- Email: [email protected]
Epidemiologia e ecologia de micobactérias não tuberculosas
Epidemiologia e ecologia de micobactérias não tuberculosas
Joseph O Falkinham III1
Epidemiology and ecology of nontuberculous mycobacteria
As micobactérias não tuberculosas (MNT) são patogénios oportunistas dos humanos e animais encontrados no meio ambiente1,2. Nos Estados Unidos, a prevalência de doenças por MNT vem aumentando 8% ao ano, atingindo atualmente quase 35 casos por cada 100 0003. Em Ontário, Canadá, a prevalência de doença pulmonar por MNT aumentou de 1,5 para 9,0 por 100 000 (6 vezes) no período 1997-20034. A evidência de que o ambiente é a fonte das doenças por MNT em seres humanos foi conseguida a partir do ADN de isolados de MNT de doentes com SIDA, de água de beber5 e de doentes imunocompetentes e de isolados de MNT de terra de vasos6 ou de um chuveiro doméstico7. Os seres humanos estão continuamente expostos a MNT, uma vez que estes vivem e crescem normalmente nos sistemas de distribuição da água de beber8, e 20% das amostras recolhidas em biofilmes nas cabeças dos chuveiros domésticos nos Estados Unidos tinham M. avium9.
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Nontuberculous mycobacteria (NTM) are opportunistic human and animal environmental pathogens1,2. In the United States, the prevalence of NTM disease is increasing by 8% per year and now stands at almost 35 cases per 100 0003. In Ontario, Canada the prevalence of NTM pulmonary disease increased from 1.5 to 9.0 per 100 000 (6-fold increase) over the period 1997-20034. Evidence that the environment was the source of NTM disease in humans was gained from the identity of DNA fingerprints of NTM isolates from AIDS patients and drinking water5 and from immunocompetent patients and NTM isolates from potting soils6 or a home shower7. Humans are continually exposed to nontuberculous mycobacteria (NTM) as they are normal inhabitants and grow in drinking water distribution systems8 and 20 % of showerhead biofilms (swab samples) collected from households in the United States had M. avium9.
Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0406 Phone 1-540-231-5931 Fax 1-540-231-9307 e-mail: [email protected]
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Os fatores de risco para doenças por MNT incluem: imunocompetência diminuída devido a infeção por VIH, cancro, quimioterapia, ou imunossupressão associada a transplantação, doença pulmonar preexistente, como pneumoconiose, silicose e doença do pulmão negro, alterações na arquitetura normal do tronco, alcoolismo e hábitos tabágicos10. Recentemente, mutações no regulador da condutância transmembranária na fibrose quística (RCTFQ) e genes de α-1-antitripsina têm sido associados ao risco aumentado de doença pulmonar por MNT11. É preocupante o facto de a doença pulmonar por MNT ter aumentado drasticamente entre homens e mulheres idosos magros que, não tendo os fatores de risco clássicos para doença micobacteriana, parecem ser substancialmente mais suscetíveis a doenças por MNT12. Com o envelhecimento das populações, é expectável que o número de idosos com doença pulmonar por MNT aumente, com o consequente peso para os prestadores de cuidados de saúde. A terapêutica recomendada para infeções por MNT inclui múltiplos antibióticos (e.g., claritromicina, etambutol e rifampin) por períodos de 24 meses13. As micobactérias não tuberculosas sobrevivem, crescem e persistem em habitats partilhados por seres humanos e animais. São oligotróficos, podendo crescer em água com mais de 50 μg de carbono orgânico assimilável (COA/)L14. A presença de grandes quantidades de MNT em pântanos de águas escuras e ácidas15 e no solo de pinhais16 deve-se, em parte, ao crescimento estimulado pela matéria orgânica do solo raramente metabolizada por outros microrganismos, nomeadamente ácidos húmico e fúlvico17. As micobactérias têm uma verdadeira membrana externa18, cujos ácidos micólicos de
