C-Mastroianni

Le micobatteriosi
Catania, 9 novembre 2015
Claudio Mastroianni
Dipartimento Sanità Pubblica e Malattie Infettive
UOC Malattie Infettive
Latina
NTM Microbiology
• NTMs
• ~150 species
• Environmental Source
• Daily Exposure
Non-Tuberculous Mycobacteria (NTM) Phylogeny
Approximately 50
new species
described in the last
8 years are
reviewed, and their
role in human
infections is
assessed on the
basis of reported
clinical cases.
Clin Microbiol Rev, 2014
NTM
• Despite the fact that NTM are characterized
by a moderate pathogenicity, the diseases
caused by NTM at various body sites are
increasing on a worldwide level.
• Among over 150 officially recognized NTM
species, only two or three dozen are
familiar to clinicians, and even to most
microbiologists.
Mycobacterium marinum
infection
32 yrs old man
Personal report
Zidovudine-induced restoration of cellmediated immunity to mycobacteria in
immunodeficient HIV-infected patients
“The
development of localized MAI infection and/or
fevers shortly after commencing ZDV in immunodeficient
HIV-infected patients may reflect restoration of cellular
immunity to mycobacterial antigens in some patients
rather than early failure of therapy or hypersensitivity to
ZDV”
French MA, AIDS 1992
Patients with MAC have better survival than patients with
other mycobacteria
Rapidly growing mycobacteria (< 7 days)
M. fortuitum, M. chelonae, M. abscessus
Relatively low virulence
Infections establish in deep tissues after
introduced by trauma or iatrogenic
infections.
No person-to-person spread
Incidence increases as invasive procedures
increases.
Prevots R, Clin Chest Med 36 (2015) 13–34
Lung infection with nontuberculous mycobacteria
Arend et al. Current Opinion in Pulmonary Medicine 2009
Prevots R, Clin Chest Med 36 (2015) 13–34
Figure 1. Cumulative incidence of respiratory failure among patients with non-TB mycobacterial
infection (dashed line) and among compared subjects.
Yeh JJ, Wang YC, Lin CL, Chou CYT, Yeh TC, et al. (2014) Nontuberculous Mycobacterial Infection Is Associated with Increased
Respiratory Failure: A Nationwide Cohort Study. PLoS ONE 9(6): e99260. doi:10.1371/journal.pone.0099260
http://journals.plos.org/plosone/article?id=info:doi/10.1371/journal.pone.0099260
Figure 1. NTM and TB-related mortality rates per 100,000 person-years by year, United States,
1999–2010.
TB
NTM
Mirsaeidi M, Machado RF, Garcia JGN, Schraufnagel DE (2014) Nontuberculous Mycobacterial Disease Mortality in the United
States, 1999–2010: A Population-Based Comparative Study. PLoS ONE 9(3): e91879. doi:10.1371/journal.pone.0091879
http://127.0.0.1:8081/plosone/article?id=info:doi/10.1371/journal.pone.0091879
Geographical distribution
• Annual prevalence in North America and Australia:
3.2 to 9.8/100.000
• Europe: below 2 per 100,000.
• In the US, MAC, followed by M. kansasii, is the most
frequently recognized pathogen.
• The third most common cause of NTM pulmonary
disease is M. abscessus complex, which produces 80%
of pulmonary infections caused by RGM
• In Canada, some parts of the United Kingdom, and
Europe, M. xenopi ranks third, whereas M. malmoense
is second after MAC in Scandinavia and northern
Europe.
• In southeast England, M. xenopi and M. kansasii
(known to be present in local water supplies) are both
more common than MAC
Pathogenesis of NTM Disease
The interaction of host risk factors and
significant environmental exposure to
NTM are likely requirements for
establishment of disease
Why do nontuberculous Mycobacteria
Inhabit the Human Environment?
• Physiologic characteristics
• Surface hydrophobicity of NTM.
• Attached cells, will not be washed out of a
flowing system (eg, river or pipe).
• Hydrophobicity also drives the enrichment of
NTM in aerosols above bodies of water and is
responsible, in part, for NTM’s resistance to
disinfectants.
Environmental sources of
nontuberculous mycobacteria
• Soils, especially acidic pine forest or coastal swamp
soils
• Dusts from agriculture, garden, and potting soils
• Drainage waters from acidic pine forests or coastal
swamps
• Natural waters
• Drinking water
• Water and ice from refrigerators
• Water from granular-activated charcoal filters
• Aerosols from natural and drinking waters
• Aerosols from indoor humidifiers
• Mist from indoor swimming pools
Risk factors for NTM lung disease.
