CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
Unlike chlamydia, M. genitalium is not reportable, so there is less data. “With chlamydia, we have surveillance data we can track over time,” she says, “and we’re not able to do that with M. genitalium. That said, in the general population, the prevalence of M. genitalium is one to three percent, a little less than chlamydia,” at four percent, but more than twice as common as gonorrhea.
In high-risk populations, the prevalence of M. genitalium can be high, she says, comparing the organism with HIV. “With HIV, people are virtually at an infinitesimally small risk of HIV in a low-risk population, but in higher-risk populations like highly sexually active people with a high rate of partner change, the prevalence can be high—in the case of M. genitalium, as high as 16 to 20 percent, which in some recent studies would be higher than the prevalence of chlamydia.”
To Dr. Manhart, that finding suggests the prevalence may be increasing because the effectiveness of treatment has diminished due to antibiotic resistance. In fact, in an important way, M. genitalium is more like gonorrhea than chlamydia: “Gonorrhea develops resistance to almost every antibiotic you treat it with, and that’s what we’re seeing with M. genitalium.”
The M. genitalium bacterium lacks a cell wall, and because a number of antibiotics work by damaging the cell wall of bacteria (penicillin, β-lactams, glycopeptides), that entire class of antibiotics is not going to work, Dr. Manhart says. “But the greater concern with M. genitalium is that it has a fairly high mutation rate. People get infected with an entire population of organisms and some have a variety of different mutations. And there are single point mutations that confer almost complete resistance to one of the primary antibiotics that is used as syndromic treatment for reproductive tract infections: azithromycin. That is where we are seeing huge emergence of high levels of resistance—in the U.S., probably on the order of 50 percent or greater, depending on your area.”
Dealing with this development has required creativity, Dr. Manhart says. “Some companies have included detection of mutations for the macrolide class of antibiotics in their diagnostic assays. That tells you whether the infection would be susceptible or resistant to azithromycin.” If resistance mutations are detected, the provider can prescribe the more potent broad-spectrum drug moxifloxacin, which is the recommended second-line therapy. If no resistance mutations are detected, the provider can still use azithromycin. M. genitalium has already begun to show resistance to moxifloxacin, she says, so less frequent use will slow that process.
In the U.S., Dr. Geisler notes, the three main classes of antibiotics used to treat M. genitalium are tetracyclines, macrolides, and quinolones. His recent retrospective studies at the University of Alabama looked at testing of HIV-infected men who have had sex with men and testing of a heterosexual population enrolled in a sexually transmitted disease clinic in Birmingham (Dionne-Odom J, et al. Clin Infect Dis. 2018;66[5]:796–798). He found that more than 70 percent of infected men had M. genitalium strains with evidence for macrolide resistance and more than 20 percent had strains with evidence for both quinolone and macrolide resistance. “In the tetracycline class, doxycycline is not a very good antibiotic; it cures only 30 to 40 percent of infections. In the macrolide class, azithromycin historically was a good antibiotic, but now cure rates for M. genitalium urethritis are below 50 percent.”
In sum, he says, “We found that the resistance, even in Alabama, is high enough at this point that we have some patients we might not be able to effectively treat with the antibiotics we have available in the U.S.” Newer antibiotics available in Europe and elsewhere outside the U.S. appear to be effective against M. genitalium. Pristinamycin, made in France, is one example. “But you can’t get it here unless you go through the FDA to get it imported and have special circumstances.”
Dr. Geisler’s findings are concerning, Dr. Manhart says. “Macrolide resistance correlates very well with treatment failures. We know when people have detected macrolide resistance, they probably are not going to be cured if they’re given azithromycin. For quinolone resistance, the mutations have been less consistently correlated with treatment failure.”
A couple of studies already in the literature have demonstrated this inconsistent correlation of quinolone resistance-associated mutations and treatment failure, and a forthcoming UW study has also shown this, she says. “So clearly we don’t know the significance of those mutations for quinolone resistance. In some cases, treatment failure results—but not always. We have a little more work to do to understand which mutation—and maybe it’s more than one—and how the mutations actually result in failure of moxifloxacin to cure the infection.”