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Risk factors for NTM disease include: reduced immune competence as a result of HIV infection, cancer, chemotherapy, or immunosuppression associated with transplantation, preexisting lung disease such as pneumoconiosis, silicosis, and black lung disease, altered normal chest architecture, alcoholism, and smoking10. Recently, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) and α-1-antitrypsin genes have been associated with increased risk of NTM pulmonary disease11. Quite alarming is the fact that pulmonary NTM disease has increased dramatically amongst elderly slender men and women, who lack the classic risk factors for mycobacterial disease, yet appear to be substantially more susceptible to NTM disease12. As the human population ages, it would be expected that the number of elderly with NTM pulmonary disease will increase, placing further demands on healthcare providers. Recommended therapy for NTM infections include multiple antibiotics (e.g., clarithromycin, ethambutol, and rifampin) for periods as long as 24 months13. NTM survive, grow, and persist in a number of habitats that are shared with humans and animals. NTM are oligotrophs; able to grow in water containing greater than 50 μg assimilable organic carbon (AOC/)L14. The presence of high numbers of NTM in coastal acidic, brown water swamps15 and pine forest soils16 is due, in part, to the growth stimulation by soil organic matter material rarely metabolized by other microorganisms; namely humic and fulvic acids17. Mycobacteria have a true outer membrane18, whose long chain mycolic acids
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Vol XVI Suplemento 1 A Janeiro 2010
Epidemiologia e ecologia de micobactérias não tuberculosas (MNT) Joseph O Falkinham III
cadeia longa contribuem para a hidrofobicidade, impermeabilidade e crescimento lento das células de MNT19. A hidrofobicidade da superfície das células de MNT é a mais elevada de todas as bactérias e é uma importante determinante da fagocitose dos macrófagos20. Embora a parede hidrofóbica reduza o índice de transferência de nutrientes hidrofílicos, contribui para a resistência a desinfetantes (e.g., cloro e biócidos) e a antibióticos21,22. As MNT penetram nos sistemas de tratamento de águas aderentes a partículas, sobrevivem à desinfeção e crescem em biofilmes na ausência de competidores mortos pela disinfeção8. A formação de biofilme também aumenta a resistência das MNT a desinfetantes23 e a antibióticos24. A hidrofobicidade também promove a aerossolização de micobactérias da água para o ar em ambientes como chuveiros e banheiras domésticos e nas profissões onde se manuseiam aerossóis25.
contribute to the hydrophobicity, impermeability, and slow growth of NTM cells19. The surface hydrophobicity of NTM cells is the highest amongst bacteria and is a major determinant of phagocytosis by macrophages20. Although the hydrophobic wall reduces the rate of transfer of hydrophilic nutrients, it contributes to disinfectant- (e.g., chlorine and biocides) and antibiotic-resistance21,22. NTM enter a water treatment system on particulates, survive disinfection, and grow in biofilms in the absence of competitors killed by disinfection8. Biofilm formation also increases NTM resistance to disinfectants23 and antibiotics24. Hydrophobicity also promotes the aerosolization of mycobacteria from water to air in environments such as showers and hot tubs in the home and occupations where aerosols are generated25.
Bibliografia/Bibliography 1. Wallace RJ, Brown BA, Griffith DE. Nosocomial outbreaks pseudo-outbreaks caused by nontuberculous mycobacteria. Annu Rev Microbiol 1998; 52;453-490. 2. Falkinham JO III. Surrounded by mycobacteria: nontuberculous mycobacteria in the human environment. J Appl Microbiol 2009; 107;356-367. 3. Iseman MD, Marras TK. The importance of nontuberculous mycobacterial lung disease. Am J Respir Crit Care Med 2008; 178:999-1000. 4. Marras TK, et al. Isolation prevalence of pulmonary non-tuberculous mycobacteria in Ontario, 1997-2003. Thorax 2007; 62;661-666. 5. von Reyn CF, et al. Persistent colonisation of potable water as a source of Mycobacterium avium infection in AIDS. Lancet 1994;343;1137-1141. 6. De Groote MA, et al. Relationships between Mycobacterium isolates from patients with pulmonary mycobacterial infection and potting soils. 2006; Appl Environ Microbiol 2006;72;7602-7606.
