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Nontuberculous Mycobacteria (Ntm)

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Nontuberculous Mycobacteria (Ntm) Ting-Shu Wu, M.D. Infection Control Committee Infect Dis, Int Med, Chang Gung Memorial Hospital, Linkou Medical Center, Tao-Yuan, Taiwan NTM Other than M. tuberculosis, M. africanum, M. bovis, M. caprae, M. microti, M. canettii, M. mungi, M. orygis, and M. pinnipedii (M. tuberculosis complex), and M. leprae. Previous names: atypical mycobacteria, mycobacteria other than M. tuberculosis (MOTT) Taxonomic Tree M. tuberculosis complex Mycobacteriaceae Mycobacterium M. leprae Nocardia NTM Actinomycetales Actinomycetaceae Actinomyces S. griseus Streptomycetaceae Streptomyces S. mediterranei Currently recognized species of the genus Mycobacteria isolated form humans Group Obligatory Facultative Potential Saprophyte Strict pathogens M. africanum M. bovis M. leprae M. tuberculosis M. ulcerans Photochromogens M. asciaticum M. kansasii M. marinum M. simiae Scotochromogens M. scrofulaceum M. gordonae M. szulgai M. flavescens M. xenopi Nonchromogens M. genavense M. avium M. gastri M. haemophilum M. nonchromogenicum M. intracellulare M. terrae M. malmoense M. triviale M. shimoidei Rapid growers M. chelonae M. fallax M. agri…….. M. fortuitum M. smegmatis Strict animal M. farcinogens M. microti pathogens M. lepraemurium M. paratuberculosis M. porcinum M. senegalense Runyon classification Class I (photochromogens) Class II (scotochromogens) Class III (nonchromogens) Class IV ( rapid growers) Structure A: plasma membrane B: complex polymer C: peptidoglycans D: arabinogalactans E: mycolic acids F: methoxy type & keto type G: glycolipid H: lipoarabinomannan Microbiology Acid fast stain Ziehl-Neelson stain (dry stain), or Kinyoun stain (wet stain) Fluorescent staining Culture: 7H9 (broth), 7H11 (agar), Löwenstein-Jensen medium (slant), MGIT 960 (Mycobacteria Growth Indicator Tube) Manual of Clinical Microbiology, Vols. 1 and 2: Eighth Edition RFLP (Telenti et al.) MALDI-TOF/MS Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry Slowly Growing Mycobacteria Mycobacterium avium complex At present, the M avium complex M avium M intracellulare M chimaera (MAC-A) M colombiense (MAC-X) M vulneris (MAC-Q) M marseillense M timonense M bouchedurhonense M arosiense Claudio Piersimoni, Claudio Scarparo Lancet Infect Dis 2008; 8: 323–34 Manual of Clinical Microbiology 11/e Mycobacterium avium M. avium subsp. avium M. avium subsp. silvarticum M. avium subsp. paratuberculosis M. avium subsp. hominissuis Mycobacterium avium complex M. intracellulare represents about 70% of M. avium complex isolates and its prognosis appears to be slightly more favourable than that of M. avium disease. PROPHYLAXIS AGAINST DISSEMINATED MYCOBACTERIUM AVIUM COMPLEX WITH WEEKLY AZITHROMYCIN, DAILY RIFABUTIN, OR BOTH Weekly azithromycin is a simple, highly effective prophylactic regimen. The combination of azithromycin and rifabutin is more efficacious, but its use may be limited by its tolerability and cost and by potential drug interactions. Havlir DV et al. N Engl J Med 1996;335:392-398. Regimens for the treatment of disseminated MAC disease in patients with HIV infection Preferred regimens Additional drugs CLR 500 BID + EMB for macrolide- 15 mg/kg QD (+RFB resistant infections 300 QD) Moxifloxacin 400 QD, AZI 600 QD + EMB or Levofloxacin 500– 15 mg/kg QD (+RFB 750 mg QD + EMB 15 300 QD) mg/kg QD + RFB 300 QD + AMK 10–15 mg/kg QD Mycobacterium avium complex Primary prophylaxis : azithromycin alone > rifabutin alone at reducing the incidence of MAC at 1 year in HIV positive people. Azithromycin or rifabutin alone < AZI+RFB Mortality: AZI = RFB = AZI+RFB ADR: AZI < AZI+RFB Jakko van Ingen et al. AJRCCM Am J Respir Crit Care Med. 2012 Sep 15;186(6):559-65. Mycobacterium kansasii Tenosynovitis Mycobacterium kansasii Mycobacterium marinum Wu TS et al. PLoS ONE. 2012;7(7):e41296 Wu TS et al. PLoS ONE. 2012;7(7):e41296 Wu TS et al. PLoS ONE. 2012;7(7):e41296 Figure 1. Cutaneous manifestations of Mycobacterium marinum infections. Wu