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Episode #7 – MACsterclass

7 Cover Art (OPT)

Summary

Dr. Ruvandhi Nathavitharana provides a master class on pulmonary NTM disease

Credits

Host: Sara Dong

Guest: Ruvandhi Nathavitharana

Writing: Kushal Vaishnani, Sara Dong

Producing/Editing/Cover Art: Sara Dong

Infographics: Sara Dong

Our Guests

Ruvandhi Nathavitharana, MD, MPH

Twitter

Dr. Ruvandhi Nathavitharana is an attending physician in Infectious Diseases at Beth Israel Deaconess Medical Center and an Assistant Professor at Harvard Medical School. Dr. Nathavitharana’s clinical efforts are focused on the longitudinal, multidisciplinary care of patients with TB and non-tuberculous mycobacteria. Dr. Nathavitharana’s research interests center around the use of implementation science to evaluate TB diagnostic algorithms and interventions to decrease TB transmission in high TB incidence countries with a focus on Peru and South Africa, funded by an NIH K23 Career Development Award and ASTMH Burroughs Wellcome Fellowship. Dr. Nathavitharana has served as a technical expert analyzing data to inform WHO guideline development group panel recommendations on the use of line probe assays and the urine LAM lipoarabinomannan test for the diagnosis of TB. Dr. Nathavitharana is also the Chair of TB Proof, an advocacy organization based in South Africa that seeks to destigmatize TB and mobilize national and global resources to end TB. Check out some Op-Eds written by Dr. Nathavitharana and colleagues focused on centering the perspectives of TB survivors and supporting the essential role of community health workers.

Ruvandhi Nathavitharana, MD, MPH

Twitter

Dr. Kushal Vaishnani is a hospitalist in North Carolina with an interest in infectious diseases and clinical reasoning

Culture

Check out Ruvandhi’s recommendation:

Girl, Woman, Other

Bernardine Evaristo

Consult Notes

Consult Q

Request for help with working up a pt with COPD and UC on infliximab with weight loss and cough

One-liner

61 yo female with history of COPD and ulcerative colitis on infliximab who presented with cough, dyspnea, and weight loss and was found to have pulmonary M.avium infection

Key Points

Jump to:

Nontuberculous mycobacteria (NTM) species are a collection of >200 mycobacterial spp other than those belonging to M.tuberculosis complex (M.tuberculosis, M.bovis, M.africanum, M.microti) and M.leprae. They are ubiquitous in the environment.

  • Clinical syndromes due to NTM can be classified by:
      • Pulmonary disease
      • Superficial lymphadenitis, especially cervical lymphadenitis in children
      • Disseminated disease in severely immunocompromised patients
      • Skin and soft tissue infection
  • We focused on pulmonary disease for this episode!

 

A little on the epidemiology of NTM infections

A few pediatric notes related to NTM: 

  • The predominant NTM disease in children is cervical lymphadenitis (MAC, M.scrofulaceum) and cutaneous disease (M.marinum, M.ulcerans)
      • For NTM lymphadenitis in otherwise healthy children, surgical excision is curative and limits scar formation
  • NTM pulmonary disease in children usually affects those with underlying lung disease such as cystic fibrosis. Typical spp would be MAC and M.abscessus
  • Disseminated NTM infections are associated with impaired cell-mediated immunity, such as that found in children with congenital immune defects (eg, IL-12 deficiency, NEMO mutation and related disorders, IFNg receptor defects), HSCT, advanced HIV.

Diagnosis of pulmonary NTM disease = combination of clinical criteria and micro assessment

The ATS/IDSA criteria was recently updated in 2020:

    • Daley CL, Iaccarino JM, Lange C, et al. Treatment of Nontuberculous Mycobacterial Pulmonary Disease: An Official ATS/ERS/ESCMID/IDSA Clinical Practice Guideline. Clin Infect Dis. 2020;71(4):905-913. doi:10.1093/cid/ciaa1125
    • Clinical: consistent pulmonary or systemic symptoms 
        • Signs and symptoms are variable and influenced by whether patient has pre-existing symptomatic lung disease
        • Cough, fatigue, malaise, weakness, dyspnea, chest discomfort, sometimes hemoptysis
        • Fever, weight loss can occur, although less than in TB
    • Radiographic: 
        • chest radiograph with nodular or cavitary opacities or 
        • high-resolution computed tomography (HRCT) with multifocal bronchiectasis with multiple nodules.
    • Microbiologic (assess over time): 
        • Two positive sputum cultures from two separate expectorated sputum samples OR
        • One positive bronchial washing or BAL specimen positive for NTM OR 
        • Pathology/histologic features consistent with NTM infection (granulomatous inflammation; +AFB) in combination with 1 or more culture positive pulmonary specimens (e.g. lung biopsy) 
        • Positive culture from pleural fluid or any other normally sterile extrapulmonary site
    • AND Exclusion of other diseases (TB, malignancy)
  • Should have clinical and radiographic criteria with at least one micro criteria

 

  • NTM are environmental organisms → it can be difficult to distinguish transient infection, colonization, lab/specimen contamination, true infection/disease, pseudo-outbreaks
  • **Isolation of NTM in a single sputum culture without (and sometimes even with) associated clinical and radiographic features does not establish a diagnosis of pulmonary disease
    • Especially in patients with co-morbidities such as CF
  • **Just because a patient meets diagnostic criteria for NTM pulmonary disease does not necessarily mean they need antibiotics
  • Patients need close longitudinal follow-up and repeat sampling
  • You can check out some other guideline resources in the “Other miscellaneous” section

This episode featured a case of Mycobacterium avium complex, which includes multiple species. Previously MAC was thought to include M.avium and M.intracellulare only.