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7. Falkinham JO III, et al. Mycobacterium avium in a shower linked to pulmonary disease. J Water Health 2008; 6;209-213. 8. Falkinham JO III, Norton CD, LeChevallier MW. Factors influencing numbers of Mycobacterium avium, Mycobacterium intracellulare, and other Mycobacteria in drinking water distribution systems. Appl Environ Microbiol 2001; 67;1225-1231. 9. Feazel LM, et al. Opportunistic pathogens enriched in showerhead biofilms. Proc Natl Acad Sci USA 2009;106;16393-16399. 10. Marras TK, Daley CL. Epidemiology of human pulmonary infection with nontuberculous mycobacteria. Clin Chest Med 2002; 23;553-567. 11. Kim JS, et al. Nontuberculous mycobacterial infection: CT scan findings, genotype, and treatment responsiveness. Chest 2005; 128;3863-3869. 12. Kennedy TP, Weber DJ. Nontuberculous mycobacteria – an underappreciated cause of geriatric lung di-
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sease. Am Rev Respir Crit Care Med 1994;149;1654-1658. 13. Griffith DE, et al. An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175;367-416. 14. Norton CD, LeChevallier MW, Falkinham JO III. Survival of Mycobacterium avium in a model distribution system. Water Res 2005; 38;1457-1466. 15. Kirschner RA Jr, Parker BC, Falkinham JO III. Epidemiology of infection by nontuberculous mycobacteria. Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium scrofulaceum in acid, brown-water swamps of the southeastern United States and their association with environmental variables. Am Rev Respir Dis 1992; 145;271-275. 16. Iivanainen EK, et al. Mycobacteria in boreal coniferous forest soils. FEMS Microbiol Ecol 1997;23;325-332. 17. Kirschner RA, Parker BC, Falkinham JO III. Humic and fulvic acids stimulate the growth of Mycobacterium avium. FEMS Microbiol Ecol 1995; 30;327-332. 18. Hoffmann C, et al. Disclosure of the mycobacterial outer membrane: Cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proc Natl Acad Sci USA 2008; 105;3963-3967.
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19. Brennan PJ, Nikaido H. The envelope of mycobacteria. Annu Rev Biochem 1995; 64;29-63. 20. van Oss CJ, Gillman CF, Neumann AW. Phagocytic engulfment and cell adhesiveness. 1975; Marcel Dekker, New York. 21. Rastogi N, et al. Multiple drug resistance in Mycobacterium avium – Is the wall architecture responsible for the exclusion of antimicrobial agents. Antimicrob Agents Chemother 1981; 20;666-677. 22. Taylor R, et al. Chlorine, chloramine, chlorine dioxide, and ozone susceptibility of Mycobacterium avium. Appl Environ Microbiol 2000; 66;1702-1705. 23. Steed KA Falkinham JO III. Effect of growth in biofilms on chlorine susceptibility of Mycobacterium avium and Mycobacterium intracellulare. Appl Environ Microbiol 2006; 72;4007-4011. 24. Falkinham, JO III. Growth in catheter biofilms and antibiotic resistance of Mycobacterium avium. J Med Microbiol 2007; 56;250-254. 25. Parker BC, George KL, Falkinham JO III. Epidemiology of infection by nontuberculous mycobacteria. IV. Preferential aerosolization of Mycobacterium intracellulare from natural waters. Am Rev Respir Dis 1984; 123;652-656.
