Transcript Mycoplasma - Infectious Diseases

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
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
Human Mycoplasmas (a few)
Respiratory
Genital
M. pneumoniae (P)
Mycoplasma
M. orale (C )
M. fermentens (C )
Etc etc
M. genitalium (P)
M. hominis (C and
opportunist)
Ureaplasma sp.
U. urealyticum (P)
U. parvum (C)
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
Slow growing; colonies < 0.1mm
(dissecting microscope)
• Membrane glycolipids similar
to human cells (sterols)
Review: M. pneumoniae…. Clin Micro Rev 2004; 17:697-728
M. pneumoniae
adherence
Tip organelle contains large
amounts of P1 adhesin and other
tip adhesins necessary for
adherence to respiratory
epithelium.
Other adhesins also identified
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
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?)
M. pneumoniae CNS syndromes in
Children
1. No respiratory prodrome (20%)
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< 5 days of symptoms
M. pneumoniae present in CSF (PCR/culture)
but not in resp secretions
2. Respiratory prodrome (80%)
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> 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
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
Cold agglutinins
Rapid bedside test
correlates with titres
of >1/32
Cool to 40C for a few minutes
Reverses on warming to 370C
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
Cold agglutinins and M. pneumoniae 2
• Said to occur in 50% of cases of M pneumoniae(?)
• Not usually symptomatic except:
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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.
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
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
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
Treatment of M. pneumoniae
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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
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
Big Pharma Hits Back
Am 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%
Human Mycoplasmas (a few)
Respiratory
M. pneumoniae (P)
M. orale (C )
M. fermentens (C )
Etc etc
C = commensal
P = pathogen
Genital
Mycoplasma sp.
M. genitalium (P)
M. hominis (C and
opportunist)
Ureaplasma sp.
U. urealyticum (P)
U. parvum (C)
Prevalence in normal sexually active
humans
Men healthy
Women healthy
Ureaplasma
10-20%
M. hominis equal to urethritis
Ureaplasma(p)
M. hominis
M genitalium
66%
10%
2%
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
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
Do genital Mycoplasmas cause
urethritis (NGU)?
Results confirm that both chlamydia and
ureaplasma cause symptomatic treatable
urethritis
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
Non-Gonococcal Urethritis
(European STI Guidelines)
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Chlamydia
M genitalium
U urealyticum
Adenovirus
T vaginalis (based on PCR)
HSV
11-43%
9-25%
???
2-4%
1-20%
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
Females and treatment
• M genitalium associated with
– Post partum endometritis
– Pelvic inflammatory disease
– Cervicitis (data a bit more variable)
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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
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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