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Class: Mollicutes Order: Mycoplasmatales (includes plant, bird and animal Mycoplasmas)

Class: Mollicutes Order: Mycoplasmatales (includes plant, bird and animal Mycoplasmas) Family: Mycoplasmataceae (humans and animals) Genera: Mycoplasma; Ureaplasma Ecological niche: mucosal surfaces in humans Respiratory tract GU tract. Mycoplasmas.

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Class: Mollicutes Order: Mycoplasmatales (includes plant, bird and animal Mycoplasmas)

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  1. Class: Mollicutes Order: Mycoplasmatales (includes plant, bird and animal Mycoplasmas) Family: Mycoplasmataceae (humans and animals) Genera: Mycoplasma; Ureaplasma Ecological niche: mucosal surfaces in humans Respiratory tract GU tract

  2. Mycoplasmas Do not have peptidoglycan or rigid cell wall Widely spread as commensals and pathogens throughout animals (insects, plants) Small genome e.g. 25% of E.coli Metabolic poverty Not found free living

  3. Respiratory M. pneumoniae (P) M. orale (C ) M. fermentens (C ) Etc etc Genital Mycoplasma M. genitalium (P) M. hominis (C and opportunist) Ureaplasma sp. U. urealyticum (P) U. parvum (C) Human Mycoplasmas (a few)

  4. Mycoplasma pneumoniae • 1-2m x 0.1 –0.2m wide • No cell wall; cytoskeleton maintains shape • Filtrable through 0.45m filters • Genome 800 kb • Not related to known bacteria closest to Streptococci • Metabolically impoverished require serum for growth • Grow very well in tissue culture • Membrane glycolipids similar to human cells (sterols) Slow growing; colonies < 0.1mm (dissecting microscope) Review: M. pneumoniae…. Clin Micro Rev 2004; 17:697-728

  5. M. pneumoniaeadherence Tip organelle contains large amounts of P1 adhesin and other tip adhesins necessary for adherence to respiratory epithelium. Other adhesins also identified

  6. Epidemiology • Person to person transmission • Isolated or as family outbreaks and high attack rates in closed populations (military recruit barrack, boarding schools) • Population rates vary from year to year • Clinical incubation period 2-3 weeks • Organisms may be cultured for weeks –months after successful treatment and recovery • Highest rates age 5-20 but can occur at any age

  7. Mycoplasma pneumoniae • URI • Tracheobronchitis • Pneumonia (almost any picture subsegmental, patchy, lobar, interstitial, ARDS) • Fulminant MP pneumonia occurs rarely may be seen as CAP admitted to ICU (West J Med 1995;162:133) • Multiple distinct neurological conditions • Cold hemolytic anemia, Raynaud’s • Severe complications in SS with gangrene of extremities • Erythema multiforme, Stevens Johnson (what’s more common?)

  8. M. pneumoniae CNS syndromes in Children • No respiratory prodrome (20%) • < 5 days of symptoms • M. pneumoniae present in CSF (PCR/culture) but not in resp secretions • Respiratory prodrome (80%) • >7 days of symptoms (1-2 wks) • M. pneumoniae present in resp secretions but not in CSF. Key reference on M. pneumoniae in CNS disease: Bitnun et al. Clin Inf Dis 2001;32:1674-1683

  9. Neurological complications • CNS invasion or reactive inflammation with childhood encephalitis or aseptic meningitis. • Fever, seizures, coma, focal signs almost anywhere in CNS • ADEM, transverse myelitis • Cipro being used in children (HSC) • Steroids may help in severe cases (Crit Care Med 2002; 30:925) • Guillain Barre, (less important than Campylobacter and EBV) • cranial nerve palsies

  10. Cold agglutinins Rapid bedside test correlates with titres of >1/32 Cool to 40C for a few minutes Reverses on warming to 370C

  11. Cold agglutinins and M. pneumoniae 1 • IgM antibodies directed against I (big I) antigen present on all non-fetal erythrocytes regardless of blood group (M pneumoniae and benign lymphoproliferative disorders) • Directed against little (i) antigen present on fetal erythrocytes (EBV infection and aggressive lymphomas) • Bind in cold (40C ) and elute at higher temperature • Medical significance determined by “Thermal amplitude” and titre • hemolytic anemia should be active at 300C and >1/256 titre

  12. Cold agglutinins and M. pneumoniae 2 • Said to occur in 50% of cases of M pneumoniae(?) • Not usually symptomatic except: • high titre (>1/2000) • higher thermal amplitude (300C ) • low environmental temperature • Pathogenesis is IgM – complement mediated direct lysis of RBCs • Useful diagnostic marker • High MCV with broad size range • Bedside test • Can be associated with distal limb gangrene in the presence of SS sickle cell disease.

