educational material · 6. brode sk, daley cl, marras tk. the epidemiologic relationship between...

ERS Annual Congress Amsterdam

26–30 September 2015

EDUCATIONAL MATERIAL

Meet the expert 9

Management of non-tuberculous mycobacterial

(NTM) infections

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To help you provide advice to your patients, ELF produces factsheets on lung health and disease. These are informed by patient and professional interviews and written in language that is easy to understand.

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EUROPEANLUNGFOUNDATION

Bringing together patients and the public with respiratory professionals

3

Management of non-tuberculous mycobacteria (NTM) infections

Prof. Christoph Lange

Research Center Borstel/ University of Lübeck

Biowissenschaften, Parkallee 35

23845 Borstel

GERMANY

[email protected]

AIMS: To provide updated information on the management of NTM disease.

TARGET AUDIENCE: Pulmonologists, intensivists, emergency medicine doctors, nurses,

respiratory physicians, and clinical researchers.

AIMS

To become familiar with the clinical spectrum of NTM diseases

To discuss the case management of patients with NTM diseases

To become familiar with current gaps in knowledge on the topic

SUMMARY

Non-tuberculous mycobacteria (NTM) isolation and disease are reported to rise many parts of the

world. NTMs include >160 ubiquitous environmental acid-fast staining bacterial species of which

some occasionally cause disease in humans. The most commonly isolated organisms from human

biospecimen in Western Europe are Mycobacterium intracellulare M. avium, M. gordonae, M.

fortuitum, M. chelonae, M. abscessus and M. malmoense. In other areas of the world (and within

regions of Western Europe) the spectrum is different. While M. abscessus and M. malmoense are

usually related to active disease, the isolation of M. gordonae is a result of water contamination and

not associated to disease, until proven otherwise. Host and pathogen factors leading to NTM disease

are not well understood and preventive therapies are lacking. Chronic pulmonary infection is the most

common clinical manifestation. Although patients suffering from chronic lung diseases are

particularly susceptible to NTM pulmonary diseases, many affected patients have no apparent risk

factors. Differentiation between contamination, infection and disease with treatment indication after

isolation from pulmonary samples remains challenging. Treatment is difficult, long and costly, and in

vitro-in vivo correlation of drug susceptibility tests and treatment outcome are often lacking for the

majority of antibiotics and NTMs causing pulmonary disease. The evidence base for the use of

antimycobacterial drugs in combination treatment for specific NTM diseases and the duration of

therapy is poor. This session will cover the clinical manifestations and management issues for

pulmonary diseases caused by common NTM species in non-cystic fibrosis patients.

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EVALUATION

1. NTM species that are often related to respiratory disease, if isolated from bronchopulmonary

specimen are

a. M. abscessus

b. M. kansasii

c. M. gordonae

d. M. malmoense

2. Cure rates for pulmonary infections by the following NTM species are >50 %

a. M. abscessus ssp. abscessus

b. M. kansasii

c. M. abscessus ssp. massiliense

d. M. simiae

3. A triple combination of a macrolide, a rifamycin and ethambutol is typically used for the

treatment of

a. M. abscessus ssp. massiliense

b. M. avium

c. M. malmoense

d. M. intracellulare

4. Which of the following sentences are true?

a. Currently there is no consensus definition for the outcome “cure” in pulmonary NTM disease

b. Isolation of >1 species of NTM from tracheobronchial specimen in parallel or over the course

of time in a single patient is a rare exception

c. Once an appropriate therapy against any NTM pulmonary disease has been started it is

required to continue the treatment for at least 12 months to achieve relapse-free cure

d. The concept of an induction phase (IP) followed by an continuation phase (CP) of treatment is

especially important for slow growing NTMs

88

Non-tuberculous mycobacteria diseases

Professor Christoph Lange

Research Center Borstel, Germany

99

Conflict of interest disclosure

I have no, real or perceived, direct or indirect conflicts of interest that relate to

this presentation.

This event is accredited for CME credits by EBAP and speakers are required to disclose their potential conflict of interest going back 3 years prior to this presentation. The intent of this disclosure is not to prevent a speaker with a conflict of interest (any significant financial relationship a speaker has with manufacturers or providers of any commercial products or services relevant to the talk) from making a presentation, but rather to provide listeners with information on which they can make their own judgment. It remains for audience members to determine whether the speaker’s interests or relationships may influence the presentation.Drug or device advertisement is strictly forbidden.

1010

Introduction

AIMS

• To become familiar with the clinical spectrum of NTM diseases

• To discuss the case management of patients with NTM diseases

• To become familiar with current gaps in knowledge on the topic

1111

Am Rev Respir Dis 1979 Clin Infect Dis 1995Clin Infect Dis 1992

Emanuel Wolinsky...

1313

When is an infection disease?

Wolinsky E, Rev Infect Dis 1981

1. Quantity of growth

2. Repeated isolation

3. The site of origin of a positive specimen

4. The species of mycobacterium recovered may be crucial

5. Host risk factors should be considered

1414

Mycobacterium wolinskyi...

