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M. genitalium demands new STI treatment strategy.


VIENNA--Mycoplasma genitalium is a new bad boy of sexually transmitted infections, prompting experts to rethink how to treat nongonococcal urethritis, pelvic inflammatory disease, and other infections caused by the pathogen.

The full scope of M. genitalium in sexually transmitted infections (STI) of men and women is just now becoming clear--as are the treatment demands of M. genitalium's susceptibility profile.

Given that it's notoriously hard to culture and that genetic-based assays are only recently available and not yet sold commercially, reliable management of M. genitalium depends on the fluoroquinolone moxifloxacin. Yet the threat of widespread resistance to that drug looms, with no good back-up agents currently available.

Because successful treatment of M. genitalium differs sharply from that of gonorrhea and Chlamydia trachomatis--the other two pathogens most common in urethritis, cervicitis, and pelvic inflammatory disease--clinicians increasingly confront infections unresponsive to or persistent despite a course of doxycycline or azithromycin (Zithromax).

Podium talks from a series of researchers in the United States and Europe at the joint meeting of the International Society for Sexually Transmitted Diseases Research and the International Union Against Sexually Transmitted Infections documented the STI niche that M. genitalium occupies and how well various antibiotics work against the pathogen.

"M. genitalium is associated with 15%-22% of nongonococcal urethritis cases, and 10%-15% of cervicitis cases, and in many settings is more common that Neisseria gonorrhoeae with treatment outcomes often far worse," said Lisa E. Manhart, Ph.D., an epidemiologist at the University of Washington, Seattle. "There is no characteristic clinical syndrome for M. genitalium infections; they look very similar to Chlamydia. Clinical judgment is the only option for treatment decisions in many settings, and no FDA-approved diagnostic test [for M. genitalium] exists."

Persistent cases of nongonococcal urethritis, cervicitis, and possibly pelvic inflammatory disease could benefit from treatment with moxifloxacin (Avelox), Dr. Manhart noted. But "it is becoming clear that resistance in M. genitalium develops rapidly"

"M. genitalium is an important STI, and guidelines should reflect this; but there is no good evidence base for optimal treatment. Optimal treatment is a moving target," said Dr. J[empty set]rgen S. Jensen, a researcher at the Statens Serum Institut in Copenhagen.

"Widespread use of azithromycin and moxifloxacin will select for multidrug-resistant strains; the time for single-durg, one-dose regimens is probably over," said Dr. Jensen, specifically referring to the common practice of treating nongonococcal urethritis with a single dose of azithromycin.

M. genitalium invades U.S.

Dr. Manhart and a second U.S. researcher, Dr. Harold C. Wiesenfeld from the University of Pittsburgh, each reported new data at the meeting showing how common M. genitalium STI infections have become among U.S. patients.

Dr. Manhart presented new data from the MEGA (Mycoplasma Genitalium Antibiotic Susceptibility and Treatment) trial, which enrolled 606 men with nongonococcal urethritis (NGU) at an STI clinic in Seattle. The study's primary endpoint was a comparison of 100 mg doxycycline b.i.d. for 7 days and a single 1-g dose of azithromycin.

The two regimens produced similar cure rates--76% in the doxycy-dine arm, and 80% in the azithromycin arm, Dr. Manhart and her associates reported earlier this year (Clin. Infec. Dis. 2013;56:934-42). The initial report also identified M. genitalium in 13% of those men--identified using an in-house polymerase chain reaction assay--compared with 24% who tested positive for Chlamydia and 23% infected with Ureaplasma urealyticum biovar.

The new analyses Dr. Manhart reported tracked the outcomes of patients infected with M. genitalium. Treatment with either of the standard doxycycline or azithromycin regimens failed about half the time, Dr. Manhart said: 29% of men with doxycycline-resistant infections who were retreated with azithromycin as part of the study's extended protocol carried M. genitalium, and 70% of the men who failed initial azithromycin treatment who were then retreated with doxycycline had persistent infection with M. genitalium.

The full results suggest that moxifloxacin is potentially effective for treating various persistent STIs, not only NGU but also cervicitis and possibly pelvic inflammatory disease (PID). But resistance to moxifloxacin develops "rapidly," meaning that surveillance for resistance is needed, as well as new drug alternatives, she said.

