percent co-infection with chlamydia. 00:13:35 So they they note the prior prevalence estimates of being less than 1 percent and that their case characteristics seem to be quite similar to that initial MMWR report out of Columbus and Michigan. So they raise a couple of questions if if in your clinical practice if you have a presumptive diagnosis of gonorrhea because of a heavily purulent discharge and a negative nat test might you not interpret that as either a chlamydia or trihomonas infection and not really be thinking about possible meaning infection. They question could there be asymptomatic cases if really the clue to this depends on having a positive gram stain which is typically only done with urithral discharge. And they note that in their sequencing they did idenify one particularly conserved locus that was distinct from that scene in the sequence of gonorrhea and maybe that was a target where a specific Meningococcal PCR assay could be developed. 00:14:45 So then I'm going to tell you one more report. This is sort of a follow up from Columbus that was published just this summer, in July, of this same group and it does include some of those original cases that they described in the MMWR report. So they report on 75 cases in 2015 between January and November in Columbus. They all had urethral swabs for gram stain and culture. They had urine obtained for Naats for both GCM and chlamydia and they did a trichomonas culture. Their protocol was that if the gram stains suggested gonorrhea there was a presumptive GC diagnosis and treatment and the culture was then inoculated and and the treatment was given. If the culture was found to be GC,they ultimately did antibiotic susceptibilities. But if the culture was more consistent with Meningococcus it was sent to CDC for further testing. And there they did a variety of biochemical tests, PCR testing, whole genome sequencing, sliced agglutination, and some antimicrobial susceptibility to us. 00:16:01 They ended up with 76 cases that fit that criteria were they were gram stain positive, naat tests negative for GC. And 75 of those 76 were confirmed to actually be due to Neisseria Meningitidis and one of those was was confirmed to actually be GC by culture and then naat was a false negative for GC. For comparison, as we mentioned earlier, they had zero cases in the prior year during the same timeframe. 4

6 And just three cases in December before this sort of cluster started. This was sort of startling. They also had 297 that were culture positive for GC. They were all also gram stain positive and naat positive. So as a result, they had 75 of 373 gram stain positives who actually had meningococcal urethritis and that was 20 percent of their gram stains that were positive. As reported in the MMWR, they had no difference in age race ethnicity between men with GC or meningococcal urethritis. You can see here on the side, 81 percent were African-American versus 71 percent with GC. The median age was 31 with mening as opposed to 28 with GC. There was a statistical difference in that. Ninety-nine percent of those with meningococcal urethritis were heterosexual, whereas only 78 percent with gonococcal urethritis were heterosexual. 00:17:37 There were no differences in condom use, relationships status, sex with alcohol or drug use, anonymous partners or exchange of sex for money or drugs. There was a statistical difference with oral sex with a female partner with ninety nine percent of the meningococcal cases versus 73 percent of the GC cases. However, that statistical difference fell away when you only included men who had sex with women. There was no difference in urethral chlamydia infection, 15 percent of those with meningococcal infection versus 24 percent with GC. You can see there were no cases of meningococcus identified in the pharynx where there were nine percent GC identified in the pharynx. Ninety-nine percent had symptoms with a median duration of symptoms of four which was the same in both groups and both groups had a mean of two partners in the prior 90 days. 00:18:45 So they do some reporting on the characteristics of the organism and they all were non-groupable by slided agglutination. They do an rt PCR technique and they did two different methods that have been described in the literature. There was no identified serogroup by one method but the alternate method did link to the serogroup C that was similar to the phylogenetic analysis in the in the Indiana paper. They all typed the same ST11 clonal complex and they were able to do antibiotic susceptibility testing on 12 isolates and like the other report they were all susceptible to the antibiotics tested they were slightly different antibiotics in this report. Ceftriaxone, Azithro, Ciprofloxacine, Levofloxacine, Rifampin, and Trimethoprim-Sulfamethoxazole. 00:19:43 They were all treated as if they had GC and they had no treatment failures. And then just a month later they had another 47 cases. So they raised several interesting discussion points. One was why the low rates in men who have sex with men given known prior high rates of meningococcal carriage, they know that they've done no sexual partner evaluations. They've not tested women because by their protocol, there is protocol, they're only testing men. They do note that there have been some other reports that are not yet in the literature but through personal communication. So there have been some cases reported in Philadelphia. I know there have been some cases in Syracuse. And we actually have a similar rate over the last three month of approximately 20 percent of our gram stain positives in our STD the clinic being actually due to meningococcal infection. So clearly there is something happening that is new since 2015,

7 00:20:50 So, in summary, there are clusters of meningococcal urethritis beginning in about 2015 in multiple locations in the U.S. Most of the reports have been through, from sort of the central portion of the country, Midwest. To date, the presentation is described as a very frank purulent urethritis in heterosexual men. All have been responsive to standard gonococcal therapy, although there are no sort of test of cure done. But clinically, their symptoms have resolved. They seem to be due to a distinct clonal complex. There is some I guess fledgeling kind of information that this may be linked back to a serogroup C organism and that there have been some change in the organism that has resulted in its ability to adhere to the urethra. One report that I read that I didn't put into this talk, talked about the currently isolated organisms have enhanced anaerobic growth that sort of standard invasive meningococcal disease doesn't have. 00:21:59 So I guess to be aware that when you see something that looks like classic GC with frank purulent urethral discharge with a negative NAAT test that we might want to consider meningococcal urethritis as the etiology. The CDC has not sort of updated the recommendations so it is to treat as usual with regin effective against gonorrhea to continue to treat the partners with a regimen consistent with gonorrhea. It's not really invasive disease so not officially reportable but CDC is requesting notification at that same address nmurethritis@cdc.gov. I have talked with our state surveillance people and they ask that you remove that case from the GC surveillance report because it is no longer a case of gonorrhea. 00:22:51 And you know I think there will be much more research about this organism coming out in the future. 00:22:59 Here's a brief bibliography and we'll end up posting this slide set. So you'll be able to see that. 00:23:06 There is our organism again. [Video end] 6