Educational Workshop EW13: Infections due to non-tuberculous mycobacteria
Arranged with the ESCMID Study Group for Mycobacterial Infections
Convenors: J.S. Friedland (London, GB) J. Gonzalez (Barcelona, ES)
Faculty: E. Tortoli (Milan, IT) E. Cambau (Paris, FR) G. Bloemberg (Zurich, CH) M. Viveiros (Lisbon, PT)
1
2 Tortoli - The world of nontuberculous mycobacteria
The world of nontuberculous mycobacteria
Enrico Tortoli
23rd ECCMID, Berlin April 27, 2013
Emerging Bacterial Pathogens Unit
The origin of mycobacteria
Merhej et al. Biology Direct 2009
Emerging Bacterial Pathogens Unit
The Actinobacteria
KINGDOM Bacteria TYPE Actinobacteria CLASS Actinobacteria ORDER Corynebacteriales SUB-ORDER Corynebacterineae FAMILY Mycobacteriaceae
Gao and Gupta. Microbiol.Mol.Biol.Rev. 2012
Emerging Bacterial Pathogens Unit
3 Tortoli - The world of nontuberculous mycobacteria
M. ulcerans coeval of dinosaurs?
Hayman. Lancet. 1984
Emerging Bacterial Pathogens Unit
The NonTuberculous Mycobacteria
Environmental and opportunistic pathogens of humans and animals
Emerging Bacterial Pathogens Unit
The history
• 1889. M. smegmatis “agent of syphilis” • 1953. Buhler and Pollak: Two cases of pulmonary disease caused by “yellow bacillus” • 1956. Prissick et Masson: Cervical lymphadenitis in children caused by chromogenic mycobacteria • 1959. Runyon’s classification • 1979. Wolinsky: Nontuberculous mycobacteria and associated diseases • 1982. First reports of disseminated MAC infections in AIDS
Emerging Bacterial Pathogens Unit
4 Tortoli - The world of nontuberculous mycobacteria
Habitat
• Waters – natural waters • acidic swamps – drinking water distribution systems • biofilms • aerosols •Soil – forests – peats – potting
Emerging Bacterial Pathogens Unit
The cell wall
Lipid-rich hydrophobic impermeable
Emerging Bacterial Pathogens Unit
The hydrophobicity
• Promotes the attachment to surfaces • Provides protection from a wide range of antimicrobial agents • Is responsible of biofilm formation • Causes the concentration at air-water interfaces such facilitating the aerosol formation • Allows the utilization of hydrocarbons
Emerging Bacterial Pathogens Unit
5 Tortoli - The world of nontuberculous mycobacteria
The slow growth
The growth rate is limited by: • the costly synthesis of mycolic acids • the impermeability to hydrophilic nutrients • the low number of copies of RNA operons which affects the rate of protein synthesis
Emerging Bacterial Pathogens Unit
The slow growth
• Disadvantages – poor competitors in nutrient-rich habitats • Advantages – survival and proliferation in marginal environments – adequate time to adapt to changed conditions • dormant state to survive anaerobiosis or starvation • increased resistance in biofilms
Emerging Bacterial Pathogens Unit
Other factors influencing environmental distribution
• Growth at low pH – acidic swamps and peats • Temperature resistance – survival in hot springs and hot water pipes • Oligotrophism – survival in environments with low level of nutrients, in particular when competitors have been eliminated by disinfectants
Emerging Bacterial Pathogens Unit
6 Tortoli - The world of nontuberculous mycobacteria
Intracellular organisms
Intracellular growth, in either amoebae or macrophages, results in increased virulence
Emerging Bacterial Pathogens Unit
Slow- and rapid-growers
Clear phylogenetic separation of slow- and rapid-growers with the latter being the more ancestral
Emerging Bacterial Pathogens Unit
The transmission of human infections
• Aerosol droplets (shower, hot tub, SPAs) – Pulmonary infections • Waterborne transmission – Cervical lymphadenitis in children – Cutis and soft tissues infections • Soil and dust – Post-traumatic infections (cutis and soft tissues, bone and joints)
Emerging Bacterial Pathogens Unit
7 Tortoli - The world of nontuberculous mycobacteria
Differences in pathogenicity
M. gordonae M AC M. malmoense M. terrae M. xenopi M. kansasii M. triviale M. celatum M. szulgai ...... M. shimoidei
Emerging Bacterial Pathogens Unit
. . . and in the genomic size
SPECIES ORFs M. smegmatis 6,940 M. rhodesiae 6,340 M. fortuitum 6,300 M. chubuense 6,070 M. kansasii 5,960 M. vanbaalenii 6,050 M. kansasii 5,960 M. marinum 5,500 M. avium 5,400 M. intracellulare 5,280 M. abscessus 4,990 M. ulcerans 4,310 M. tuberculosis 4,060 M. leprae 2,750 http://www.genomesonline.org
Emerging Bacterial Pathogens Unit
NTMs in the European Union
Croatia
Denmark M. avium Estonia M. gordonae Finland M. intracellulare Germany M. fortuitum
Greece M. xenopi M. malmoense Italy
Luxembourg
Netherlands
Slovenia
0 10203040506070 ECDC. Eurosurveillance. In press
Emerging Bacterial Pathogens Unit
8 Tortoli - The world of nontuberculous mycobacteria
NTMs in the European Union
M. avium M. gordonae M. intracellulare M. fortuitum M. xenopi M. chelonae M. abscessus M. kansasii M. malmoense Others
ECDC. Eurosurveillance. In press
Emerging Bacterial Pathogens Unit
NTMs, “green” bacteria?
