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Mycoplasmas of the female genital tract

Mycoplasmas of the female genital tract. Lisa Rahangdale, MD RID seminar March 15, 2005. Outline. Microbiology Epidemiology Clinical Manifestations in ♀ Diagnosis Treatment Lingering questions. Microbiology. 16 species: affect genital and respiratory tract

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Mycoplasmas of the female genital tract

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  1. Mycoplasmas of the female genital tract Lisa Rahangdale, MD RID seminar March 15, 2005

  2. Outline • Microbiology • Epidemiology • Clinical Manifestations in ♀ • Diagnosis • Treatment • Lingering questions

  3. Microbiology • 16 species: affect genital and respiratory tract • Prokaryotes: smallest free-living organisms known • Evolved from clostridia-like, Gm+ bacteria • Absent cell-wall (insensitve to β-lactams, stain poorly) • Flexible, 3 layer membrane assume variety of shapes • Polar tip organelles for attachment to host cells • Complex nutritional requirements Taylor-Robinson 1998

  4. Epidemiology • Not well-defined (esp in ♀) • Most studies in STD populations

  5. Genital Tract Bartholin’s abscess? Vaginitis (BV) Cervicitis PID Endometritis NGU Reproductive tract Infertility Miscarriage PTL Urinary tract Kidney stones Pyelo, UTI Arthritis Immunodeficiency HIV/AIDS Hypogammoglobulinemia Malignancy (Leukemia) Chronic Fatigue syndrome Crohn’s disease Gulf War syndrome Respiratory illness Clinical manifestations

  6. Clinical ManifestationsGenital Tract Species • M. hominis • NGU, Role in BV  role in vaginitis, PID, PTL • M. genitalium • No assoc w/ BV • NGU, Role in cervicitis, ?PID, ?arthritis • Ureaplasma urealyticum • NGU, ??? Role in PID, infertility, miscarriage, arthritis • M. penetrans • ? Role in MSM HIV infection and Kaposi’s • M. fermantans • No assoc w/ NGU, gen tract disease, ?progression of HIV Taylor-Robinson 1998 Jensen 2004

  7. Clinical ManifestationsColonization • Infants • Less likely if delivered by c/sec • Ureaplasma, M. hominis in infant girl genitalia • Neonatal colonization diminishes • Unlikely in pre-pubertal boys • 5-22% pre-pubertal girls • Sexual abuse – 22-34% • Adults – sexual contact • Asymptomatic Foy 1975 Taylor-Robinson 1984 Iwasaka 1986 Hammerschlag 1987 Robinson 1998

  8. Clinical ManifestationsCervicitis • Cross-sectional study, Seattle STD clinic • 50/719 (7%) w/ MG and mucopurulent cervicitis (MPC) • Associations (multi-variate analysis) • ≥ 2 partners in 30 days (OR 3.3, CI 1.2-9.5) • Smoking (OR 2.7, 95% CI 1.3-5.7) • > 2 douches/mon (OR 2.5, 95% CI 1.1-5.6) • H/O SAB (OR 2.4, 95% CI 1.0-5.8) • MG assoc w/ 3.3 (95% CI 1.7-6.4) fold increased risk of MPC • Conclusion: MG should be considered an etiologic agent for MPC like GC,CT, HSV and treated Manhart 2003

  9. Clinical ManifestationsCervicitis • Cross-sectional study, Wisconsin STD & Student Health Clinics • 39 sx ♀ 70 asx ♀ • Sx: 13-54% w/ M genitalum, M. hominis, U. ureaplasma • Asx: 0-16% • 0-3% with GC or CT • Conclusion: Urogenital findings assoc with mycoplasma infxn Schlicht 2004

  10. Clinical ManifestationsCervicitis • Cross-sectional study, Sweden • 465♀ STD clinic (10% CT, 6% MG, 1% both) • Partners of infected ♀: 59% CT, 56% MG • 157 controls (2% CT, 0% MG) • Conclusion: Must consider MG’s role in cervicitis & as potential STD • Cross-sectional study, Ghana, Bénin • 826 SW: 26% MG, 16% GC, 3% CT, 23% TV • GC & MG signif assoc w/ signs of cervicitis • D/C, Pus, bleeding, inflamm, CMT (only assoc w/ NG) • Conclusion: Must consider MG in syndromic mgt of SW Falk 2005 Pépin 2005

