# Non-Tuberculous Mycobacterial Infections

## Overview

### Classification and Epidemiology

Non-tuberculous mycobacteria comprise more than 200 species of mycobacteria other than the Mycobacterium tuberculosis complex and Mycobacterium leprae. These organisms are ubiquitous in the environment, found in water sources including biofilms within plumbing systems, soil, and dust. Unlike tuberculosis, NTM infections are not transmitted from person to person and are not reportable in most US states. The incidence of NTM disease is increasing, with current estimates of 15 to 20 per 100,000 in the United States, and prevalence is higher among elderly women, residents of the southern US states, and those living in Hawaii. NTM lung disease is now more common than tuberculosis in most developed countries.

### Clinically Significant Species

The clinically significant NTM species are broadly divided into slow-growing and rapid-growing organisms based on the time required to produce visible colonies in culture. | NTM Species | Growth Rate | Frequency | Key Features | Treatment Notes |
| --- | --- | --- | --- | --- | --- |
| M. avium complex (MAC) | Slow | Most common (50-70%) | Nodular/bronchiectatic or fibrocavitary | Azithromycin + ethambutol + rifampin |  |
| M. kansasii | Slow | Common | Most TB-like; most drug-susceptible NTM | INH + rifampin + ethambutol; >90% cure |  |
| M. xenopi | Slow | Common in Europe/Canada | Poorer prognosis | Macrolide-based; outcomes variable |  |
| M. abscessus complex | Rapid | Common | Most treatment-resistant NTM | IV-based intensive phase; 30-60% cure |  |
| M. fortuitum | Rapid | Moderate | Skin/soft tissue; often self-limited | TMP-SMX, FQ, doxycycline |  |
| M. chelonae | Rapid | Less common | Skin, catheter-related, disseminated | Clarithromycin-based |  |
| M. marinum | Slow | Uncommon | Fish tank granuloma; aquatic exposure | Clarithromycin + ethambutol; 3-4 months |  |
| M. gordonae | Slow | Common isolate | Almost always a contaminant | Usually no treatment needed |  |

Among the slow-growers, which require more than seven days for visible colony formation, Mycobacterium avium complex is the most common NTM worldwide, accounting for 50 to 70 percent of NTM lung disease. M. kansasii is notable for its clinical resemblance to tuberculosis and is the most drug-susceptible NTM. M. xenopi is more commonly encountered in Europe and Canada and carries a poorer prognosis. M. simiae and M. malmoense are additional slow-growing species of clinical significance.

Among the rapid-growers, which produce visible colonies in fewer than seven days, M. abscessus complex is the most clinically important and the most treatment-resistant NTM. The complex encompasses three subspecies: M. abscessus subspecies abscessus, M. abscessus subspecies massiliense, and M. abscessus subspecies bolletii. M. fortuitum causes skin and soft tissue infections that are often self-limited or responsive to oral therapy. M. chelonae causes skin infections, catheter-related infections, and disseminated disease in immunosuppressed patients.

Other notable species include M. marinum, which causes "fish tank granuloma" through skin and soft tissue infection following aquatic exposure, and M. ulcerans, which causes Buruli ulcer, a necrotizing skin infection in tropical regions. M. gordonae is almost always a contaminant when isolated and is colloquially known as the "tap water bacillus."

## NTM Pulmonary Disease

### Risk Factors and Phenotypes

The risk factors and clinical phenotypes of NTM pulmonary disease follow distinct patterns. Lady Windermere syndrome describes the classic presentation in tall, thin, elderly women who may have associated body habitus features including pectus excavatum, scoliosis, and mitral valve prolapse, and who present with a nodular bronchiectatic pattern of disease, most commonly caused by MAC. Patients with pre-existing structural lung disease including COPD, bronchiectasis, cystic fibrosis, prior tuberculosis, and pneumoconiosis are predisposed to the fibrocavitary pattern of NTM disease. Immunosuppression from HIV with CD4 counts below 50, TNF-alpha inhibitors, and solid organ transplant predisposes to disseminated NTM infection. CFTR heterozygotes are increasingly recognized as susceptible to NTM lung disease.

### ATS/IDSA 2020 Diagnostic Criteria (ALL required)

The diagnosis of NTM pulmonary disease requires the simultaneous fulfillment of all three of the following criteria as established by the ATS/IDSA 2020 guidelines. First, the clinical criterion requires the presence of pulmonary symptoms along with nodular or cavitary opacities on chest radiography, or multifocal bronchiectasis with multiple small nodules on CT. Second, the microbiologic criterion requires at least one of the following: positive cultures from two or more separate sputum specimens, a positive culture from at least one bronchoalveolar lavage specimen, or a transbronchial or lung biopsy demonstrating mycobacterial histopathology with a positive NTM culture from the biopsy specimen or from sputum or BAL. Third, other diagnoses, particularly tuberculosis, must be excluded. Critically, meeting these diagnostic criteria does not mandate treatment initiation, as clinical judgment regarding the timing and necessity of treatment is essential.

