Have You Heard About the New Bug Around Town? Mycoplasma genitalium Clinical Epidemiology and Treatment Considerations Gale R. Burstein, MD, MPH, FAAP, FSAHM Commissioner, Erie County Department of Health, Clinical Professor of Pediatrics, SUNY at Buffalo School of Medicine and Biomedical Sciences, Buffalo, NY Faculty, NYC STD/HIV Prevention Training Center

Special Acknowledgments Lisa E. Manhart, PhD Associate Professor, Epidemiology University of Washington

Boston University School of Medicine asks all individuals involved in the development and presentation of Continuing Medical Education (CME) activities to disclose all relationships with commercial interests. This information is disclosed to CME activity participants. Boston University School of Medicine has procedures to resolve apparent conflicts of interest. In addition, presenters are asked to disclose when any discussion of unapproved use of pharmaceuticals and devices is being discussed. I, Gale Burstein, MD, MPH, FAAP, FSAHM, have no commercial relationships to disclose.

Mycoplasma genitalium First isolated in 19811 Genital and reproductive tract disease Frequency more common than N. gonorrhoeae but less common than C. trachomatis coinfection with C. trachomatis not uncommon1-3 That statement is really supported by the Add Health data among young adults (18-24 years). It was a nationally representative sample, so represents the population-level prevalence (symptomatic and asymptomatic individuals combined) across the nation. The association with age usually shows highest prevalence in younger age groups, but not always. So yes, similar to CT, but less consistently so. 1Mena L, 2002; 2Falk L, 2010; 3Anagrius C, 2005

M. genitalium: More common than you think Young adults 18-24 yrs1,2 STD Clinic/ED Attendees3-9 Those were all ages with the exception of Huppert’s study that was in adolescents (14-21), and her results were somewhat different. But the rest of the studies were essentially a broad age range. Huppert’s study was different in the following ways: Age range – much younger than other studies Significant association between MG and CT – not always seen in other studies (although it has also been reported in New Orleans among men) No association with cervicitis (and a trend to an inverse association)   They used the APTIMA TMA assay and Marcia Hobbs did the testing, so I’d be surprised if there was contamination in the lab.  But the only other studies to have reported inverse associations between MG and cervicitis are studies that had methodologic concerns. It seems like Huppert’s study was well-done, so I don’t really know why they observed an inverse association – unless MG is more often asymptomatic in younger women.  But that’s a pretty far stretch.  It may just be random chance. MG CT GC TV 3Totten 2001; 4Mena 2002; 5Manhart 2003; 6Huppert 2008; 7-8Gaydos 2009a & 2009b; 9Mobley 2012 1 Miller 2004; 2 Manhart 2007

Male urethritis & M. genitalium Acute urethritis 1 15% MG+ in urethritis overall 22% MG+ in CT-/GC- urethritis Summary OR = 5.5 (4.3-7.0) Persistent urethritis 2 13 – 41% males w/ persistent/recurrent urethritis MG+ 1 Taylor-Robinson & Jensen, Clin Microbiol Rev, 2011; 2 Sena et al, JID 2012

Female Reproductive Tract Disease & M. genitalium M. genitalium’s pathogenic role less definitive in females than males Can be found in vagina, cervix, and endometrium M. genitalium in females commonly asymptomatic Detected in10-30% of clinical cervicitis cases1-7 Detected in 2-22% of PID cases (median 10%)8-17 evidence suggests that M. genitalium can cause PID, but less frequently than C. trachomatis17,18 There’ve been fewer studies in women than in men, the OR’s are smaller and not always significant in women, and I also think it’s because women in general have more asymptomatic infections than men for all STI’s. The same is sometimes true for CT (e.g., no significant association with cervicitis) – although less so than for MG. 1Falk L, 2010; 2Anagrius C, 2005; 3Falk L, 2005; 4Manhart LE, 2003; 5Gaydos C, 2009; 6Mobley VL, 2012; 7Lusk MJ, 2011; 8Bjartling C, 2010; 9Cohen CR 2002; 10Cohen CR, 2005; 11Haggerty CL, 2006, 12Irwin KL, 2000; 13Short VL, 2009; 14Simms I, 2003; 15Taylor-Robinson D, 2012; 16 Wiesenfeld HC, 2013; 17Bjartling C, 2013; 18Oakeshott P, 2010