  11. CervicitisLR’s CONCLUSIONS MG most likely plays a role like other STDs. When does colonization become pathology?

  12. Clinical ManifestationsPID • Hungary, 2215 ♀ with PID • Goal: Evaluate current tx strategies based on bacteria present • Cervical samples for CT, GC, MG, & UU • Rate of U. urealyticum 21-23%, MG 3%, CT 10-12% over 3 yrs • Conclusion: CT and mycoplasmas likely main causative agents (but also mixed infxn) Skapinyecz 2003

  13. Clinical ManifestationsPID • Case-control, UK • 45 ♀w/ PID dxs, 37 controls • MG: 13% PID, 0% controls • CT: 27% PID, 0% controls • No BV • Conclusion: Independent assoc of MG to PID (p<.001) Simms 2003

  14. Clinical ManifestationsPID • Case-control, Kenya • 115 ♀with pelvic pain, 33% HIV+ • Em Bx • 50% (58) ♀ w/ histologically confirmed endometritis • 9% with MG • Endometritis significantly assoc with MG detected in endometrium and/or cervix (p=.02) • MG without coinfection assoc with endometritis (p=.03) • Conclusion: CT & GC are not the only important causes of upper gen tract infxn Cohen 2002

  15. Clinical ManifestationsPID • Case-Control, Kenya • 123 ♀ with PID (LSC dxs) • Laparoscopy • 7%(9) w/ MG in cervix or endometrium • 1 pt with fallopian tube infxn • Presence of MG assoc with HIV infxn (p=.03) • Conclusion • Unclr why MG not found: ?severity of PID, other pathogens, PCR assay inadequate Cohen, publication pending 2005

  16. PIDLR’s CONCLUSIONS MG most likely plays a role. It is not definitively proven whether it is part of the multiple pathogens required for PID or if it is a causative agent, itself.

  17. Clinical ManifestationsInfertility - ♀ • Cohort, Denmark, 308 infertile ♀ • 132 secondary to tubal factor (TFI) • 22% (29) w/ ab to MG (MgPa)OR 3.8 (95% CI 1.7-9.4) • 21/29 also seropositive to CT • Assoc of TFI and MG, p=.005 when adjusted for CT • Limitation: Cross-reactivity with M. pneumoniae • Conclusion: MG may be independent factor leading to TFI Clausen 2001

  18. Clinical ManifestationsInfertility - ♀ • Cohort, Denmark, 304 infertile ♀ • 42% (55) ♀ w/ TFI have ab to M. Hominis (p<.01) • 23 positive for only M. Hominis • 14 positive for both MG and M. Hominis • 28 positive for M. Hominis and CT • 10 positive for all 3 • No cross-reactivity w/ MG, M. pneumoniae, U. urealyticum • Conclusion: M. Hominis independent factor in TFI Baczynska 2005

  19. Clinical ManifestationsInfertility - ♂ • MG attaches to spermatozoa • M. hominis and U. urealyticum found in routine semen analyses • No evidence of role in sperm quality Svenstrup 2003 Andrade-Rocha 2003

  20. InfertilityLR’s CONCLUSIONS Indirect evidence that mycoplasmas play a role in TFI

  21. Clinical ManifestationsMiscarriage • Cohort, Belgium, 221 ♀ • <14 wks, cervical cultures • 10% with SABs <20 wks • BV assoc bacteria  increased risk of loss • G. vaginalis (RR 5.8), M. hominis (RR 12.5), U. Urealyticum (RR 5.8) • Cohort, Croatia, 108 D&C specimens (4-19 wks) • No U. urealyticum, M. hominis • UK, 915 ♀ <10 wks in PNC • First void urine & Self-admin vag swab • <1% (6) with MG • 1/6 MG+ w/ SAB before 16 wks Donders 2000, Matovina 2003, Oakeshott 2004

  22. MiscarriageLR’s CONCLUSIONS Unclear role of mycoplasmas and miscarriage Association may be their connection to BV?

  23. Clinical ManifestationsPreterm Delivery • Cohort, Switzerland, 254 asx ♀, 15-17 wk amnios • U. urealyticum 11.4% (29) • Carriage assoc w/ PTL (59%, p<.0001) , PTD<34wks (7%, p<.01) , PPROM (21%, p<.0001) • Cohort, US, 179 asx ♀, 15-19 wk amnios • Neg BV screen • M. hominis 6.1% (11) • U. urealyticum (12.8%) 22 • All 5 of subseq PPROM infected w/ mycoplasma • No PTD infected with mycoplasma Gerber 2003 Perni 2004