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Vol XVI Suplemento 1 A Janeiro 2010
Joseph O Falkinham III1
Epidemiology and ecology of nontuberculous mycobacteria
As micobactérias não tuberculosas (MNT) são patogénios oportunistas dos humanos e animais encontrados no meio ambiente1,2. Nos Estados Unidos, a prevalência de doenças por MNT vem aumentando 8% ao ano, atingindo atualmente quase 35 casos por cada 100 0003. Em Ontário, Canadá, a prevalência de doença pulmonar por MNT aumentou de 1,5 para 9,0 por 100 000 (6 vezes) no período 1997-20034. A evidência de que o ambiente é a fonte das doenças por MNT em seres humanos foi conseguida a partir do ADN de isolados de MNT de doentes com SIDA, de água de beber5 e de doentes imunocompetentes e de isolados de MNT de terra de vasos6 ou de um chuveiro doméstico7. Os seres humanos estão continuamente expostos a MNT, uma vez que estes vivem e crescem normalmente nos sistemas de distribuição da água de beber8, e 20% das amostras recolhidas em biofilmes nas cabeças dos chuveiros domésticos nos Estados Unidos tinham M. avium9.
1
Nontuberculous mycobacteria (NTM) are opportunistic human and animal environmental pathogens1,2. In the United States, the prevalence of NTM disease is increasing by 8% per year and now stands at almost 35 cases per 100 0003. In Ontario, Canada the prevalence of NTM pulmonary disease increased from 1.5 to 9.0 per 100 000 (6-fold increase) over the period 1997-20034. Evidence that the environment was the source of NTM disease in humans was gained from the identity of DNA fingerprints of NTM isolates from AIDS patients and drinking water5 and from immunocompetent patients and NTM isolates from potting soils6 or a home shower7. Humans are continually exposed to nontuberculous mycobacteria (NTM) as they are normal inhabitants and grow in drinking water distribution systems8 and 20 % of showerhead biofilms (swab samples) collected from households in the United States had M. avium9.
Department of Biological Sciences, Virginia Tech, Blacksburg, Virginia 24061-0406 Phone 1-540-231-5931 Fax 1-540-231-9307 e-mail: [email protected]
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Epidemiologia e ecologia de micobactérias não tuberculosas (MNT) Joseph O Falkinham III
Os fatores de risco para doenças por MNT incluem: imunocompetência diminuída devido a infeção por VIH, cancro, quimioterapia, ou imunossupressão associada a transplantação, doença pulmonar preexistente, como pneumoconiose, silicose e doença do pulmão negro, alterações na arquitetura normal do tronco, alcoolismo e hábitos tabágicos10. Recentemente, mutações no regulador da condutância transmembranária na fibrose quística (RCTFQ) e genes de α-1-antitripsina têm sido associados ao risco aumentado de doença pulmonar por MNT11. É preocupante o facto de a doença pulmonar por MNT ter aumentado drasticamente entre homens e mulheres idosos magros que, não tendo os fatores de risco clássicos para doença micobacteriana, parecem ser substancialmente mais suscetíveis a doenças por MNT12. Com o envelhecimento das populações, é expectável que o número de idosos com doença pulmonar por MNT aumente, com o consequente peso para os prestadores de cuidados de saúde. A terapêutica recomendada para infeções por MNT inclui múltiplos antibióticos (e.g., claritromicina, etambutol e rifampin) por períodos de 24 meses13. As micobactérias não tuberculosas sobrevivem, crescem e persistem em habitats partilhados por seres humanos e animais. São oligotróficos, podendo crescer em água com mais de 50 μg de carbono orgânico assimilável (COA/)L14. A presença de grandes quantidades de MNT em pântanos de águas escuras e ácidas15 e no solo de pinhais16 deve-se, em parte, ao crescimento estimulado pela matéria orgânica do solo raramente metabolizada por outros microrganismos, nomeadamente ácidos húmico e fúlvico17. As micobactérias têm uma verdadeira membrana externa18, cujos ácidos micólicos de
