Ting-Shu Wu, M.D. Infection Control Committee Infect Dis, Int Med, Chang Gung Memorial Hospital, Linkou Medical Center, Tao-Yuan, Taiwan

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1 Ting-Shu Wu, M.D. Infection Control Committee Infect Dis, Int Med, Chang Gung Memorial Hospital, Linkou Medical Center, Tao-Yuan, Taiwan

2 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)

3 Taxonomic Tree M. tuberculosis complex Mycobacteriaceae Mycobacterium M. leprae Nocardia NTM Actinomycetales Actinomycetaceae Actinomyces Streptomycetaceae Streptomyces S. griseus S. mediterranei

4 Currently recognized species of the genus Mycobacteria isolated form humans Group Obligatory Facultative Potential Saprophyte Strict pathogens Photochromogens M. africanum M. leprae M. tuberculosis M. ulcerans M. bovis M. asciaticum M. kansasii M. marinum M. simiae Scotochromogens M. scrofulaceum M. szulgai M. xenopi Nonchromogens M. genavense M. avium M. haemophilum M. intracellulare M. malmoense M. shimoidei Rapid growers Strict animal pathogens M. farcinogens M. lepraemurium M. porcinum M. chelonae M. fortuitum M. microti M. paratuberculosis M. senegalense M. gordonae M. flavescens M. gastri M. nonchromogenicum M. terrae M. triviale M. fallax M. smegmatis M. agri..

5 Runyon classification Class I (photochromogens) Class II (scotochromogens) Class III (nonchromogens) Class IV ( rapid growers)

6 Structure A: plasma membrane B: complex polymer C: peptidoglycans D: arabinogalactans E: mycolic acids F: methoxy type & keto type G: glycolipid H: lipoarabinomannan

7 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)

8 Manual of Clinical Microbiology, Vols. 1 and 2: Eighth Edition

9 RFLP (Telenti et al.)

10 MALDI-TOF/MS Matrix-Assisted Laser Desorption/ Ionization Time of Flight Mass Spectrometry

11 Slowly Growing Mycobacteria

12 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: Manual of Clinical Microbiology 11/e

13 Mycobacterium avium M. avium subsp. avium M. avium subsp. silvarticum M. avium subsp. paratuberculosis M. avium subsp. hominissuis

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15 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.

16 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:

17 Regimens for the treatment of disseminated MAC disease in patients with HIV infection Preferred regimens CLR 500 BID + EMB 15 mg/kg QD (+RFB 300 QD) AZI 600 QD + EMB 15 mg/kg QD (+RFB 300 QD) Additional drugs for macrolideresistant infections Moxifloxacin 400 QD, or Levofloxacin mg QD + EMB 15 mg/kg QD + RFB 300 QD + AMK mg/kg QD

18 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 Sep 15;186(6):

19 Mycobacterium kansasii Tenosynovitis

20 Mycobacterium kansasii

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23 Mycobacterium marinum Wu TS et al. PLoS ONE. 2012;7(7):e41296

24 Wu TS et al. PLoS ONE. 2012;7(7):e41296

25 Wu TS et al. PLoS ONE. 2012;7(7):e41296

26 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): e doi: /journal.pone

27 Treatment regimens Species Disease Drug Dose Duration M. avium complex Pulmonary CLR+EMB +RIF or RFT Disseminated, HIV+ LAP, children CLR+EMB +RFT Surgery, CLR+RFT, OR EMB 500 bid, 15 mg/kg, 600 mg, mg 500 bid, 15 mg/kg, 300 mg Until negative culture for 12 mo For life?

28 Treatment regimens (2) Species Disease Drug Dose Duration M. Kansasii pulmonary INH+RIF +EMB?? disseminated same 300, 600, 15 mg/kg same 18 mo, culture negative for 12 mo HIV+ RIF RFB

29 Treatment regimens (3) Species Disease Drug Dose Duration M. marinum cutaneous CLR or minocycline or RIF+EMB 500 bid, 100 bid, 600, 15 mg/kg At least 3 mo

30 Rapidly Growing Mycobacteria

31 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

32 Breakpoints of RGM S I R AMK <16 32 >64 FOX < >128 CIP <1 2 >4 CLR <2 4 >8 DOX <1 2-4 >8 IPM < >32 LZD <8 16 >32 MEM < >32 MXF <1 2 >4 SXT <2/38 >4/76 TOB <2 4 >8

33 ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Oct. 2002, p

34 CID 2006:42 (15 June) 1759

35 Clincal significance Common in environment Most identified in tap water M. fortuitum, M. abscessus, M. chelonae for > 80%

36 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

37 M. abscessus sensu lato M. abscessus sensu stricto M. massiliense M. bolletii

38 Mycobacterium abscessus M. abscessus M. abscessus subsp. abscessus M. massiliense and M. bolletii M. abscessus subsp. bolletii

39 Mother Daughter

40 M Mo D1 D2 D Kb Lin CY, Hsu CY, Wu TS et al. Unpublished data

41 Before After

42 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

43 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

44 Macrolide resistance Bacterial resistance to macrolides occurs by posttranscriptional methylation of the 23S bacterial ribosomal RNA, thereby inhibiting drug attachment This acquired resistance results in crossresistance to macrolides, lincosamides and streptogramins Resistance to macrolides acquired by mutation in the rrl gene encoding the 23S rrna generally occurs in mycobacterial species

45 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

46 Case 1. erm(41) of M. massiliense ATCC19977 Soft tissue infection cases Wu T.-S. et al. JMII. Online published

47 Antibiotics for Rapid Growers Bacteria Parenteral Oral M. abscessus Amikacin, imipenem Clarithromycin, quinolones, sulfonamides M. chelonae Amikacin (tobramycin), imipenem Clarithromycin M. fortuitum Amikacin, cefoxitin Clarithromycin M. smegmatis Amikacin, imipenem Doxycycline, quinolones, sulfonamides

48 Thank you for your attention!