Honda et al Clin Chest Med - (2014)
Risk factors for NTM infection and
disease
Prevots R, Clin Chest Med 36 (2015) 13–34
Risk factors for NTM infection and disease
Prevots R, Clin Chest Med 36 (2015) 13–34
Nontuberculous Mycobacteria infections and Anti–Tumor Necrosis
Factor-α Therapy
epidemiologic features of patients who use anti–TNF-α drugs are similar to those
who are at risk for NTM pulmonary disease in the absence of these drugs (i.e.,
elderly women, many of whom who have underlying lung disease
Risk factors for NTM infection and
disease
Prevots R, Clin Chest Med 36 (2015) 13–34
Spectrum of NTM disease
• Lung disease
– Nodules/bronchiectasis
– Cavity
– Hypersensitivity pneumonitis
•
•
•
•
•
Lymphadenitis
Traumatic skin and soft tissue infections
Disseminated infections
Healthcare associated infections
Tenosynovitis/bone infections
KIM, ET AL. PULMONARY NONTUBERCULOUS MYCOBACTERIAL
DISEASE AM J RESP CRIT CARE MED 178:1066, 2008
NTM Morphotype
“Lady Windermere Syndrome”
•
•
•
•
•
•
•
Middle aged white females
Slender, tall,
Middle Lobe and lingula disease
Scoliosis, Pectus excavatum
Mitral Valve prolapse
Higher percentage of CFTR genes
No cellular immune defects
Iseman & Marras AJRCCM 178:999, 2008, Kim et al. 1066-1074.
Slender individuals with low
body fat
• Hypothesis
– relative deficiency of leptin, an adipokine
whose canonical function is that of a satiety
hormone.
– leptin has several immunomodulatory
functions that can potentially enhance host
immunity against NTM
– leptin-deficient mice are more susceptible to
Mycobacterium abscessus experimental lung
infection.
NTM lung disease
Natural History
Diagnosis = Treatment ???
Colonization?
Infection
Disease (treatment)
Pulmonary NTM Disease
- ATS / IDSA 2007
“Disease” Criteria
Clinical Pulmonary symptoms, or
Nodules or cavities on CXR, or
Multifocal bronchiectasis & multiple small
nodules on HRCT
(and exclusion of other diagnoses)
Micro
With > 2 sputa  2 cultures +
With 1 BAL/wash  1 BAL/wash +
With biopsy 
• 1 biopsy culture +, or
• 1 culture + and bx evidence of disease
Proposed algorithm for optimizing microbiological
diagnosis of nontuberculous mycobacterial pulmonary
disease
Clinical relevance of nontuberculous
mycobacteria isolated from respiratory samples
in the Netherlands.
Van Ingen et al. Thorax 2009;64:502-506
Bronchoscopy Related
Pseudo-Outbreaks
• Contamination of broncoscopy pseudo-outbreaks of
M. gordonae can still be detected as a result of
uncorrected disinfection.
• Environmental investigations are mandatory.
• Molecular analysis is the most valid tool to adopt for
infection control.
• Clinical surveillance is the only strategy to avoid
delayed true diagnosis and unnecessary
antimycobacterial treatment.
Pseudo-outbreak da Mycobacterium gordonae: criticità delle
procedure di sanificazione dei broncoscopi
L Scorzolini*, F Mengoni*, L Marinelli§, A Cottarelli§, CM Mastroianni*, A D’Abramo*, M De Giusti§, R Baldan°, L
Fattorini#, V Vullo*.
*Dipartimento di Sanità Pubblica e Malattie Infettive, “ Sapienza” Università di Roma.
§Dipartimento di Igiene e Sanità Pubblica, “Sapienza” Università di Roma.
°Unità Patogeni Batterici Emergenti, IRCCS San Raffaele, Milano.
#Dipartimento di Malattie Infettive, Parassitarie e Immunomediate, ISS, Roma.
OBIETTIVI E METODI I
Obiettivo dello studio è stato quello di verificare uno pseudo-outbreak di
M. gordonae isolato dal broncolavaggio alveolare (BAL) di 7 pazienti
sottoposti a fibrobroncoscopia ricoverati nel periodo compreso tra
Gennaio-Aprile 2013..
490 nessuna
crescita NTM
497 BAL effettuati
7 Mycobacterium
PULSED FIELD GEL
ELECTROPHORESIS
(PGFE)
gordonae
ISOLAMENTO DI
FOLLOW-UP 6 MESI
SEGNALAZIONE CIO
SORVEGLIANZA
CLINICA PAZIENTI
CON BAL POSITIVO
AUDIT
INTERDISCIPLINARE
Mycobacterium
gordonae
SORVEGLIANZA
AMBIENTALE
OBIETTIVI E METODI II
Per la definizione di caso di infezione polmonare da NTM (PINTM) sono
stati adottati i criteri diagnostici della American Thoracic Society (ATS).
Sono state effettuate presso il servizio di broncoscopia le indagini su:
broncoscopi, lavaendoscopi e acqua di adduzione alla lavaendoscopi.
L’identificazione del M. gordonae è stata eseguita tramite indagine
molecolare (GenoType Mycobacterium CM assay Arnika).