T-S, Chiu C-H, Yang C-H, Leu H-S, et al. (2012) Fish Tank Granuloma Caused by Mycobacterium marinum. PLoS ONE 7(7): e41296. doi:10.1371/journal.pone.0041296 http://www.plosone.org/article/info:doi/10.1371/journal.pone.0041296 Treatment regimens Species Disease Drug Dose Duration M. avium Pulmonary CLR+EMB 500 bid, 15 Until +RIF or mg/kg, 600 negative complex mg, 150-300 culture for RFT mg 12 mo Disseminated, CLR+EMB 500 bid, 15 For life? HIV+ +RFT mg/kg, 300 mg LAP, Surgery, children CLR+RFT, OR EMB Treatment regimens (2) Species Disease Drug Dose Duration M. pulmonary INH+RIF 300, 600, 18 mo, 15 mg/kg culture Kansasii +EMB ?? negative for 12 mo disseminated same same HIV+ RIF RFB Treatment regimens (3) Species Disease Drug Dose Duration M. cutaneous CLR or 500 bid, 100 At least 3 minocycline bid, 600, 15 mo marinum or RIF+EMB mg/Kg Rapidly Growing Mycobacteria RGM Grow within 7 days on laboratory media. M. fortuitum group M. chelonae/M. abscessus group M. mucogenicum group M. smegmatis group Early-pigmented group M. mageritense/M. wolinskyi group Breakpoints of RGM S I R AMK <16 32 >64 FOX <16 32-64 >128 CIP <1 2 >4 CLR <2 4 >8 DOX <1 2-4 >8 IPM <4 8-16 >32 LZD <8 16 >32 MEM <4 8-16 >32 MXF <1 2 >4 SXT <2/38 >4/76 TOB <2 4 >8 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 2002, p. 3164–3167 CID 2006:42 (15 June) • 1759 Clincal significance Common in environment Most identified in tap water M. fortuitum, M. abscessus, M. chelonae for > 80% Clincal significance Skin and soft tissue infections Disseminated cutaneous disease Bone and joint infections Pulmonary infections Central nervous system disease Corneal infections Otitis media Health care-associated infections M. abscessus sensu lato M. abscessus sensu stricto M. massiliense M. bolletii Mycobacterium abscessus M. abscessus M. abscessus subsp. abscessus M. massiliense and M. bolletii M. abscessus subsp. bolletii Mother Daughter M Mo D1 D2 D3 48.5 Kb Lin CY, Hsu CY, Wu TS et al. Unpublished data Before After Antibiotic susceptibility and efficacy Modal MICs are below the tissue or serum levels only for clarithromycin, aminoglycosides, cefoxitin, tigecycline and TMC-207. Recommendations are now to combine clarithromycin with one aminoglycoside (usually amikacin) and one other injectable drug such as cefoxitin or imipenem. Clinical efficacy of this multidrug therapy is still controversial, with success for some patients and failure for others Natural resistance The mycobacterial cell envelope Antibiotic-modifying / inactivating enzymes Target-modifying enzymes Efflux pumps Transcriptional regulator whiB gene family Genetic polymorphism of target genes Mercury resistance Macrolide resistance Bacterial resistance to macrolides occurs by post- transcriptional methylation of the 23S bacterial ribosomal RNA, thereby inhibiting drug attachment This acquired resistance results in cross- resistance to macrolides, lincosamides and streptogramins Resistance to macrolides acquired by mutation in the rrl gene encoding the 23S rRNA generally occurs in mycobacterial species M. abscessus group: M. abscessus (sensu stricto), M. massiliense and M. bolletii M. massiliense, which harbours a truncated erm(41) gene, is intrinsically susceptible to clarithromycin, whereas M. abscessus sensu stricto contains a complete erm(41) gene Strains identified as M. abscessus with a C28 polymorphism are associated with clarithromycin susceptibility, whereas a T28 polymorphism is associated with clarithromycin resistance. M. bolletii, which contains the T28 polymorphic erm(41) gene, was shown to be clarithromycin resistant Case 1. erm(41) of M. massiliense ATCC19977 Soft tissue infection cases Wu T.-S. et al. JMII. Online published Antibiotics for Rapid Growers Bacteria Parenteral Oral M. abscessus Amikacin, imipenem Clarithromycin, quinolones, sulfonamides M. chelonae Amikacin (tobramycin), Clarithromycin imipenem M. fortuitum Amikacin, cefoxitin Clarithromycin M. smegmatis Amikacin, imipenem Doxycycline, quinolones, sulfonamides Thank you for your attention! .
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