Hospital Medicine

Mycobacterial infections

Mycobacterial Infections, Nontuberculous

I. Problem/Condition.

Mycobacterial infections are a group of multisystem infections caused by the members of the family Mycobacteriaceae. These organisms are characterized by their staining and are identified as acid fast bacilli. The most notable mycobacterial infections are those that are caused by Mycobacterium tuberculosis complex and Mycobacterium leprae. These topics have been dealt with elsewhere in the CDS. The following discussion will focus on non tuberculous mycobacterium (NTM) infections. NTM include all mycobacteria except Mycobacterium tuberculosis complex and Mycobacterium leprae. More than 160 NTM species have been identified and our focus in this discussion will remain on the more commonly seen NTM infections including M. avium, M. intracellulare, M. kansasii, M. abscessus, M. chelonae, M. fortuitum, M. marinum, M. simiae, M. ulcerans, M.xenopi.

In general, NTM are ubiquitous and are primarily found in soil and water. As highlighted above, NTM is a multisystemic infection, however, it does commonly present as cutaneous, pulmonary and lymphadenitic disease. Another common presentation, predominantly in patients with immunocompromised state, is that of disseminated disease. The various NTM infections can also, in rare instances, involve several other organs and organ systems. These miscellaneous involvements include pericardium, peritoneum, sinuses, breast, appendix, prostate, kidney, heart valves and catheter sites.

The common presentations for the pulmonary disease include chronic cough, hemoptysis, fever, weight loss, fatigue and night sweats. Pulmonary NTM is associated with higher rate of respiratory failure and is a risk factor for development of chronic obstructive lung disease. Extreme fatigue, weakness, fever, night sweats, hepatomegaly, splenomegaly and dizziness are frequently seen in disseminated NTM infections. Cutaneous presentation may be as nodular or ulcerating lesions, which may or may not spread along lymphatic lines.

II. Diagnostic Approach.

A. What is the differential diagnosis for this problem?

Clinical suspicion in the epidemiologic context is important in approaching the diagnosis of NTM infections. Several other differential diagnoses need to be ruled out before arriving to a conclusive diagnosis. Another important consideration in working up for NTM infections is that presence of such an organism does not always indicate an active infection.

NTM pulmonary diseases have several differentials. These include primary tuberculosis, and other causes of pneumonia including atypical bacterial pneumonia, viral pneumonia, fungal pneumonia and parasitic pneumonia. Chest x-ray and computed tomography (CT) findings can also pose bronchiectasis, BOOP, primary or metastatic lung malignancies, sacroidosis, fungal infections, silicosis and asbestosis as other considerations for differential diagnoses.

NTM cutaneous diseases also have a broad differential. These include fungal cutaneous diseases including Blastomyces dermatidis, Cryptococcus neoformans, Coccidiodes immitis, Histoplasma, Aspergillosis among many others. Serology can be helpful in identifying these differentials. Pertinent history of exposure, bites and travel can point towards tularemia, nocardiosis, lesihmaniasis and chancroid lesions. The broad differential of lymphadenopathy should also be considered when dealing with NTM cutaneous lesions.

NTM lymphadenitis is mostly caused by M. scrofulaceum and MAC. Infection due to M. scrofulaceum is known as scrofula and usually presents as superficial lymphadenitis. M. ulcerans is commonly implicated in cutaneous mycobacterial infections. The characteristic disease state is called Buruli ulcer. Important differentials that need to be considered include filariasis, leishmaniasis, pyoderma gangrenosum, squamous cell carcinoma, actinomycosis, Kaposi sarcoma. The clinical presentation can be that of non ulcerative lesions or ulcerative ones. The characteristic features of a Buruli ulcer consists of undermined edges, white cotton wool-like appearance with the surrounded skin that is thickened and darkened. Usually painless and progressive, these ulcers tend to affect the limbs mainly.

NTM disseminated disease presentation includes an extensive differential diagnosis including malignancies, sarcoidosis and sepsis.