### Radiographic Patterns

NTM pulmonary disease manifests in two principal radiographic patterns and one additional syndrome. The fibrocavitary pattern demonstrates upper lobe cavitation similar to tuberculosis and is more common in older men with a history of COPD or smoking. This pattern tends to be more progressive and carries a poorer prognosis. The nodular bronchiectatic pattern features middle lobe and lingular bronchiectasis with tree-in-bud nodularity, representing the classic Lady Windermere presentation, and typically follows a slower progression. Hot tub lung represents hypersensitivity pneumonitis caused by MAC in aerosolized water from hot tubs or showers, manifesting radiographically as diffuse ground-glass opacities and centrilobular nodules.

<image>A CT chest comparison showing two classic NTM pulmonary disease patterns. Panel 1: "Fibrocavitary MAC" - axial CT showing right upper lobe thick-walled cavity with surrounding consolidation, similar to TB reactivation. Panel 2: "Nodular/Bronchiectatic MAC (Lady Windermere)" - axial CT showing middle lobe and lingular bronchiectasis with tree-in-bud nodularity and scattered small nodules. Panel 3: "Hot tub lung" - axial CT showing diffuse ground-glass opacities with centrilobular nodules. Include labels pointing to key findings: cavitation, bronchiectasis, tree-in-bud pattern, ground-glass. Note the typical patient demographics below each panel. Use standard radiology presentation style.</image>

## Treatment of MAC Pulmonary Disease

### ATS/IDSA 2020 Guidelines

The decision to treat MAC pulmonary disease is based on the presence of symptoms, radiographic progression, and positive cultures meeting diagnostic criteria. Not all patients who meet diagnostic criteria require treatment, and watchful waiting is appropriate for patients with mild nodular bronchiectatic disease and minimal symptoms. The preferred treatment regimen consists of azithromycin 250 milligrams daily or 500 milligrams three times weekly, plus ethambutol 15 milligrams per kilogram daily, plus rifampin 450 to 600 milligrams daily. The minimum treatment duration is 12 months of negative sputum cultures, which translates to a total treatment duration typically ranging from 18 to 24 months.

### Intermittent vs. Daily Therapy

For nodular bronchiectatic disease without cavitation, a thrice-weekly intermittent regimen is acceptable, consisting of azithromycin 500 milligrams, ethambutol 25 milligrams per kilogram, and rifampin 600 milligrams, all administered on Monday, Wednesday, and Friday. For fibrocavitary disease or severe presentations, a daily regimen is required, and the addition of amikacin, either intravenous or inhaled, should be considered for the first two to three months of therapy.

### Adjunctive Amikacin

Amikacin liposome inhalation suspension, known as ALIS or Arikayce, received FDA approval for refractory MAC lung disease and is administered as 590 milligrams nebulized daily. The CONVERT trial demonstrated that adding ALIS to guideline-based therapy achieved sputum culture conversion in 29 percent of patients compared to 8.9 percent with guideline-based therapy alone by six months. Systemic amikacin at 15 milligrams per kilogram intravenously three times weekly during the initial two to three months is considered for cavitary or severe disease, with mandatory monitoring of audiology and renal function.

### Treatment Monitoring

Monthly sputum cultures should be obtained until culture conversion, then every one to two months thereafter. Macrolide susceptibility testing is critical, as macrolide resistance, defined as an azithromycin MIC greater than 32, can be mediated by the erm(41) gene in M. abscessus or by 23S rRNA mutations, and renders the cornerstone of therapy ineffective. Ethambutol requires monthly monitoring of visual acuity and Ishihara color plate testing. Rifampin necessitates awareness of its extensive CYP3A4-inducing drug interactions and monitoring of liver function tests. A minimum of 12 months of culture negativity must be achieved before treatment can be discontinued.

## M. abscessus Complex

### Unique Challenges

M. abscessus complex represents the most treatment-resistant NTM, with intrinsic resistance to most first-line TB and NTM drugs. Subspeciation has critical therapeutic implications. M. abscessus subspecies abscessus possesses a functional erm(41) gene that confers inducible macrolide resistance, meaning the organism may appear susceptible to clarithromycin at day three of incubation testing but demonstrates resistance at day fourteen on extended incubation testing. In contrast, M. abscessus subspecies massiliense has a non-functional erm(41) gene, which precludes inducible macrolide resistance and translates into significantly better treatment outcomes. Clinicians must always request extended incubation macrolide susceptibility testing with a 14-day read for any M. abscessus isolate.

### Treatment

Treatment of M. abscessus pulmonary disease follows a two-phase approach. The intensive phase, lasting a minimum of one month, consists of intravenous amikacin at 15 milligrams per kilogram daily, intravenous imipenem at 1 gram every six hours (or alternatively cefoxitin at 2 grams every six hours or tigecycline at 50 milligrams twice daily), plus oral azithromycin at 250 milligrams daily. The continuation phase consists of oral azithromycin, inhaled amikacin, and two to three additional oral agents selected from clofazimine 100 milligrams daily, linezolid 600 milligrams daily, tedizolid, and omadacycline. The total treatment duration extends to 12 months of negative cultures, often requiring 18 to 24 months or more of total therapy. Surgical resection should be considered for localized disease that is unresponsive to medical therapy, as cure rates improve when surgery is combined with antibiotic therapy. Overall cure rates range from 30 to 60 percent, with M. massiliense demonstrating better outcomes at 60 to 70 percent compared to 30 to 40 percent for M. abscessus subspecies abscessus.