• Evidence of the presence of rapid-growers in polluted soils • Ability to metabolize a variety of hydrocarbon pollutants
Emerging Bacterial Pathogens Unit
9 Cambau - Procedures for drug susceptibility testing in rapid and slow growing NTM
10 Cambau - Procedures for drug susceptibility testing in rapid and slow growing NTM
11 Cambau - Procedures for drug susceptibility testing in rapid and slow growing NTM
12 Cambau - Procedures for drug susceptibility testing in rapid and slow growing NTM
13 Cambau - Procedures for drug susceptibility testing in rapid and slow growing NTM
14 Cambau - Procedures for drug susceptibility testing in rapid and slow growing NTM
15 Cambau - Procedures for drug susceptibility testing in rapid and slow growing NTM
16 Cambau - Procedures for drug susceptibility testing in rapid and slow growing NTM
17 Cambau - Procedures for drug susceptibility testing in rapid and slow growing NTM
18 Bloemberg - Molecular mechanisms of drug resistance in NTM
Institut für Medizinische Mikrobiologie
Molecular mechanisms of drug resistance in NTM
Dr. Guido V. Bloemberg Institute of Medical Microbiology University of Zürich Zürich, Switzerland
12:00-12:30 Saturday 27th April ©CNRT
Institut für Medizinische Mikrobiologie Medical relevance of nontuberculous mycobacteria (NTM)
Examples:
M. leprae Leprosy M. abscessus, M. kansasii Lung disease M. avium Lymphadenitis M. ulcerans Cutaneous ulcers M. haemophilum Joint infections M. genavense Disseminated infections
Tortoli. Clinical manifestations of nontuberculous mycobacteria infections. Clin Microbiol Infect. 2009 Oct;15(10):906-10.
Institut für Medizinische Mikrobiologie Non-tuberculous mycobacteria - Slow growers; approx.60 species - M. avium - M. intracellulare - M. kansasii - M. genavense - M. leprae - M. xenopi
- Fast growers; approx. 70 species - M. fortuitum group - M. chelonae/M.abscessus group - M. smegmatis group - M. margeritense / M. wolinskyi group
19 Bloemberg - Molecular mechanisms of drug resistance in NTM
Institut für Medizinische Mikrobiologie What do we detect in the diagnostic laboratory?