  13. Prognosis/Clinical Course • Post-infectious Cold agglutinin disease: • onset within 0-3 wk • self-resolving within 1-3 wk • titers to baseline within 3-4 mo • Malignant / lymphomatous Cold agglutinin disease: • mounting titers, anti-i, negative viral serology

  14. Diagnosis 1 • IgM against M. pneumoniae starts to appear 7-10 days after symptoms • Excellent test for immunocompetent children and young adults • IgM EIA used in Ontario • Sensitivity poor days 1-6 of symptoms; improves with testing day 7-15 and >16 • Adults may have low or undetectable IgM (~20%) • IgM may persist for 1 yr after infection

  15. Diagnosis 2 • PCR (against P1 tip adhesin gene) excellent sensitivity but may be positive with carrier state and doesn’t absolutely show that M. pneumoniae is cause of current illness. • Quantity is said to be less in carrier than disease state • Culture less sensitive and requires transport medium. • M. pneumoniae is not infrequently present with other pathogens Conclusion: Combination of culture/PCR and serology will give most definite evidence but warranted only in severe or unusual cases

  16. Treatment of M. pneumoniae • Doxycycline • Erythromcin • Azithromycin • Fluoroquinolones • Macrolides most active, then FQ then doxy • macrolide resistance noted in Japan due to 23S rRNA mutations • Shortens the course of symptoms but doesn’t decolonize • 7-14 days for adults; 10-14 days for children

  17. Is coverage for “atypical” agents important in mild-moderate CAP? Meta-analysis of double-blind RCT comparing b-lactam antibiotics with macrolides, fluoroquinolones, ketolides (18 trials; 6749 subjects) for mild to moderate CAP Mortality rate 1.9% (similar to PORT 1-3) Overall no significant difference for clinical improvement or cure including atypical agents RR for failure = 0.97 (.87-1.07) Number needed to treat is 150 Legionella: Legionella-specific agents significantly better than b-lactams (numbers = 38/37): RR for failure = 0.4 (.19 - .85) Mills GD Oehley MR Arrol B BMJ online Jan 31 2005

  18. Big Pharma Hits BackAm J Resp Crit Care Med 2007; 175: 1086 2,878 patients hospitalized with CAP About 37% Class IV and 17% Class V 22% “atypical agent”: 11% MP, 8% CP, 4% LP 2,220 received macrolide or quinolone as part of therapy 658 did not Mortality Overall 10% vs 17% CAP 4.5% vs 6%

  19. Respiratory M. pneumoniae (P) M. orale (C ) M. fermentens (C ) Etc etc Genital Mycoplasma sp. M. genitalium (P) M. hominis (C and opportunist) Ureaplasma sp. U. urealyticum (P) U. parvum (C) Human Mycoplasmas (a few) C = commensal P = pathogen

  20. Men healthy Ureaplasma 10-20% M. hominis equal to urethritis Women healthy Ureaplasma(p) 66% M. hominis 10% M genitalium 2% Prevalence in normal sexually active humans Ureaplasma urealyticum but not parvum plays a role in NGU Ureaplasma parvum accounts for 70% of vaginal isolates but is not associated with disease M.hominis may cause arthritis in agammaglobulinemia Has been isolated from blood and wounds in compromised hosts

  21. Do genital Mycoplasma/Ureaplasma cause (NGU)? • Self innoculation of pure culture • Specific treatment trial • Sulfonamides treat Chlamydia but not mycoplasmas (or ureaplasma) • Urethral cultures done for ureaplasma and chlamydia before and after treatment • Patients given sulfonamide alone • C+ U- cases gives 100% complete or partial response vs 47% for U+C- cases p<.002 Bowie W et al. J Clin Investig. 1977; 59:735

  22. Do genital Mycoplasmas cause urethritis (NGU)? Results confirm that both chlamydia and ureaplasma cause symptomatic treatable urethritis

  23. T. vaginalis may be more important in NGU than previously thought. This is based on using PCR to detect it. See: Schwebke and Hook JID 2003;188:465

  24. Non-Gonococcal Urethritis(European STI Guidelines) • Chlamydia 11-43% • M genitalium 9-25% • U urealyticum ??? • Adenovirus 2-4% • T vaginalis (based on PCR) 1-20% • HSV 2-3% See 2009 European STI guidelines which suggest adding metronidazole to 5 day course on azithromycin for NGU that persists after or recurs after first line treatment. (First line treatment is still Azithro 1 gm single dose OR 7 days of doxycycline.) Ref: Int J Std & AIDS 2009; 20:458-64

  25. Females and treatment • M genitalium associated with • Post partum endometritis • Pelvic inflammatory disease • Cervicitis (data a bit more variable) • REF:Sex Transm Dis 229; 36:607 Oct 2009 for editorial on M. genitalium. Treatment of M genitalium Tetracycline failures common 55% Some failures with Azithro 1gm single dose Azithromycin 500 followed by 250 daily for 4 days has been used • REF: above editorial for treatment of M genitalium in women • urethritis in men: Clin Infect Dis 2009; 48: 1649-54 randomized trial doxy vs azithro for Rx of M genitalium urethritis in men

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