Danger in the Water Theodore Marras MD FRCPC University of Toronto & University Health Network.

Danger in the Water

Theodore MarrasMD FRCPC

University of Toronto&

University Health Network

Potential conflicts of interestFinancial – noneOther – clinical and academic interest in

pulmonary NTM disease (especially epidemiology, long term outcomes)

Off label use of therapiesNone of the medications mentioned have a

formal indication for the treatment of pulmonary NTM disease

Declarations

1. Identify relevant potential infective exposures

2. Review management of pMAC:– Recommended drug treatment

– Approach to comprehensive management

3. Review data on treatment outcomes

4. Combining knowledge of:– Environment / interventions (relevance, uncertainty)

– Treatment outcomes

… to better inform clinical decisions

Objectives- Pulmonary Mycobacterium avium complex (pMAC)

Background

Pulmonary NTM- Microbiology

NTM M.tb.

Where they live Environment (water, soil)

Infected host

Infection Environmental exposure / inoculation

Infective aerosols

Spread person-person?

No Yes

Pathogenic Weakly Strongly

Diagnosis


NTM M.tb.


Infected host


Infective aerosols


No Yes


Diagnosis


NTM M.tb.


Infected host


Infective aerosols


No Yes


Diagnosis


NTM M.tb.


Infected host


Infective aerosols


No Yes


Diagnosis


NTM M.tb.


Infected host


Infective aerosols


No Yes


Diagnosis Micro + Micro


NTM M.tb.


Infected host


Infective aerosols


No Yes


Diagnosis Micro / Clin / Rad Micro

“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

Pulmonary NTM Disease- ATS / IDSA 2007

Age and sex distribution

Increasingly common disease of the elderly

in Ontario

Where does it come from?

• Moist environments– Natural and treated water– Soils

• Very disinfectant resistant

The Water we Drink- MAC

Hot Tub Lung:Hypersensitivity Pneumonitis to NTM

•Embil et al. Chest 1997 5

•Kahana et al. Chest 1997 1

•Mangione et al. Emerg Inf Dis 2001 5

•Case record NEJM 2000 1

•Khoor et al. Am J Clin Pathol 2001 10

•Rickman et al. Mayo Clin Proc 2002 2

•Cappelluti et al. Arch Intern Med 2003 1

•Pham et al. J Thoracic Imaging 2003 1

•Grimes et al. Respiration 2001 1

•Aksamit Respir Infect 2003 9

•Lumb et al. Appl Environ Micro 2004 4

•Systrom & Wittram NEJM 2005 1

TOTAL 41

Study Design

Pulmonary NTMSource of infection

… Multiple respiratory samples and shower and bathtub specimens grew MAC, with matching PFGE patterns…

Hypersensitivity Pneumonitis Reaction to Mycobacterium avium in Household Water*Theodore K. Marras, MD; Richard J. Wallace, Jr., MD, FCCP; Laura L. Koth, MD; Michael S. Stulbarg, MD;† Clayton T. Cowl,

MD, FCCP; and Charles L. Daley, MD

(CHEST 2005; 127:664–671)


… M. avium isolated from showerhead water and biofilm in the home of a woman with M. avium disease. DNA fingerprinting demonstrated identical M. avium isolates from showerhead and patient …

Mycobacterium avium in a shower linked to pulmonary diseaseJoseph O. Falkinham III, Michael D. Iseman, Petra de Haas and Dick van Soolingen

J Water Health 06(2):209–213

Study DesignOccupational soil exposure - risk factor

for MAC skin test reactivity

MAC skin testing- Soil exposure




Study Population Risk FactorOdds Ratio

(95% CI)P

value

ReedAm J Epi 2006

Random sample, West Palm Beach FL (N=447)

Soil occupation (> 6 years)

2.7(1.3-6.0)

0.01

KhanAJRCCM 2007

Representative sample, USA (N=7,384)

Farming / Construction

1.43(1.07-1.92)

0.02





(95% CI)P

value

ReedAm J Epi 2006



2.7(1.3-6.0)

0.01

KhanAJRCCM 2007



1.43(1.07-1.92)

0.02





(95% CI)P

value

ReedAm J Epi 2006



2.7(1.3-6.0)

0.01

KhanAJRCCM 2007



1.43(1.07-1.92)

0.02

High numbers of … M. avium, M. intracellulare, and M. chelonae, recovered from aerosols produced by pouring commercial potting soil and potting soil samples provided by patients with pulmonary mycobacterial infections.

Dominant mycobacteria in soil samples corresponded to dominant species implicated clinically. Pulsed-field gel electrophoresis demonstrated a closely related pair of M. avium isolates recovered from a patient and from that patient’s own potting soil.

App Env Microbiol 2006; 72:7602-6.


Management of pMAC

“Making the diagnosis of NTM lung disease does not, per se, necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy for individual patients”

- ATS / IDSA 2007

ATS / IDSA guidelines- Diagnosis Treatment

Symptoms + Imaging + Cultures

= NTM Disease

“Making the diagnosis of NTM lung disease does not, per se, necessitate the institution of therapy, which is a decision based on potential risks and benefits of therapy for individual patients”

- ATS / IDSA 2007

ATS / IDSA guidelines- Diagnosis Treatment

Symptoms + Imaging + Cultures

= NTM Disease

When to treat?Micro– Repeated isolates / AFB smear +

Symptoms– Systemic* – fatigue, fever/sweat, weight loss – Local – cough, sputum, hemoptysis, dyspnea

Significant burden on imaging– Consolidation, nodules, cavities …– Progression

Pulmonary NTM- Diagnosis Treatment

Non-destructive infection• CureLocalized destruction• Cure (?)Diffuse destruction• SuppressSevere drug intolerance• SuppressRecurrence• Cure or Suppress?