<image>A treatment protocol timeline for M. abscessus pulmonary disease. Show a horizontal timeline divided into two phases. Intensive Phase (1-3 months, shaded red): "IV Amikacin 15 mg/kg daily + IV Imipenem 1g q6h (or IV Cefoxitin, or IV Tigecycline) + PO Azithromycin 250mg daily." Continuation Phase (12+ months after culture conversion, shaded blue): "PO Azithromycin + Inhaled Amikacin + 2-3 oral agents (clofazimine, linezolid, omadacycline)." Include monitoring checkpoints along the timeline: "Monthly sputum cultures, audiology q1-3 months, CBC (linezolid), visual acuity (ethambutol if used)." Sidebar box: "Key considerations: Request 14-day macrolide susceptibility, subspeciate (abscessus vs. massiliense), surgical consultation for localized disease." Use a clinical treatment protocol format.</image>

## M. kansasii

M. kansasii is the most TB-like of the NTM species, commonly presenting with upper lobe cavitary disease. It is also the most drug-susceptible NTM, producing excellent treatment outcomes with cure rates exceeding 90 percent. Treatment consists of isoniazid 300 milligrams daily, rifampin 600 milligrams daily, and ethambutol 15 milligrams per kilogram daily for a minimum of 12 months or 12 months of negative cultures. Rifampin susceptibility is the key predictor of treatment success, and if rifampin resistance is identified, the treatment approach should shift to a macrolide-based regimen similar to that used for MAC.

## Disseminated NTM Disease

### Disseminated MAC in HIV

Disseminated MAC in HIV typically occurs at CD4 counts below 50 and presents with fever, night sweats, weight loss, diarrhea, hepatosplenomegaly, and cytopenias. Diagnosis is established through AFB blood cultures using the mycobacterial blood culture system, which is positive in 85 to 90 percent of cases. Treatment consists of azithromycin 500 milligrams daily plus ethambutol 15 milligrams per kilogram daily, with or without rifabutin 300 milligrams daily. Treatment must continue for a minimum of 12 months, with the additional requirement that the CD4 count has exceeded 100 for at least six months on ART. ART should be initiated within two weeks, as the IRIS risk is lower with MAC than with TB or cryptococcal disease.

### NTM in Non-HIV Immunosuppression

Anti-TNF-alpha agents carry a risk of mycobacterial reactivation, and patients should be tested for LTBI and evaluated for NTM disease before initiating these therapies. In solid organ transplant recipients, disseminated disease may occur with M. abscessus, MAC, or M. kansasii. Treatment principles are similar to those in immunocompetent patients but are complicated by the significant drug interactions between rifamycins and calcineurin inhibitors.

## Other NTM Syndromes

### M. marinum

M. marinum causes "fish tank granuloma," presenting as a papulonodular lesion at the site of aquatic exposure that may develop sporotrichoid spread along lymphatic channels. Treatment consists of clarithromycin plus ethambutol or rifampin for three to four months, with minor lesions potentially requiring only monotherapy or excision. The organism grows optimally at 30 degrees Celsius, and cultures should be incubated at a lower temperature when M. marinum is suspected.

### Skin and Soft Tissue (Rapid Growers)

Rapid-growing NTM cause skin and soft tissue infections in the setting of post-surgical wound infections, cosmetic procedures, and injection sites. M. fortuitum is usually susceptible to trimethoprim-sulfamethoxazole, fluoroquinolones, and doxycycline. M. chelonae is typically treated with a clarithromycin-based regimen. Treatment duration for skin and soft tissue NTM infections is four to six months.

## Key Clinical Pearls

- NTM lung disease diagnosis requires clinical, radiographic, AND microbiologic criteria -- a single positive sputum culture alone is NOT sufficient
- Meeting diagnostic criteria does NOT mandate treatment -- consider watchful waiting for mild nodular/bronchiectatic disease in patients with minimal symptoms
- Macrolide susceptibility is the cornerstone of MAC treatment -- never use macrolide monotherapy (rapid resistance development)
- For M. abscessus, always request 14-day extended incubation macrolide susceptibility -- day 3 susceptibility is misleading due to inducible erm(41) resistance
- M. abscessus subsp. massiliense has a non-functional erm(41) and responds better to macrolide-containing regimens than M. abscessus subsp. abscessus
- Treatment durations are long (12+ months of negative cultures) -- patient education and monitoring for drug toxicity are essential
- M. gordonae is almost always a contaminant -- think twice before attributing clinical disease to this organism

## References
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3. Griffith DE, Eagle G, Thomson R, et al. Amikacin liposome inhalation suspension for treatment-refractory lung disease caused by MAC (CONVERT). *Am J Respir Crit Care Med*. 2018;198(12):1559-1569.
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