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Risk factors for NTM disease include: reduced immune competence as a result of HIV infection, cancer, chemotherapy, or immunosuppression associated with transplantation, preexisting lung disease such as pneumoconiosis, silicosis, and black lung disease, altered normal chest architecture, alcoholism, and smoking10. Recently, mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) and α-1-antitrypsin genes have been associated with increased risk of NTM pulmonary disease11. Quite alarming is the fact that pulmonary NTM disease has increased dramatically amongst elderly slender men and women, who lack the classic risk factors for mycobacterial disease, yet appear to be substantially more susceptible to NTM disease12. As the human population ages, it would be expected that the number of elderly with NTM pulmonary disease will increase, placing further demands on healthcare providers. Recommended therapy for NTM infections include multiple antibiotics (e.g., clarithromycin, ethambutol, and rifampin) for periods as long as 24 months13. NTM survive, grow, and persist in a number of habitats that are shared with humans and animals. NTM are oligotrophs; able to grow in water containing greater than 50 μg assimilable organic carbon (AOC/)L14. The presence of high numbers of NTM in coastal acidic, brown water swamps15 and pine forest soils16 is due, in part, to the growth stimulation by soil organic matter material rarely metabolized by other microorganisms; namely humic and fulvic acids17. Mycobacteria have a true outer membrane18, whose long chain mycolic acids
d e
P n e u m o l o g i a
Vol XVI Suplemento 1 A Janeiro 2010
Epidemiologia e ecologia de micobactérias não tuberculosas (MNT) Joseph O Falkinham III
cadeia longa contribuem para a hidrofobicidade, impermeabilidade e crescimento lento das células de MNT19. A hidrofobicidade da superfície das células de MNT é a mais elevada de todas as bactérias e é uma importante determinante da fagocitose dos macrófagos20. Embora a parede hidrofóbica reduza o índice de transferência de nutrientes hidrofílicos, contribui para a resistência a desinfetantes (e.g., cloro e biócidos) e a antibióticos21,22. As MNT penetram nos sistemas de tratamento de águas aderentes a partículas, sobrevivem à desinfeção e crescem em biofilmes na ausência de competidores mortos pela disinfeção8. A formação de biofilme também aumenta a resistência das MNT a desinfetantes23 e a antibióticos24. A hidrofobicidade também promove a aerossolização de micobactérias da água para o ar em ambientes como chuveiros e banheiras domésticos e nas profissões onde se manuseiam aerossóis25.
contribute to the hydrophobicity, impermeability, and slow growth of NTM cells19. The surface hydrophobicity of NTM cells is the highest amongst bacteria and is a major determinant of phagocytosis by macrophages20. Although the hydrophobic wall reduces the rate of transfer of hydrophilic nutrients, it contributes to disinfectant- (e.g., chlorine and biocides) and antibiotic-resistance21,22. NTM enter a water treatment system on particulates, survive disinfection, and grow in biofilms in the absence of competitors killed by disinfection8. Biofilm formation also increases NTM resistance to disinfectants23 and antibiotics24. Hydrophobicity also promotes the aerosolization of mycobacteria from water to air in environments such as showers and hot tubs in the home and occupations where aerosols are generated25.
Bibliografia/Bibliography 1. Wallace RJ, Brown BA, Griffith DE. Nosocomial outbreaks pseudo-outbreaks caused by nontuberculous mycobacteria. Annu Rev Microbiol 1998; 52;453-490. 2. Falkinham JO III. Surrounded by mycobacteria: nontuberculous mycobacteria in the human environment. J Appl Microbiol 2009; 107;356-367. 3. Iseman MD, Marras TK. The importance of nontuberculous mycobacterial lung disease. Am J Respir Crit Care Med 2008; 178:999-1000. 4. Marras TK, et al. Isolation prevalence of pulmonary non-tuberculous mycobacteria in Ontario, 1997-2003. Thorax 2007; 62;661-666. 5. von Reyn CF, et al. Persistent colonisation of potable water as a source of Mycobacterium avium infection in AIDS. Lancet 1994;343;1137-1141. 6. De Groote MA, et al. Relationships between Mycobacterium isolates from patients with pulmonary mycobacterial infection and potting soils. 2006; Appl Environ Microbiol 2006;72;7602-7606.
