Guidelines vary, but be careful what you look for.
Don’t test asymptomatic patients, because then you’ll have to treat them.
That was one of the messages delivered at a 7.30am session of the International Union against Sexually Transmitted Infections (IUSTI) conference in Sydney last month.
“We think that the 11th commandment is thou shalt not screen people for m. genitalium,” said Professor Lisa Manhart, epidemiologist from Washington University.
“Despite the fact that we do see these relatively consistent associations with upper reproductive tract sequelae, we still really don’t have great natural history data to show that m. genitalium causes the syndromes, and we have absolutely no data demonstrating that we can reduce the sequelae by screening,” Professor Manhart said.
“The other leg of this rationale for the 11th commandment is antimicrobial resistance. So the more testing we do, the more infections we find, and the more we treat, and that results in additional antimicrobial pressure, which is likely to result in even more resistance.”
Another key message is that the guidelines differ globally, depending on availability of testing and antibiotics, “and” (dramatic pause) “politics”, Dr Jørgen Jensen, from the Statens Serum Institut in Denmark, told delegates.
And that’s why, even though the guidelines are based on the same evidence, they can give the opposite recommendation.
M. genitalium is a known cause of urethritis and it’s associated with cervicitis, PID, infertility, pre-term delivery and, most recently, low birth weight. However, there isn’t a huge amount of evidence and the consequences of asymptomatic infection are unknown. In Australia, the prevalence of infection is 1-4% in the general community, 9.5% in men who have sex with men, and 1% in women.
Antibiotic resistance is the big issue in treatment of Mycoplasma genitalium, and there are a growing number of untreatable cases, conference delegates heard. Globally, about 33% of infections are macrolide (azithromycin)-resistant, 13% are quinolone-resistant and around 6.5 are resistant to both classes of drugs. Macrolide resistance in Australia is high, exceeding 60% in most cases and 80% in men who have sex with men, according to the Australian STI management guideline.
To test or not to test?
The Danish and American experts presenting the session – titled Testing for Mycoplasma genitalium: when and whom? – explained that the overall aims of guidelines around the world were the same (to identify infections that needed to be treated and to limit antimicrobial use to those who would benefit from it) but the answer depended on where you were.
Australia does not recommend asymptomatic testing, other than for ongoing sexual contacts of men who have sex with men who test positive for M. genitalium.
The Australian STI guideline lists “acute, persistent and recurrent non-gonococcal urethritis; cervicitis; pelvic inflammatory disease; post-coital bleeding; ongoing sexual contacts of M. genitalium infection” as “clinical indications for testing” and under “special considerations” notes “Ongoing sexual contacts, even if asymptomatic should be offered testing”.
In addition, the Mycoplasma genitalium treatment guidelines say testing should be considered prior to pregnancy termination, in proctitis, balanoposthitis and sero-reactive arthritis.
UK and European guidelines do not recommend asymptomatic screening of men, Dr Jensen and Professor Manhart explained. Canada and the US recommend it when there is recurrent non‐gonococcal urethritis (NGU). The UK guidelines say to consider testing for M. genitalium in cases of acute epididymo-orchitis in those under 50 (not the US, Canada, Europe or Australia) or proctitis after excluding N. gonorrhoeae and C. trachomsitis. Everyone with symptoms of proctitis should be tested in the US too except for those with extragenital symptoms. Contacts should be tested and treated if positive. Canada says go ahead and treat contacts without testing.
In women, the main difference in recommendations is around pelvic inflammatory disease. Europe strongly recommends testing, partly based on Australian research showing one in 10 women with PID had M. genitalium, whereas the US only recommends consideration.
Acute urethritis is another good example of differing recommendations. Testing in the US usually results in a finding of chlamydia, said Professor Manhart, whereas in recurrent cases it’s usually M. genitalium. Furthermore, in the US acute urethritis is treated with doxycycline and this cures 30-40% of M. genitalium cases, with no need for further treatment.
“In Europe, we recommend testing upfront, and this is based on a lot of studies showing that M. genitalium is clearly associated with acute urethritis,” said Dr Jensen.
“The second thing is that we know that if we fail to eradicate M. genitalium, we will have a high risk of recurrent urethritis … In those that are coming back, especially if they’re coming back after doxycycline treatment, as many as 50% will have M. genitalium, so we consider that diagnosing the patient up front will save healthcare cost, because we can treat the patient appropriately at first presentation.”
A third of the roomful of early-bird attendees indicated on their conference voting app that they would test people with acute urethritis. Half said they would only do so for recurrent infection. Around 7% said they didn’t know what they would do.