Pulmonary MAC- Goals of treatment









ATS / IDSA guidelines- Drug treatment – MAC

Drug / classDisease type

Fibronodular Cavitary or Advanced / recurrent

MACROLIDEClari 1000 tiw or

Azi 500-600 tiw

Clari 500-1000 qd

or

Azi 250-300 qd

Ethambutol 20-25 mg/kg tiw 15 mg/kg/d

Rifamycin RMP 600 tiw

RMP 450-600 qd

or

RFB 150-300 qd

Amikacin (SM, KM)

Not recommendedConsider / recommended

(10-15 mg/kg/d)

ATS / IDSA guidelines- Drug treatment – MAC

Drug / classDisease type

Fibronodular Cavitary or Advanced / recurrent

MACROLIDEClari 1000 tiw or

Azi 500-600 tiw

Clari 500-1000 qd

or

Azi 250-300 qd

Ethambutol 20-25 mg/kg tiw 15 mg/kg/d

Rifamycin RMP 600 tiw

RMP 450-600 qd

or

RFB 150-300 qd

Amikacin (SM, KM)

Not recommendedConsider / recommended

(10-15 mg/kg/d)

Other agents - Fluoroquinolones, clofazimine, linezolid

When to stop?Sputum cultures negative for 12 months

Pulmonary NTM- Treatment duration

Comprehensive management

• Start with guidelines• Expect drug intolerance (staggered start)• Macrolides whenever possible• Amikacin for advanced cases*• Fluoroquinolones, clofazimine, linezolid as needed /

tolerated• Aim for >3 drugs*

– More drugs, higher doses greater efficacy

• Tailor therapy– Switch drugs to minimize AE’s– Re-evaluate objectives based on response, toxicity

* When treating intensively

Pulmonary MAC- Drugs

Other interventions• Nutrition• Bronchodilators /

Inhaled steroids?• Pulmonary hygiene• Surgery• Avoid exposure

– Hot tubs– Shower?

Pulmonary MAC- Treatment – Other










Inhaled steroids?• Pulmonary hygiene• Surgery (?)


Pulmonary MAC- Following patients on therapy

Assess responseMicrobiologic – sputum q 2-4 monthsClinical – periodicRadiographic – LDCT scan 4-6 mo, then q 6-12 mo

Follow for drug toxicities• Education important toxicity stop drugs• Clinical• Rifamycin CBC, liver tests• Ethambutol visual acuity, colour etc.• Amikacin ‘lytes, creatinine, serum level, audiograms

Outcomes

Clinical practice (geographic region)• Leeds, UK; MAC 1999-2001

• 41% disease recurrence or mortality at 2 years post treatment

Henry, ERJ 2004

pNTM – a chronic disease?- Clinical practice

Clinical practice (specialty clinic)• 50% didn’t achieve sputum culture

conversion

• 60% didn’t tolerate initial antibiotics

• 85% remain symptomaticHuang, Chest

1999

pNTM – a chronic disease?- Clinical practice

Study Rx (months)

N Sputum convert (%) Success (%)

PP ITT PP ITT

Dautzenberg ’95 12 39 77 65 77 65

Wallace ’96 > 5 48 97 75 86 67

Roussel ‘98 15 29 67 48 57 41

Griffith ’98 > 6 68 66 56 66 56

Tanaka ’99 6 46 72 61 63 48

Huang ’99 >12 27 71 37 36 19

Griffith ‘00 > 6 59 78 54 78 54

Griffith ‘01 12 103 61 54 61 54

Field ’02 > 5 30 100 87 81 70

Kobashi ‘03 12 71 58 58 32 32

Fujikane ’05 >6 137 97 79 82 66

Lam ’06 12 91 21 13 83 53

Kobashi ’07 24 73 57 51 14 12

Kobashi ’07 24 146 61 61 18 18

Jenkins ’08 24 170 90 90 33 33

Total (weighted) - 1,137 72% 62% 50% 43%

pNTM – a chronic disease?- Clinical studies

StudyFollow-up (months)

NRecurrence

N %

Huang ’99 <72 27 3/10 30Kobashi ’07 36-48 73 21/37 57Kobashi ’07 36 146 29/89 33Total (weighted) - 246 53/136 39%

pNTM – a chronic disease?- Recurrence

Treatment– Poorly tolerated– Suboptimal efficacy

Pulmonary MAC (NTM)- Chronicity

Treatment– Poorly tolerated– Suboptimal efficacy

Cause(s) not identified or reversible– Host defect– Exposure remains…

Pulmonary MAC (NTM)- Chronicity

Am J Resp Crit Care Med 2007, 175:367-416 Canadian Tuberculosis Standards, 6th ed

www.ntminfo.org

Danger in the Water Theodore Marras MD FRCPC University of Toronto & University Health Network.

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