< 30 patients described

Courtesy: Dr. T.T. Lam, Dr. V. Herbert, Würzburg1515

NTM pulmonary disease criteria

1717

Risk factors for pulmonary NTM disease

• predisosposing pulmonary disease– bronchiectasis (OR=187,5)– previous pulmonary tuberkulose (OR=9,6-178,3)– COPD (OR=15,7)– pneumoconiosis (OR=9,8)– silicosis (OR=5,0)– cystic fibrosis

• diabetes mellitus• advanced age• alcohol abuse• smoking• Lady Windermere syndrome• warme climate, living in costal areas

Corbett E et al. AJRCCM; Marras et al. Clin Chest Med 2002; Sexton P et al. ERJ; Andrejak C et al. AJRCCM 2010 1818

Transmission

Human-to-human transmission of NTMs can happen

but

it is a rare event

Aitken ML, AJRCCM 2012; Bryant JM, Lancet 2013

1919

often pathogenic:

M. abscessusM. kansasiiM. malmoenseM. szulgai

sometimes pathogenic:

M. aviumM. intracellulareM. masilienseM. xenopi

usually non pathogenic

M. simiaeM. gordonaeM. noviomagenseM. chelonaeM. fortuitum

Pathogenity ofnon tuberculous mycobacteria

v Ingen J et al. Thorax 2009

2020

Cure rates

> 75%:

M. massilienseM. kansasiiM. szulgai

50-75 %

M. avium complexM. malmoense

< 50 %

M. abscessusM. simiaeM. xenopi

v Ingen et al IJTLD2012

2121

Dai J et al. J Clin Microbiol 20112222

Mycobacteria isolates (n >10)at the NRC Borstel Germany, 2014

M. tuberculosis complex

M. tuberculosis 1.478M. bovis ssp. bovis 13M. africanum 29

Non-tuberculous mycobacteria

M. abscessus 46M. avium 177M. chelonae-Komplex 42M. chimaera 26M. fortuitum-Komplex 68M. gordonae 128M. intracellulare Komplex 212M. kansasii 22M. malmoense 27M. marinum 21M. simiae 11M. szulgai 18M. vulneris 16M. xenopi 172323

66 y.o. XY, has aquariumM. marinum

At presentation After 5 months of therapy

2626

Therapy ofM. marinum

Combination of 2-3 drugs for approx 2 months after healing of the lesion:

Rifampicin, Ethambutol, Clarithromycin, Doxycyclin

2727

58 y.o. XY, COPDM. kansasii

10/2009

10/2010

12 months treatment with rifampicin, isoniazid and ethambutol3030

Therapy ofM. kansasii

Combination of 3 drugs for approx 12 months after culture conversion:

rifampicin,isoniazid, ethambutol

Alternative drugs:macrolides, moxifloxacin

3131

09/2009

02/2011

M. avium

Therapy: Clarithromycin, Rifabutin, Ethambutol over 17 months3333

van Ingen J et al. AJRCCM 2012

Insufficient drug levelsin MAC therapy

3434

van Ingen J et al. AJRCCM 2012

Effect of rifampicin on drug levelsin MAC therapy

3535

Koh WJ et al. AJRCCM 2012

Effect of rifamycins on drug levelsin NTM therapy

CLMRMPEMBd

MAC

CLMRMPEMBi

MAC

CLMRFBEMBd

MAC

CLMd

M. abscessus

3636


No effect of drug levels on outcomein MAC therapy

3737

0 10 20 30 40 50 60 70 80 Age

cerv LN

pulmonary (CF); bronchiektasis

disseminiated; HIV (AIDS)

localized; HIV (IRIS)

pulmonary (non-CF); bronchiectasis

pulmonary; COPD

Host dependant spectrum of MAC infections

3838

75 y o XX, chronic bronchitis (COPD)M. intracellulare (9/2012)

3939

75 y o XX, chronic bronchitis (COPD)M. intracellulare (4/2015)

4040

Therapy ofM. avium-intracellulare

Combination of 3 drugs for approx. 12 months after culture conversion:

macrolide, rifamycine, ethambutol

Alternative drugs:amikacin (consider nebulized application), streptomycin,

moxifloxacin, clofazimine

4141

45 y o XX, CHD, on ivabradin(macrolides not indicated)

M. avium (6/2015)

4242

57 y.o. XY, COPDM. malmoense (9/2013)

4343


4444


4545

Therapy ofM. malmoense

Combination of 3 drugs for approx 12 months after culture conversion:

macrolide, rifampicin, ethambutol

Alternative drug:moxifloxacin

4646

04/2010 06/201107/200810/2007

M. abscessus

stopped therapy03/2009Therapy:

AmikacinCefoxitin/ImipenemClarithromycinMoxifloxacin

4848

33 y.o. XX, fibronodular bronchiectasisM. intracellulare (8/2014)

Azithromycin 250mg/d; Rifabutin 150 mg/d, Ethambutol 1000 mg/d

4949

33 y.o. XX, fibronodular bronchiectasisM. abscessus ssp. abscessus (2/2015)