The US guideline recommendations on testing with acute cervicitis are unclear. “But I think most people interpret the guidelines as saying it really only should be performed in cases of recurrent cervicitis and the rationale for this is that the relationship between M. genitalium and cervicitis is less robust,” said Professor Manhart.
Delegates laughed when Professor Jensen immediately followed with, “In Europe, we use exactly the same evidence to say that you should test because there is an association.” Around 40% of them had voted for this option, with a small majority taking the US line of waiting for recurrent cervicitis to test for M. genitalium.
CDC guidelines don’t recommend testing for extragenital symptoms (rectal and oral pharynx). The Europeans did recommend it, but have amended their guidelines due to microbial resistance that saw “huge issues” with treatment failure, said Dr Jensen. Now it’s only where other aetiologies are excluded.
“So that’s sort of giving up and saying we cannot really use that much antimicrobials on most commonly asymptomatic carriers. And we have the same statement about oro-pharyngo testing.”
Guided cure
Managing a patient based on knowledge of antimicrobial resistance is the holy grail of M. genitalium treatment. Australian guidelines recommend running macrolide resistance assays, noting an improvement in first-line treatment from 60% to 90% when treatment is guided this way.
Voting results at the conferenced session showed that 70% of delegates had access to resistance testing and were able to use it to guide treatment.
“Not many people from the United States in the room,” Professor Manhart noted. Perhaps surprisingly, there isn’t widespread availability of testing in the US, although some large commercial laboratories were starting to make it available, she said.
Australia does have testing, strongly recommends it and provides guidance on treatment based on testing. However, “without access to resistance testing, it is reasonable to assume macrolide resistance is present in infections persisting after failure of azithromycin and in men who have sex with men, where macrolide resistance exceeds 80% in most urban settings in Australia,” the STI management guideline says.
“MG already treated with azithromycin on the same day as they were tested may be cured but confirm this with a test of cure 2-3 weeks later. If treatment fails, resistance is likely, particularly if reinfection is unlikely. Clinicians with no access to resistance testing can assume resistance in azithromycin treatment failures.”
In addition to avoiding more microbial resistance and shortening the length of infection, it also avoids unnecessary side effects, said Dr Jensen. “Moxifloxacin comes with a label that is really worrying for the patients, so we definitely want to limit [its] use … as much as possible.”
Moxifloxacin is not approved for treatment of M. genitalium in Australia. It can be prescribed off-label and costs over $70 for five tablets on a private prescription.
Europe also recommends parC-based resistance testing after moxifloxacin treatment failure “to reserve third-line antimicrobials for patients with documented … resistance” – but “not up front” said Dr Jensen. “Not all mutations are equally important, and again, we don’t have good treatment alternatives, so testing up front would be really a disaster.”
Test of cure
Europe recommends testing for cure; the US does not. The Australian STI guideline states: “A need for a test of cure should be informed by presence of ongoing symptoms and/or ongoing risk of reinfection or sequelae.
“Test of cure by NAAT [nucleic acid amplification test] should not be done earlier than 14-21 days after treatment is completed. Test of cure before this time can result in false positive results.”
Meanwhile, the M. genitalium guideline says “Test of cure is important in managing MG because of the risk of persisting, asymptomatic, resistant infection. Test of cure should be performed 2-3 weeks after completing all antimicrobial therapy.”
Some patients will continue to have a positive test of cure. What then? “It depends on why,” said Dr Jensen. If you’ve already tried a third line of treatment, “I would think your options were almost out,” he said.
“Then they just have to appreciate that they are asymptomatic, because we don’t have anything to offer them. In those that are highly symptomatic, you can consider long-term suppression therapy with doxycycline, but it’s not a good option because it’s not eradicating the infection. It’s just keeping the symptoms away.”
When the testing horse has bolted
“My heart sinks when I get a referral for an asymptomatic patient who’s got a positive m. gen,” a Brisbane doctor said in the Q&A session. (Sympathetic sounds from the crowd.)
“I try to say, ‘this is probably not worth treating’ and the patient says ‘I’ve got a sexually transmitted disease, I want treatment’.”
It was a great point, said Professor Manhart. “Once we know, we can’t do nothing. The patient is demanding it.”
Professor Jensen said they had the same problem in Denmark. “I don’t know how we can diminish this issue, but I think it’s really an issue. And we also think that if you have diagnosed it then you have to treat it. It would be very difficult and maybe unethical not to do that.”