  • M.avium
  • M.intracellulare
  • M.chimaera
  • M.colombiense
  • M.arosiense
  • M.marseillense
  • M.timonense
  • M.bouchedurhonense
  • M.vulneris
  • M.yongonense

A few micro details on MAC:

  • Slowly growing
  • Readily detected by AFB smear and culture
  • Grows well in standard media such as MGIT broth, Middlebrook 7H10 and 7H11 agar
  • In broth, these organisms do not show clustering or “cording”
  • On agar: usually small, flat, translucent, smooth colonies +/- pale yellow color
  • These are different than M.tuberculosis, which would show cording in broth with rough, buff colored colonies on agar

 

Does the NTM species matter in terms of outcomes like cure?   

So how do you decide to treat NTM?

    • As Ruvandhi discussed, the decision involves consideration of a constellation of clinical sxs, radiographic changes, microbiologic evidence, other comorbidities like immunosuppression, spp isolated
    • Weighing risk/benefit ratio carefully (drug toxicities, prolonged duration of therapy, comorbidities, goals of therapy)
    • Decision often not made at a single timepoint

 

Do I need to get drug susceptibility testing? How do I interpret DST results?

  • In patients with MAC pulmonary disease, the AST/IDSA 2020 guidelines recommend susceptibility-based treatment for macrolides and amikacin over empiric therapy
  • Currently established breakpoint concentrations have very limited clinical evidence base
  • Aside from macrolide (and aminoglycoside) susceptibility, there is little evidence to correlate DST with clinical outcomes
  • Discrepancies between drug susceptibility in vitro and activity of drug observed in vivo
  • However DST may facilitate Rx choices
  • Synergy testing is sometimes available
    • Currently performed for rifampin and ethambutol
    • May also see results for amikacin and clofazamine

We focused on approaching therapy for MAC specifically this episode.  Ruvandhi walked us through how many drugs we need and a few other treatment related learning points!

  • For initial treatment of MAC pulmonary disease → would choose a 3-drug regimen containing:
      • Macrolide: preferred is Azithromycin (most patients will have macrolide-susceptible MAC)
      • Rifamycin: preferred is Rifampin
      • Ethambutol
  • If patients have cavitary or severe nodular bronchiectatic disease or macrolide-resistant MAC, would add an parenteral aminoglycoside in initial phase of treatment

Did you know that macrolide susceptibility has been a consistent predictor of treatment success for pulmonary MAC?  Loss of macrolide from treatment regimen is associated with markedly reduced rate of conversion of sputum cultures to negative and higher mortality

Covering some key questions regarding MAC treatment

Macrolides are a critical component of MAC therapy.  The new guidelines now favor azithromycin over clarithromycin.  Why?

How do we choose daily vs intermittent therapy?

Can we use two drugs vs three drugs for MAC? Guidelines still recommend 3-drug because we don’t really have enough data on 2-drugs.  You can read what we have available below:

Of course the most anticipated question from your patient – how long do we treat?  What informs treatment duration?

    • Guidelines suggest at least 12 months after culture conversion (conditional recommendation, v low certainty in effect estimates), but really we don’t know the optimal duration
    • Clinical and microbiologic reassessment is key

What about newer drugs we are using or might be on the horizon?  How effective are they?

How do patients do with these regimens?

  • Adherence is poor
  • Only 13% of antibiotic regimens prescribed to patients with MAC met ATS/IDSA guidelines

Adjemian J, Prevots DR, Gallagher J, Heap K, Gupta R, Griffith D. Lack of adherence to evidence-based treatment guidelines for nontuberculous mycobacterial lung disease. Ann Am Thorac Soc. 2014;11(1):9-16. doi:10.1513/AnnalsATS.201304-085OC

How to approach treatment adverse effects in patients on combination therapy

  • Consider staggered initial introduction of antibiotics
  • With side effects – if no likely culprit, can stop all and attempt slow staggered re-introduction
  • Consider in-class switch (rifamycins), adjust doses or timing of day, review drug interactions
  • Specific strategies depending on drug (e.g. give bronchodilator prior to Arikayce, gargle warm water after, consider forgoing loading dose for omadacycline)
  • Collaborate with your ID PharmD!

What about other management options in addition to antimycobacterial drugs?

What is the role of surgery for pulmonary NTM disease?

What other measures do you recommend when caring for these pts?

 

One of Ruvandhi’s key points was that management of NTM disease requires longitudinal partnerships with your patient and other members of the medical team. In addition, management should be framed as a chronic disease that is individualized to specific goals of therapy

Other miscellaneous mentions and notes:

Episode Art & Infographics

Goal

Listeners will be able to diagnose and start initial treatment in a patient with pulmonary MAC

Learning Objectives

After listening to this episode, listeners will be able to:

  • Describe epidemiology of non-tuberculous mycobacteria (NTM) in the US
  • Utilize available diagnostic criteria for pulmonary NTM disease
  • List the key drugs in initial treatment of pulmonary Mycobacterium avium pulmonary disease
  • Understand possible role of surgery and non-pharmacologic interventions for pulmonary NTM disease

Disclosures

Our guest (Ruvandhi Nathavitharana) as well as Febrile podcast and hosts report no relevant financial disclosures

Citation

Nathavitharana, R., Dong, S. “#7: MACsterclass”. Febrile: A Cultured Podcast. https://player.captivate.fm/episode/04eca175-4618-4f62-b2cc-ed8b4b05a3b4

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