Amikacin 750 mg/d; Cefoxitin 3x2 g/d, Ciprofloxacin 2x500 mg/d, Zyvoxid 600 mg/d, Clofazimin 100 mg/d

5050

33 y.o. XX, fibronodular bronchiectasisM. Abscessus (4&6/2015)

Surgical resection S3 and ML R, Lingula and S8 L

5151

78 y.o. XX, UL resection R at the age of 17: TB M. abscessus (4/2015)

5252

Therapy ofM. abscessus ssp. abscessus

Combination of 5 drugs (induction phase) and 3 drugs continuationphase for approx 12 months after culture conversion:

amikacin (IP),Imipenem or cefoxitin (IP), linezolid (IP+CP), tigecyclin (IP) or doxycyclin (IP+CP),

ciprofloxacin (IP+CP) or clofazimine (IP+CP)

Alternatively:Consider nebulized (liposomal) amikacin (IP+CP)

5353

Therapy ofM. bolletti (syn. M. massiliense)

Combination of 5 drugs (induction phase) and 3 drugs continuationphase for approx 12 months after culture conversion:

amikacin (IP), imipenem or cefoxitin (IP), makrolide (IP+CP),tigecyclin (IP) or doxycyclin (IP+CP),

ciprofloxacin (IP+CP) or clofazimine (IP+CP)

Alternatively:Consider nebulized (liposomal) amikacin (IP+CP), linezolid (IP+CP)

5454


Difference in outcome between infectionwith M. abscessus and M. massiliense

5555

Choi GE et al. AJRCCM 2012

Inducible macrolide resistance in M. abscessus, but not M. massiliense, following

clarithromycin exposure

5656

Jarand J et al. Clin Infect Dis 2011

Effect of surgery on culture successfuloutcome in M. abscessus pulmonary disease

5757

Jarand J et al. Clin Infect Dis 2011

Antibiotic therapy used and duration oftherapy in M. abscessus pulmonary disease

5858

1. Macrolides: Clarithromycin, Azithromycin2. Rifamycins: Rifampicin, Rifabutin3. Ethambutol4. Fluoroquinolones: Moxifloxacin, Levofloxacin5. Aminoglycosides: Amikacin6. ß-Lactams: Cefoxitin7. Carbapenems: Imipenem, Meropenem8. Tetracyclines: Doxycyclin, Tigecyclin9. TMP/SMZ10. Oxazilidones: Linezolid11. Clofazimine12. Isoniazid13. ....

Drugs

5959

Griffith D et al. AJRCCM 2007

Examples of recommendedtreatment regimens

Clm Rif x Emb Flq Amk Cefox T/S Inh

MAC x x x

M. abscessus x x x

M. fortuitum x x

M. kansasii x x x

M. malmoense x x x

M. simiae x x x

M. xenopi x x x x

6060

NTM disease and MDR-TB are similar

M/XDR-TB NTM disease

6161



Long duration of therapy ✔ ✔

6262




Frequent adverse events ✔ ✔

6363





Poor prognosis ✔ ✔

6464






High costs of therapy ✔ ✔

6565






High costs of therapy ✔ ✔

Need for palliative care ✔ ✔

6666

Conclusions

• The outcome of medical treatment in NTM infection is species dependant, treatmentoutcomes are far from perfect

• Currently recommended indications fortreatment have to be weighted against theodds of treatment success

• Drug-drug interactions have substantial influence on drug concentrations, however this may not have an effect on outcome

• Novel antibiotics, like bedaquiline(TMC207), synergistic drug combinationsshould be explored for the treatment ofdieseases caused by NTM 6767

Faculty disclosures

There are no faculty disclosures for this session.

6969

Answers to evaluation questions

Please find all correct answers in bold below

Management of non-tuberculous mycobacteria (NTM) infections - Prof. Christoph

Lange

1. NTM species that are often related to respiratory disease, if isolated from bronchopulmonary

specimen are

a. M. abscessus

b. M. kansasii c. M. gordonae

d. M. malmoense

2. Cure rates for pulmonary infections by the following NTM species are >50 %

a. M. abscessus ssp. abscessus

b. M. kansasii

c. M. abscessus ssp. massiliense d. M. simiae

3. A triple combination of a macrolide, a rifamycin and ethambutol is typically used for the treatment

of

a. M. abscessus ssp. massiliense

b. M. avium

c. M. malmoense

d. M. intracellulare

4. Which of the following sentences are true?

a. Currently there is no consensus definition for the outcome “cure” in pulmonary NTM

disease

b. Isolation of >1 species of NTM from tracheobronchial specimen in parallel or over the course

of time in a single patient is a rare exception

c. Once an appropriate therapy against any NTM pulmonary disease has been started it is

required to continue the treatment for at least 12 months to achieve relapse-free cure

d. The concept of an induction phase (IP) followed by an continuation phase (CP) of treatment is

especially important for slow growing NTMs

educational material · 6. brode sk, daley cl, marras tk. the epidemiologic relationship between...

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