“I would say we’re at the tip of the iceberg stage, meaning there will be much more demand for M. genitalium testing in the future, and depending on where you are, pairing it with some type of resistance detection, at least of macrolide resistance, will be important.” In Seattle, she says, “Our level of resistance is already so high that it would not be of benefit to detect macrolide resistance, because most already have it. We would just go immediately to treating them with another antibiotic. But in other places where resistance is lower, it would be important to be able to do both: detect the organism and detect whether there was macrolide resistance.”
Specimen collection with M. genitalium, as with any STI, has its complexities, Dr. Manhart notes. “I think most of the forthcoming M. genitalium assays can use urine specimens, and that’s great, because those are easy specimens to obtain, particularly for men who don’t want to have a urethral swab. Self-obtained vaginal swabs, where a woman collects the specimen herself, are the best specimen for women.” The assays are versatile: “They perform well on urine, vaginal swabs, cervical swabs, or urethral swabs.”
Less work has been done to validate oropharyngeal sampling and rectal sampling for M. genitalium, Dr. Manhart says. “Those are sites that are frequently sampled when you are looking for STI pathogens like gonorrhea or chlamydia. There’s been less work done to validate them on M. genitalium, but I’m certain that’s on the horizon.”
How much female reproductive sequelae does M. genitalium cause? That is the million-dollar question, Dr. Manhart says. “A number of public health authorities feel we don’t know how important M. genitalium is until we answer that question.” The thinking is, “If it doesn’t cause infertility and adverse reproductive health outcomes, then maybe it’s not such a big problem.”
‘We found that the resistance, even in Alabama, is high enough at this point that we have some patients we might not be able to effectively treat with the antibiotics we have available in the U.S.’ — William Geisler, MD, MPH
CDC guidelines set the standard of care, and the CDC does not recommend screening now at the national level because there is not yet consensus about M. genitalium causing reproductive complications, so that often means an insurance company might not cover costs for M. genitalium testing, Dr. Geisler notes. “But even the CDC says certain individuals do warrant diagnostic testing if there is access to the test, particularly men with recurrent or persisting urethritis. If you have access to a commercial lab with a test that is validated, CDC does recommend that you think about doing diagnostic testing in that setting.”
To resolve some of the open issues, Dr. Geisler says, sometimes only retrospective studies of data collected for routine care are practical, because finding money to fund a new prospective study in which people are enrolled is difficult. Once a commercial test is approved and people start using the assay more, better research can be done. “Right now we don’t have enough testing going on, so we don’t have access to a lot of the data we need.”
Even though there is still much to learn about the epidemiology of M. genitalium, Dr. Geisler says, “we’re already losing time with resistance, and we need to move past just focusing on epidemiology studies and need to start investing more in testing and treatment strategies.”
“We may be entering an era where we won’t have drugs to treat this infection. We need a new drug in the U.S. to treat M. genitalium because of the resistance. That means either clinical trials of drugs already being used outside the U.S., which takes time and money, or having discussions with the FDA about a process to bring drugs already studied and used outside the U.S. into the U.S.”
The second priority, he says, is research to start development of a vaccine. “You can’t develop a vaccine if you don’t understand how the body fights the infection, and here we really don’t understand that or what M. genitalium proteins we might want to target for vaccine development. But unfortunately, so far there is very little research contributing to vaccine development.”
Dr. Manhart believes it could be 12 to 18 months before the FDA approves one of the two M. genitalium tests pending at the agency. Dr. Geisler, too, estimates approval sometime before the end of 2019. But in Europe, all kinds of M. genitalium tests are approved, Dr. Manhart notes. The Hologic and SpeeDx tests have a CE mark, along with a number of others. Testing and treatment guidelines for M. genitalium have been released in Europe and Australia, most recently by the British Association for Sexual Health and HIV, which published guidelines in July. “So other places in the world, for the last couple of years, have had much better access to M. genitalium testing than we do,” Dr. Manhart says.
The U.S. won’t be far behind, Roche’s Dr. McGowin says. “At some point in the near future, M. genitalium tests will be widely available that are FDA approved, and ideally there will be guidance from the CDC on how often we should screen for the pathogen.”
Anne Paxton is a writer and attorney in Seattle.