Sequence based identification of NTM directly in clinical specimens during a 6-months period:
16S rRNA gene sequence identification n M. chelonae/abscessus complex 36 M. kansasii/gastri 10 M. avium 9 M. fortuitum 7 M. xenopi 3 M. mucogenicum 2 M. asiaticum 1 M. intracellulare 1 M. malmoense 1 Non-pathogenic mycobacteria 52 (mostly rapid growers)
Institut für Medizinische Mikrobiologie Most common used antibiotics for treatment of NTM infections
- Macrolides - Aminoglycosides - Rifampicin - Ethambutol - Fluoroquinolones - Tetracyclines
Institut für Medizinische Mikrobiologie
Resistance against antibiotics
- Intrinsic resistance - Modifying enzymes
- Acquired resistance - Chromosomal mutations
20 Bloemberg - Molecular mechanisms of drug resistance in NTM
Institut für Medizinische Mikrobiologie Reviews
Institut für Medizinische Mikrobiologie
Resistance against macrolides (protein synthesis)
Resistance against clarithromycin / erythromycin
- Intrinsic resistance - erm genes - Acquired resistance - 23S rRNA gene
Institut für Medizinische Mikrobiologie Resistance against aminoglycosides (protein synthesis)
- Intrinsic resistance: - Aminoglycoside modifying enzymes - Acetyltransferases - Phosphotransferases - Acquired resistance: - Mutations in 16S rRNA gene - Aminoglycoside phosphotransferase
21 Bloemberg - Molecular mechanisms of drug resistance in NTM
Institut für Medizinische Mikrobiologie Resistance against rifampin (RNA synthesis)
Fast growing non-tuberculous mycobacteria: - naturally resistant - possibly ADP ribosylases
Slow growing non-tuberculous mycobacteria: acquired resistance: mutations in rpoB
Institut für Medizinische Mikrobiologie
Resistance against ethambutol (arabinogalactan – arabinomannan synthesis)
- Acquired resistance - Mutations in embB, embR and other genes in the emb operon
- Intrinsic resistance - Polymorphisms in embB, lfrA, efflux pump
Institut für Medizinische Mikrobiologie
Clarithromycin resistance in Mycobacterium abscessus
22 Bloemberg - Molecular mechanisms of drug resistance in NTM
Institut für Medizinische Mikrobiologie M. abscessus
General information - Pulmonary infections; chronic infections - Risk groups: underlying pulmonary diseases, e.g. bronchiectasis and cystic fibrosis - a major complication following lung transplantation in CF patients - Treatment - surgical resection of focal bronchiectasis and cavitie - combination therapy including the macrolide larithromycin - only drug of demonstrated efficacy that can be administered orally
Institut für Medizinische Mikrobiologie Clarithromycin
- Macrolide - Binds to the 23 rRNA - Inhibits translation - Acid-stable, orally taken - High concentration in phagocytes
Institut für Medizinische Mikrobiologie Clarithromycin resistance in M. abscessus Two main resistance mechanisms: - Mutations in the drug-binding pocket, in particular at nucleotide positions 2058 and 2059, of the bacterial 23S rRNA gene confering high level Cla resistance (MIC = 256 mg/L) - Inducible erm gene - erm gene encodes: ribosomal methylase Erm (41) - mono- or di-methylate the adenine at position 2058 of the 23S rRNA - Erm genes have been described in many species of rapidly growing mycobacteria - Functionality dependent on the nucleotide at position 28 - WT 28T inducible resistance; mutant 28C loss of functionality
23 Bloemberg - Molecular mechanisms of drug resistance in NTM
Institut für Medizinische Mikrobiologie Does M. abscessus acquire resistance mutations in the rrl gene in addition to the presence of an inducible Erm(41) methylase ?
- Monitoring 5 patients over 2-4 years - 29 M. abscessus clinical isolates - Genetic and phenotypic characterisation - In three out of five patients acquisition of resistance mutations in the rrl gene in addition to the presence of an inducible Erm methylase
Institut für Medizinische Mikrobiologie
Phenotypic and genotypic monitoring
Institut für Medizinische Mikrobiologie Genotyping of M. abscessus isolates using RAPD-PCR.
Maurer F P et al. J. Antimicrob. Chemother. 2012;67:2606- 2611 © The Author 2012. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: [email protected]
24 Bloemberg - Molecular mechanisms of drug resistance in NTM
Institut für Medizinische Mikrobiologie Conclusion
Clarithromycin resistance mutations in the 23S rRNA
peptidyltransferase region provide an additional
selective advantage independent of a functional
erm(41) gene.