B. Describe a diagnostic approach/method to the patient with this problem.

1. Historical information important in the diagnosis of this problem.

NTM agents are present in environment in various settings that include, water, air, biofilms, animal bodies. Identifying these risk factors alerts a clinician to investigate appropriate settings. NTM infections tend to occur more in immunocompromised patients, mainly with impaired cellular immunity. Several questions pertaining to immune status are important. HIV status, recent chemotherapy, patients’ current medication profile including immunosuppressant, chronic steroid treatment are all very important considerations that should be entertained in arriving to a more definitive diagnosis.

Travel history, exposure to family members with similar infections should also be considered. For instance, a travel to region where M. ulcerans is prevalent can be helpful. Such areas include African continent, Central and South America, Malaysia, Indonesia, Papua New Guinea and Australia. Swimming in fresh and sea water can point towards M. marinum infection, especially when such an activity is done in an endemic region. An aquarium enthusiasts or occupation that exposes a person to fish tank should alert one to M. marinum infection in the setting of cutaneous lesions.

Sharing needles and body piercing can suggest the introduction of NTM cutaneous infection. Medical history, particularly that of COPD, cystic fibrosis, lymphomas, leukemias, HIV infection, prior tuberculosis, silicosis, lung carcinoma all make patients more predisposed to acquire clinically significant NTM infections.

2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.

Often times, the diagnostic approach towards establishing NTM infections starts from reviewing pulmonary, cutaneous, lymphatic or general symptoms. This warrants a thorough systemic examination and no separate specific examination maneuver is suggested.

3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.

Establishing a diagnosis of NTM infection can be challenging. The mainstay of diagnosing NTM infections is the culture and isolation of such organisms. The interpretation of such isolation has to be contextual as it may not always mean an active infection. Commonly and not infrequently in immunocompetent hosts, isolation of NTM may represent colonization or contamination. Several clinical criteria are used to arrive at the diagnosis.

In pulmonary NTM infections, a diagnosis can be established with reasonable certainty when the diagnostic criteria are met. These are discussed in the next section.

Besides clinical suspicion, diagnostic modalities include laboratory testing, imaging and diagnostic procedures. Non specific testing includes blood work to look for anemia, elevated transaminases and LDH. More specifically, cultures from sputum, bronchial wash, bronchial lavage and biopsy material (mainly for cutaneous lesions) are helpful. Staining of these fluids can demonstrate acid fast bacilli. Chest x-ray may show nodular lesion, infiltrates, cavitations or miliary lesions. High resolution computed tomography (CT) scan may be required to further assess smaller lesions. Diagnostic procedures that are commonly used are mainly done to obtain appropriate fluid or tissue to examine for staining and cultures. These include induction of sputum, bronchoscopy for lavage fluid and biopsy sampling and tissue biopsy from cutaneous lesions.

C. Criteria for Diagnosing Each Diagnosis in the Method Above.

Pulmonary NTM infection

(Adopted from the American Thoracic Society (ATS) and Infectious Diseases Society of America [IDSA] guidelines)

Diagnosis utilizes a combination of clinical, radiologic and microbiologic criteria. The clinical and radiologic criteria that must be met include:

Clinical criteria:

1. Pulmonary symptoms, nodular or cavitary opacities on chest radiograph, or a high-resolution CT scan that shows multifocal bronchiectasis with multiple small nodules; and

2. Appropriate exclusion of other diagnoses

and

Microbiologic:

1. Positive culture results from at least two separate expectorated sputum or

2. Positive culture result from at least one bronchial wash or lavage or

3. Transbronchial or other lung biopsy with mycobacterial histopathologic features and positive culture for NTM or

4. Biopsy showing mycobacterial histopathologic features and one or more sputum or bronchial washings that are culture positive for NTM

Cutaneous NTM infection

There are no distinct set of criteria that are used as a guideline. In general, when the cutaneous lesions are chronic in nature, not responding to standard antibacterial treatment NTM cutaneous infection is suspected. The growth from sample taken from cutaneous lesion may allow isolation of offending NTM source. Biopsy of such a lesion may reveal granuloma formation and growth of NTM organism.