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7. Falkinham JO III, et al. Mycobacterium avium in a shower linked to pulmonary disease. J Water Health 2008; 6;209-213. 8. Falkinham JO III, Norton CD, LeChevallier MW. Factors influencing numbers of Mycobacterium avium, Mycobacterium intracellulare, and other Mycobacteria in drinking water distribution systems. Appl Environ Microbiol 2001; 67;1225-1231. 9. Feazel LM, et al. Opportunistic pathogens enriched in showerhead biofilms. Proc Natl Acad Sci USA 2009;106;16393-16399. 10. Marras TK, Daley CL. Epidemiology of human pulmonary infection with nontuberculous mycobacteria. Clin Chest Med 2002; 23;553-567. 11. Kim JS, et al. Nontuberculous mycobacterial infection: CT scan findings, genotype, and treatment responsiveness. Chest 2005; 128;3863-3869. 12. Kennedy TP, Weber DJ. Nontuberculous mycobacteria – an underappreciated cause of geriatric lung di-
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Epidemiologia e ecologia de micobactérias não tuberculosas (MNT) Joseph O Falkinham III
sease. Am Rev Respir Crit Care Med 1994;149;1654-1658. 13. Griffith DE, et al. An official ATS/IDSA statement: Diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases. Am J Respir Crit Care Med 2007; 175;367-416. 14. Norton CD, LeChevallier MW, Falkinham JO III. Survival of Mycobacterium avium in a model distribution system. Water Res 2005; 38;1457-1466. 15. Kirschner RA Jr, Parker BC, Falkinham JO III. Epidemiology of infection by nontuberculous mycobacteria. Mycobacterium avium, Mycobacterium intracellulare, and Mycobacterium scrofulaceum in acid, brown-water swamps of the southeastern United States and their association with environmental variables. Am Rev Respir Dis 1992; 145;271-275. 16. Iivanainen EK, et al. Mycobacteria in boreal coniferous forest soils. FEMS Microbiol Ecol 1997;23;325-332. 17. Kirschner RA, Parker BC, Falkinham JO III. Humic and fulvic acids stimulate the growth of Mycobacterium avium. FEMS Microbiol Ecol 1995; 30;327-332. 18. Hoffmann C, et al. Disclosure of the mycobacterial outer membrane: Cryo-electron tomography and vitreous sections reveal the lipid bilayer structure. Proc Natl Acad Sci USA 2008; 105;3963-3967.
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19. Brennan PJ, Nikaido H. The envelope of mycobacteria. Annu Rev Biochem 1995; 64;29-63. 20. van Oss CJ, Gillman CF, Neumann AW. Phagocytic engulfment and cell adhesiveness. 1975; Marcel Dekker, New York. 21. Rastogi N, et al. Multiple drug resistance in Mycobacterium avium – Is the wall architecture responsible for the exclusion of antimicrobial agents. Antimicrob Agents Chemother 1981; 20;666-677. 22. Taylor R, et al. Chlorine, chloramine, chlorine dioxide, and ozone susceptibility of Mycobacterium avium. Appl Environ Microbiol 2000; 66;1702-1705. 23. Steed KA Falkinham JO III. Effect of growth in biofilms on chlorine susceptibility of Mycobacterium avium and Mycobacterium intracellulare. Appl Environ Microbiol 2006; 72;4007-4011. 24. Falkinham, JO III. Growth in catheter biofilms and antibiotic resistance of Mycobacterium avium. J Med Microbiol 2007; 56;250-254. 25. Parker BC, George KL, Falkinham JO III. Epidemiology of infection by nontuberculous mycobacteria. IV. Preferential aerosolization of Mycobacterium intracellulare from natural waters. Am Rev Respir Dis 1984; 123;652-656.
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Vol XVI Suplemento 1 A Janeiro 2010