M. genitalium Detection No FDA-approved diagnostic test BUT….. Multiplex PCR assays available in Europe Bio-Rad Dx/CT/NG/MG Assay® Sacace Biotechnologies Commercial Laboratories & PCR tests CLIA certified Hologic Gen-Probe TMA assay (APTIMA Platform) Currently available only as research-use only (RUO) assay Commercially available Spring 2015? - analyte-specific reagent (ASR) platform

M. genitalium treatment M. genitalium lacks a cell wall antibiotics that target cell-wall biosynthesis are ineffective beta-lactams including penicillins and cephalosporins Given diagnostic challenges, treatment of most M. genitalium infections will occur in context of syndromic management for STD syndromes

M. Genitalium treatment Recommended NGU & Cervicitis Rx1 Azithromycin 1g (single dose) Doxycycline 100mg bid x 7d Microbiologic Cure (median; observational studies) Doxycycline: 37% (range 17-94%) Azithromycin: 91% (range 69-100%) DOX (7 studies); AZM (14 studies) 1 CDC STD Treatment Guidelines, 2010

Treatment of M. genitalium Randomized Controlled Trials Doxycycline (100mg bid x 7d) vs. Azithromycin (1g) Microbiologic Cure (%)

Azithromycin resistance Macrolide resistance mediating mutation (MRMM) SNPs in region V of 23S rRNA gene inhibit macrolide binding % tested specimens w/ macrolide resistance

PID Treatment (outpatient)1 Ceftriaxone 250 mg IM in a single dose PLUS Doxycycline 100 mg orally twice daily for 14 days WITH or WITHOUT Metronidazole 500 mg orally twice a day for 14 days 57% of MG+ w/ endometritis on biopsy had persistent endometritis 30 days after Rx with Cefoxitin PLUS Doxycycline2 PEACH study: 15% MG+ on cervical or endometrial specimens 1 CDC STD Treatment Guidelines, 2010; 2 Haggerty 2008

Treatment Effectiveness Moxifloxacin 400mg x 7-14d 7 days 10 days 14 days

Treatment Effectiveness Moxifloxacin 400mg x 7-14d 7 days 10 days 14 days The highlighted bars are just those that are <100%.  Prior to the studies that came out in 2012-2013, moxi was 100% effective.  So the point is that we’re now beginning to see treatment failures to the last drug we have available to treat MG in many settings.  Resistance appears to emerge rapidly with MG (similar to GC), so we’ll need to think about similar treatment strategies.

Challenges M. genitalium causes disease BUT… Acknowledged cause of male urethritis 2x increased risk for cervicitis, PID, and pre-term delivery Infertility risk also probably  BUT… Poor efficacy of standard therapies Resistance appears to be rapidly emerging Limited data on antimicrobial resistance patterns in U.S. No FDA-approved assay

Recommendations Syndromic therapy for NGU, cervicitis, PID still effective in most cases Consider M. genitalium in cases of treatment failure Moxifloxacin generally effective Consider testing high-risk populations for M. genitalium as diagnostic tests become more readily available

Persistent NGU Treatment Recommended regimens: Metronidazole 2 g orally in a single dose OR Tinidazole 2 g orally in a single dose PLUS Azithromycin 1 g orally in a single dose (if not used for initial episode) If treatment failure: Moxifloxacin 400 mg PO x 7d effective for NGU treatment failures due to M. genitalium

Questions Discussion KOL Meeting September 15-18, 2013