New suspect in acute PID?

Although Dr. Manhart hedged on the role of M. genitalium in PID, results from a different U.S. study created a strong case for a role in acute PID.

M. genitalium appeared in 28 (18%) of 157 diagnosed women with acute Continued on following page PID who were enrolled in a study that had primarily focused on comparing two antibiotic regimens, and in 30% of those women with histologically proven acute PID. Using an in-house transcription-mediated assay for M. genitalium, researchers at the University of Pittsburgh found that endometrial identification of M. genitalium linked independently with a fourfold increased prevalence of histologically confirmed acute PID.

Those numbers for M. genitalium put it in the same ballpark in the study with the two traditional heavy hitters of acute PID, N. gonorrhoeae and C. trachomatis. By establishing a significant role for M. genitalium in acute PID, the data immediately called into question the standard empiric therapies for acute PID.

"The PID treatments we use fall short for eradicating M. genitalium," said Dr. Wiesenfeld, an ob.gyn. and infectious diseases physician at the University of Pittsburgh, who reported the results. "Whether these findings [affect] treatment guidelines for acute PID remains to be seen; but if it is truly important to treat M. genitalium, it will completely turn around our treatment regimens."

The looming dilemma is that the azithromycin or doxycycline used for gonorrhea will not stop many of the infections by M. genitalium, while the moxifloxacin that can handle most M. genitalium today does not eradicate N. gonorrhoeae.

However, it's premature to consider routinely testing or screening for M. genitalium in patients with PID or other possible forms of M. genitalium infection, Dr. Wiesenfeld cautioned. That's in part because of the current logistical limitations on testing, and in part because the long-term impact of M. genitalium infection on reproductive health is not yet established. Longer follow-up of women in the study should shed more light on the natural history of the patients who received treatments that did not eradicate M. genitalium.

"If M. genitalium turns out to be associated with PID, it is the single organism that is not covered by current treatment with a cephalosporin, doxycycline, and metronidazole," Sharon L. Hillier, Ph.D., said in an interview during the meeting. "We are very concerned about it because it is a fairly sizable fraction of the STIs we've seen in these women with acute PID," said Dr. Hillier, professor of ob.gyn. and reproductive sciences at the University of Pittsburgh and a collaborator with Dr. Wiesen-feld on his study.

Changing the treatment strategies

While the best initial management strategy for acute PID remains unclear, the specter of M. genitalium has already changed the management strategy used by Dr. Paddy Horner to treat men with NGU, said Dr. Horner, a physician in the school of social and community medicine at the University of Bristol, U.K.

These days, his preferred approach is what he calls "infection-specific" first-line therapy: Before treatment begins, he eliminates purely empiric therapy by employing a commercially available, nucleic-acid amplification test for gonorrhea and Chlamydia at the first encounter and getting the result in 30 minutes.

That means treating men who test positive for Chlamydia with a week of doxycycline first, or starting with a 5-day course of azithromycin for men who are Chlamydia negative. However, he advised using a single, 1-g dose of azithromycin with caution, because of the prevalence of macrolide resistance. But Dr. Homer also admitted that no evidence has proved the superiority of the 5-day alternative that starts with a 1-g dose followed by 500 mg daily for 4 more days. Men who test positive for N. gonorrhoeae should receive 1 g of azithromycin plus 500 mg ceftriaxone.

If the urethritis persists 2 weeks later, Dr. Homer recommended treating patients empirically with a combination of moxifloxacin and metronidazole to cover possible infection by either M. genitalium or U. urealyticum.

Dr. Manhart, Dr. Wiesenfeld, and Dr. Hillier had no disclosures. Dr. Jensen said that his institution provides diagnostic testing for M. genitalium commercially and also evaluates various new antimicrobials under contract. Dr. Homer said that he has been a consultant to or received research support from Aquarius Population Health, Cepheid, Hologic, and Siemens.

Caption: It is becoming clear that resistance in M. genitalium develops rapidly," explained Lisa E. Manhart, Ph.D.


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Author:Zoler, Mitchel L.
Publication:Internal Medicine News
Date:Oct 1, 2013
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