  24. Clinical ManifestationsPreterm Delivery • Cohort, U.S., 456 ♀, 15-17 wk amnios • M. hominis in 29 (6.4%) • PTL 14.3% vs 3.3% (p=.01) • PTD 10.7% vs 1.9% (p=.02) • Cohort, U.S., 124 ♀ w/ spontan PTD • Cervicovaginal sample PCR 21-25 wks • MG in 3.9% (5) ♀ Nguyen 2004, Lu 2001

  25. Preterm DeliveryLR’s CONCLUSIONS Possible influence of M. hominis and U. urealyticum on PTD/PPROM No good evidence of MG influence

  26. Influence on HIV • Mycoplasmas  musocal disruption and increased risk of HIV transmission • In vitro studies: M. fermentans synergy with HIV cytopathic effects • M. fermentans activates immune system  HIV progression • M. fermentans detected in KS cells, organs, blood, urine • M. penetrans ab assoc with development of KS Blanchard 1994

  27. Influence on HIV(HIV and PID) • US, Case-control, 207 ♀ w/ PID • 44 HIV+ vs. 163 HIV- • Similar clinical outcomes • Mycoplasma species more likely isolated on Em bx (50% vs 22%, p<.05) in HIV+ • Why? • Commonly colonize sexually active ♀ • Greater use of abx in HIV grp change flora • HIV influences immunity leading to ascent of organisms Irwin 2000

  28. Influence on HIV(Genital tract shedding) • US, Case-control 406 ♀ WIHS • 203 with BV, 203 without, similar VL • Presence of BV (i.e. high M. hominis counts and low Lactobacillus) assoc with increased HIV gen tract shedding Sha 2005

  29. Diagnosis • No commercially available diagnostic tests • No common reference standard for in-house tests • Difficult to isolate by culture • PCR used in most clinical studies • Denmark STD pts: FVU, cervical/urethral swabs • MG detection rate: 88% FVU, 96% FVU + cerv swab • Denmark STD pts: FVU, endocervical swabs • MG sensitivity 65% FVU, 85% FVU + endocervical swab • Korea amnios ≤ 35wk PTL • U. urealyticum sensitivity: 75% PCR, 60% culture • Japan: Rapid Test as good as PCR in NGU FVU Jensen 2004 Jurstrand 2005 Yoon 2003 Yoshida 2003

  30. Treatment • Limited studies on treatment • Review of NGU • In vitro profile of MG simil to M. pneumoniae • Susceptible to abx that inhib protein synthesis but resistant to those that act on bact cell wall • Difficult to isolate MG so MIC based on reports • Susceptible to tetracyclines, macrolides, quinolones (cipro/oflox) have mod activity • Most of efficacy of tx depends on intact immune system Ishihara 2004 Baseman 1997

  31. Treatment • Tetracycline: evid of resistance to M. hominis & U. urealyticum; ineffective tx of MG in STD population • Azithro: eradication of MG in STD population, diminished colonization of U. urealyticum in RCT of PTL/PPROM pts • Erythro: in pts w/ U. urealyticum & M. hominis, tx  decreased Mid-trim loss (p=.04), PTD similar • Quinolones: reports of mutation assoc w/ resistance to M. hominis & U. urealyticum Christiansson 1983 Falk 2003 Berg 1999 Ishihara 2004

  32. Treatment • 2002 CDC STD Treatment Guidelines • MG addressed as factor in NGU in ♂ • Azithro or Doxy • Erythro, Oflox, Levo • If recurrent, consider U. urealyticum (& TV) • Metronidazole, Erythro • Mucopurulent cervicitis in ♀ • MG not addressed • Recommend testing for GC and CT • If negative, mgt options undefined

  33. Summary • Mycoplasma is sexually transmitted bacteria. • Colonization can be asymptomatic. • Infection can contribute to cervitis, PID, infertility, SAB, PTL, HIV pathogenesis. • Difficult to diagnose. No standard diagnostic method available. • No good evidence of best treatment strategy. However, most STD tx regimens cover mycoplasmas

  34. Questions • What is the exact role of mycoplasma? • Emerging interest in M. genitalium as an STD • When does colonization become pathologic? • Who is at risk? • Should we screen for mycoplasma in difficult cases? • Are our treatment strategies effective? • Issues of resistance

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