Institut für Medizinische Mikrobiologie Species dependent clarithromycin resistance
Interspecies differences in erm genes:
The Erm methylase in M. abscessus subsp. massiliense is dysfunctional due to: - 2 bp deletion of nucleotides 64–65 - 274 bp deletion of nucleotides 159–432
Institut für Medizinische Mikrobiologie Acknowledgements
Institute of Medical Microbiology
Florian Maurer Vera Rüegger Claudia Ritter Erik Böttger
25 Viveiros - Epidemiology of infections due to NTM
Educational Workshop / TAE Trainees Day Speaker
EW13: Infections due to non-tuberculous mycobacteria (NTM)
Epidemiology of infections due to NTM
Miguel Viveiros 27 April 2013
Instituto de Higiene e Medicina Tropical da Universidade Nova de Lisboa. Lisbon, Portugal
https://www.escmid.org/research_projects/study_groups/mycobacterial_infection/
Genus Mycobacterium: Mycobacterium tuberculosis 1882: Robert Koch Mycobacterium bovis 1896: Lehmann & Neumann Mycobacterium leprae Family: Mycobacteriaceae Order: Actinomycetales Class: Actinomycetes 1935: Pinner “Atypical acid-fast microorganisms” 1938: da Costa Cruz Mycobacterium fortuitum 1948: MacCallum et al. Mycobacterium ulcerans 1949: Cuttino & McCabe “Nocardia intracellulare” (M. intracellulare) 1951: Norden & Linell “M. balnei” (= M. marinum, 1926) 1955: Buhler & Pollak M. kansasii 1956: Masson & Prissick M. scrofulaceum 1959: Runyon: classification of “atypical” mycobacteria 1967: International Working Group on Mycobacterial Taxonomy (IWGMT)
Genus Mycobacterium
> 150 species
Mycobacterium tuberculosis complex M. tuberculosis, M. bovis, M. africanum, M. microti, M. canettii (M. caprae, M. pinnipedii, M. mungi)
v.s.
NTM – Non tuberculous mycobacteria (MNT) or MOTT - Mycobacteria other than tuberculosis or Atypical mycobacteria
26 Viveiros - Epidemiology of infections due to NTM
Genus Mycobacterium
> 150 species
Mycobacterium tuberculosis complex M. tuberculosis, M. bovis, M. africanum, M. microti, M. canettii (M. caprae, M. pinnipedii, M. mungi)
v.s.
NTM – Non tuberculous mycobacteria (MNT) or MOTT - Mycobacteria other than tuberculosis or Atypical mycobacteria – Nowdays became typical mycobacteria!
Genera Mycobacterium
> 150 species to date
Classification of nontuberculous mycobacterial diseases:
i) Risk of infection
ii) Clinical criteria
iii) The laboratorial diagnosis of NTM disease is complex and requires good communication between clinicians, radiologists, and microbiologists!
Swamps and bogs Ecology of the NTMs
• Ubiquitous, mostly environmental species • High adaptability to different ecological niches but the the still waters/ ponds/swamps/bogs are the most important source of NTMs • High temperatures, low [O2], low pH, high concentrations of [Zn] and [Fe], high concentrations of humic acids. • Hydrophobic nature >>> biofilms • Higher resistance to water treatments • Higher antibiotic resistance • Usually considered non-pathogenic • Pathogenicity depends on the immune status of the individual • Differentiation based on time of growth (slow growers vs. fast growers) and presence or absence of carotenoid pigmentation
27 Viveiros - Epidemiology of infections due to NTM
Laboratory classification of NTMs
Runyon criteria: growth rate; pigmentation
- Slow growers (> 7 days, solid media) (Runyon I, II, III) Runyon I (photochromogens: carotenoids accumulation after 1h of light exposure) e.g M. kansasii, M. marinum
Runyon II (scotochromogens: constitutive carotenoid accumulation) e.g M. gordonae, M. scrofulaceum
Runyon III (non chromogens: no pigmentation) e.g M. avium complex (M. avium, M. intracellulare) *Variable pigmentation
- Fast growers (< 7 dias) (Runyon IV) Runyon IV (non chromogens: no pigmentation) e.g M. fortuitum, M. chelonae, M. abcessus
NTM clinical syndromes in humans PULMONARY DISEASE LYMPHADENITIS Mainly in adults, rare in children, specially Commonest form of infection by in older persons with or without underlying NTM in children chronic lung disease and patients with cystic Initial injury in the gum or fibrosis; pharyngeal mucosa with subsequent Major NTM pathogens: M. avium complex lymphatic drainage to satellite and M. kansasii lymph nodes M. avium complex up to 80% in Symptoms similar to the pre-existing lung Southern Europe and in northern disease and TB Europe, M. malmoense and M. Fast growers: M. abscessus , M. fortuitum, haemophilum. M. xenopi, M. malmoense, M. szulgai, and M. simiae
NTM clinical syndromes in humans SKIN AND SOFT TISSUE DISSEMINATED DISEASE INFECTION Usually as a consequence of direct Mainly in severely immunocompromised inoculation, caused primarily by M. patients marinum and M. ulcerans and the Most commonly caused by MAC and less rapidly growing mycobacteria spp. commonly by the rapidly growing (RGM) infections in this category mycobacteria, M. abscessus, M. fortuitum, may be nosocomial, including and M. chelonae. surgical and esthetical site infections.