La clonalità degli isolati clinici e ambientali è stata determinata attraverso
l’analisi Pulse-Field Gel Electrophoresis (PGFE).
RISULTATI III: INDAGINE MOLECOLARE
genotyping by pulsed-field gel
electrophoresis
No patients met the criteria for NTM
lung disease and was therefore not
treated for M. gordonae lung disease.
RISULTATI II: INDAGINE AMBIENTALE
Type of sample
Sample
No.
Positive
No. (%)
Flushing of biopsy/suction channel from Bronchoscopes
3
0(a,b,c)
Flushing of connectors of the washer disinfector
2
0
Swabs of internal surfaces of the washer disinfector
5
0(d,e)
Tap water
1
1 (7.14)
Swab from inside tap
1
1 (7.14)
Final rinse water of the washer disinfector
1
0
Swab of water supply channel of the washer disinfector
1
1 (7.14)
Total
14
3 (21.43)
Other species: Achromobacter xylosoxidans MDR (a). Klebsiella pneumoniae (b). Sphyngomonas paucimobilis (c).
Micrococcus luteus/lylae (d). Brevundimonas diminuta/vesicularis (e). Rhizobium radiobacter (f).
Le indagini ambientali hanno evidenziato presenza di M. gordonae nel
punto di adduzione dell’acqua alla lavaendoscopi e nell’acqua di rete e
presenza di batteri patogeni quali Klebsiella pneumoniae e Achromobacter
xylosoxidans, nel canale bioptico dei broncoscopi esaminati, segno di
evidente fallimento delle procedure di decontaminazione
Health Care–Associated
Infections
• Sporadic cases of health care–associated
skin and soft tissue disease have also been
described
• Infections of long-term intravenous or
peritoneal catheters,
• Postinjection abscesses
• Surgical wound infections such as after
cardiac bypass surgery, and
augmentation mammoplasty
NTM outbreak
• A cluster of 12 cases involving M. fortuitum
and M. porcinum in postaugmentation
mammoplasty surgical site infections was
recently described in Brazil
• Recently there have been reports of eye
disease due to RGM including
postkeratoplasty and after laser-assisted in
situ keratomileusis (LASIK) surgery for
correction of myopia
Padoveze MC J Hospiatl Infection, 2007
Brown-Elliott BA, Cornea 2012
Lower-extremity folliculitis due to RGM (M.
fortuitum, M. abscessus, and M. mageritense
disease), associated with nail salons (“foot-spa
disease”), have been reported
Representative clinical findings of nontuberculous mycobacterium (NTM) tattoo infections (A,
B).
Ryan R. Falsey et al. Clin Infect Dis. 2013;57:e143-e147
© The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases
Society of America. All rights reserved. For Permissions, please e-mail:
[email protected]
• Endocarditis and prosthetic valve infections
by RGM often results in unfavourable
outcome
• Misidentification of RGM
• Subsequent delay of the specific treatment
of infection and severe complications
Misidentification of rapidly growing mycobacteria
(RGM) is an emerging problem
V Visconti, G la Martire, G
Brunetti, MC Ghezzi, M Venditti,
G Raponi. Am J Infect Control
(2015 in press)
MALDI-TOF solves misidentification of
Rapid Growing Mycobacteria
BSI sustained by
Mycobacterium
fortuitum
V Visconti, G la Martire, G Brunetti, MC
Ghezzi, M Venditti, G Raponi. Am J Infect
Control (2015 in press)
Treatment of NTM
• Long, challenging and sometimes ineffective.
• Many of the prospective studies for NTM were
conducted in patients with AIDS therapy with
disseminated MAC, before the advent of HAART
• Specific data including detailed
pharmacokinetic/pharmacodynamic data are
lacking
• NTM infections are increasingly common in the
elderly, and age-related changes in drug
absorption, metabolism, and excretion may lead to
decreased efficacy and increased toxicity
Antimycobacterium
MAC Clarithromycin or azithromycin +
ethambutol+Rifampin
M. xenopi
Rifampin+Ethambutol +INH
M. kansasii
Rifampin + Ethambutol
M. malmoense Rifampin or Ethambutol
M. marinum Rifampin or Clari + Ethambutol 2-3
months
Rapid growers: doxycycline, amikacin, imipenem,
quinolones, sulfonamides, cefoxitin, clarithromycin,
linezolid, tygecicline
Treatment for Mycobacterium abscessus
Pulmonary Disease
16 different antibiotics
were used in 42
different combinations
for an average of 4.6
drugs per
patient over the
course of therapy with
a median of 6
intravenous antibiotic
months.
Jarand J et al. CID 2011
Microbiologic outcomes
Jarand J et al CID 2011
Drug susceptibility testing (the presence of
the erm gene for macrolide)
Duration of treatment
Role fo surgery