M. ulcerans M. avium complex M. marinum
28 Viveiros - Epidemiology of infections due to NTM
"CLASSIC“ CUTANEOUS INFECTIONS BY NTM
Cutaneous infections by Mycobacterium marinum and Mycobacterium ulcerans – difficult to isolate cultures in the laboratory, incubation period may vary from one week to two years.
M. marinum M. fortuitum, M. chelonae, M. abscessus, M. ulcerans
It inhabits swamps and bogs in West Africa, Agent of “tuberculosis" in fish from fresh or low Australia, China, Mexico and Latin America, salinity water that causes erythematous nodules and causing Buruli ulcer (Uganda, 1948) or granulomatous, single or multiple, and can progress to Baimsdale (Australia, 1960), which features necrosis and ulceration of the skin in aquarist slow and progressive evolution with significant (aquarium hobbyists) and users of pools, thermal destruction of skin and underlying tissues. baths or jacuzzis (granuloma of the pools).
Geographical distribution for Buruli´s ulcer
(Boleira et al. An. Bras Dermatol. 2010;85:281)
“MODERN” NON-TUBERCULOUS MYCOBACTERIA CUTANEOUS INFECTIONS
http://www.ncbi.nlm.nih.gov/sites/entrez
29 Viveiros - Epidemiology of infections due to NTM
“MODERN” CUTANEOUS INFECTION BY NTM
• M. abscessus •M. chelonae Apparatus for liposuction •M. fortuitum Mesotherapy solutions •M. xenopi Solutions and appliances for tattoos •M. scrofulaceum •M. gordonae •M. avium •M. furunculosis
Post-treatment subcutaneous abscesses in non-hospital environment Rapid dissemination in immunosuppression
“MODERN” CUTANEOUS INFECTION BY NTM
Recreational waters • M. abscessus •M. chelonae Pools 18-25ºC •M. xenopi Saunas 35-40ºC •M. fortuitum •M. gordonae (10x more mycobacteria) •M. avium Spa tubs aerosols •M. furunculosis • M. marinum
Patients with HIV-AIDS - dental clinics and hemodialysis Lifeguards and pool regulars - long exposure to aerosols Hospital hydrotherapy pools - children with cystic fibrosis - M. chelonae Skin infections in Spas and Beauty Salons Wound infection and transplantation. Risk of transmission during immunosuppression. http://www.stoptb.org; http://www.google.pt
"CLASSIC“ MAJOR RESPIRATORY INFECTIONS BY NTM
Respiratory infections by Mycobacterium avium and Mycobacterium kansasii - difficult to distinguish from M. tuberculosis in time for the implementation of appropriate therapy, resistant to 1st line tuberculostatic drugs
M. avium M. intracellulare , M. abscessus , M. kansasii
It exists in all soils and damp Agent of “bird tuberculosis“; causes lung environments causing lung infection very infection in immunocompetents, easily similar to tuberculosis rarely disseminated in immunosuppressed patients disseminated, even in (AIDS, leukemias, neoplasies, immunosuppressed patients. Frequent immunosuppressive therapy). It exists in soils, cause of cervical lymphadenitis in moist environments and water pipes. children.
30 Viveiros - Epidemiology of infections due to NTM
“MODERN” NON-TUBERCULOUS MYCOBACTERIA RESPIRATORY INFECTIONS CLEAR ASSOCIATION WITH CYSTIC FIBROSIS AND/OR COPD
THE MOST DIFFICULT CASES AT ANY AGE GROUP
http://www.ncbi.nlm.nih.gov/sites/entrez
CLINICAL SIGNIFICANCE
Isolation of M. kansasii and M. malmoense (in northwestern Europe) from pulmonary specimens usually indicates disease, whereas Mycobacterium gordonae and, to a lesser extent, M. simiae or M. chelonae are typically contaminants rather than causative agents of true disease. M. avium complex (MAC), M. xenopi, and M. abscessus form an intermediate category between these two extremes. (Jakko van Ingen, Diagnosis of Nontuberculous Mycobacterial Infections, Semin Respir Crit Care Med 2013; 34(01): 103-109
ROUTES OF TRANSMISSION OF NTMs
Immunocompromised patients - leukemia, transplant recipients, AIDS M. avium complex Aerosols
Patients with pre-existing lung diseases (CF & COPD) M. chelonae, M. fortuitum, Aerosols Tap-pipe-drinking M. abscessus /bolletii/massiliensis and M. xenopi and non sterile Water ! Hemophiliacs Dialysis machines M. chelonae, M. fortuitum, M. abscessus
Surgery patients - Medical supplies - needles, catheters, pacemaker contaminated solutions, bronchoscopes Contaminated material M. chelonae, M. fortuitum, M. abscessus /bolletii/massiliensis and M. xenopi http://www.stoptb.org/http://www.ncbi.nlm.nih.gov/sites/entrez
31 Viveiros - Epidemiology of infections due to NTM
NTMs geographical & epidemiological distribution Significant increase in NTM isolates over time in Canada, United States, United Kingdom, Netherlands, France, Spain and Portugal. Significant predominance of M. avium complex in respiratory infections.
Estimated prevalence of average >10 per 100,000 in Europe » Marras, T. K et al. Thorax 2007 » Van Ingen J, et al. Thorax 2009 » Couto I, et al. CMI 2010 » Prevots DR, et al. AJRCCM 2009 and 2010 » Amorim A et al. Scand J Infect Dis. 2010 » McCallum AD et al. J R Coll Physicians Edinb. 2011 » Couderc C, AD et al. Med Mal Infect. 2011 » García-Martos P & García-Agudo L. Enferm Infecc Microbiol Clin. 2012.
Estimated prevalence of 14 to 35 per 100,000 in Canada and the U.S. » Marras, T. K et al. AJRCCM 2008 » Billinger ME et al. Emerg Infect Dis. 2009 » Winthrop K, et al. AJRCCM 2010 » Prevots DR, et al. AJRCCM 2010
» Kendall BA &Winthrop KL.Semin Respir Crit Care Med. 2013 http://www.ncbi.nlm.nih.gov/sites/entrez
NTMs geographical & epidemiological distribution
Significant increase in NTM isolates over time in Asia with a significant predominance of M. avium complex
THE EXAMPLE OF PORTUGAL
Mycobacteria Lab. IHMT/UNL : January 2005 to December 2007
32 Viveiros - Epidemiology of infections due to NTM
Opportunistic infections of the immunosupressed
M. avium complex: Mycobacterium Mycobacterium avium avium avium complex subspecies MAC Mycobacterium avium subspecies hominissuis Mycobacterium avium subspecies paratuberculosis Mycobacterium intracellulare
The most frequent of all NTMs causing infection in humans globally also found in Portugal
Which M. avium subspecies is most prevalent?
www.healthcaremagic.com
80% Mycobacterium avium subspecies hominissuis
Submitted to IJMM, 2013
28 strains isolated from 69 strains isolated from human samples - porcine samples (lymph hospitals from the nodes) - regions across Lisbon Health Region mainland Portugal between between 2005 and 2011 2004 and 2006
Submitted to IJMM, 2013
Typed by Mycobacterium avium tandem repeats (MATR)-VNTR
The MAH isolates were found to be genetically diverse and genotypes are randomly distributed across the country.
None of the human strains shared identical profiles with porcine isolates, albeit a few profiles differed by only a single tandem repeat copy.
Both humans and pigs seem to be infected by the pool of environment-inhabiting opportunistic MAH strains rather than by specific and/or potentially high virulent and prevalent clones.
Comparative analysis using Portuguese MAH environmental strains, including from soil or water sources, are envisaged to ascertain if environmental strains are the main source of infections.
33 Viveiros - Epidemiology of infections due to NTM
Opportunistic infections of the immunosupressed RECOMMENDED READING
NTMs ?
Look in the environment !
www.healthcaremagic.com
Acknowledgments THE IHMT TEAM
INSTITUTE OF HYGIENE AND TROPICAL MEDICINE
THE INIAV & FCT/UNL TEAM Célia Leão Ilda Santos Sanches João Inácio Ana Botelho
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