Disseminated NTM infection

Growth of NTM organism in a patient clinically thought to have disseminated infection.

D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.

NTM infections are not extremely common. In this regard, several tests for more common causes have already been performed. This makes NTM infectious diagnostic work up not very amenable to unnecessary testing.

III. Management while the Diagnostic Process is Proceeding.

A. Management of Mycobacterial Infections.

General principles

It is important to realize that presence or identification of NTM itself does not warrant treatment. It is also important to be mindful that the antibiotic treatment regimens for NTM infection have significant hepatotoxicity and do have significant adverse effect profile. Additionally, the treatment is often prolonged and requires long term commitment. The management of NTM infections, when identified as an inpatient, may be initiated in the hospital in consultation with an infectious diseases expert and should be continued with follow up arrangements with a primary care physician and/or infectious disease expert.

Although antibiotic mainstay in immunocompetent and immunocompromised patients is the same, some important considerations exist. In immunocompromised patients, institution of cellular immunity is important. In an HIV infected patient, initiation of antiretroviral treatment is important. Likewise, when feasible, discontinuation of glucocorticoid treatment is essential. The decision to alter the immunosuppressed state can be challenging. This is especially true when the patient is status post transplant and is receiving immunosuppression. Every effort to obtain susceptibility data should be made and this should be utilized to devise appropriate regimen.

Pulmonary disease

For management of pulmonary infections with NTM, the ATS/IDSA published a consensus statement and treatment recommendations. The choice of antibiotics is guided by the identification and sensitivity of NTM. Consideration is also given to potential development of antibiotic resistance, in particular to fluoroquinolones.

Mycaobacterium avium intracellualre:

The recommended initial regimen for most patients with nodular/bronchiectatic MAC lung disease is a three-times-weekly regimen including clarithromycin 1,000 mg or azithromycin 500 mg, ethambutol 25 mg/kg, and rifampin 600 mg.

The recommended initial regimen for fibrocavitary or severe nodular/bronchiectatic MAC lung disease includes clarithromycin 500–1,000 mg/day or azithromycin 250 mg/day, ethambutol 15 mg/kg/day, and rifampin 10 mg/kg/day (maximum, 600 mg). The recommended duration of treatment is considering the primary microbiologic goal of therapy of 12 months of negative sputum cultures while on therapy. This necessitates that sputum must be collected from patients for AFB examination throughout treatment.

M. kansasii:

With the objective of 12 months of negative sputum cultures, the recommended initial treatment consists of a drug regimen including rifampin 10 mg/kg/day (maximum, 600 mg), ethambutol 15 mg/kg/day, isoniazid 5 mg/kg/day (maximum, 300 mg), and pyridoxine 50 mg/day.

M. abscessus:

Antibiotic susceptibility testing of all clinically significant isolates is important and helps guide therapy. Pulmonary infection due to M. abscessus is hard to treat and often lends itself only to symptom control and prevention of disease progression. At present, there is no reliable or dependable antibiotic regimen, even based on in vitro susceptibilities and including parenteral agents, to produce cure for M. abscessus lung disease. A regimen containing amikacin plus cefoxitin 3 gm IV q6h plus clarithromycin 500 mg po bid can be used. For isolated abscesses and surgically amenable lesions, surgical resection is recommended.

Disseminated

Mycoabcterium avium intracellulare:

The recommended treatment for disseminated MAC infection consists of Clarithromycin (1000 mg/d) or azithromycin (250 mg/d) plus Etahbutol (15 mg/kg/d) ; with or without rifabutin (150–350 mg/d). It is important to reduce the dose of rifabutin in patients that are taking protease inhibitors. The treatment should be continued for at least 1 year and until the CD4+ T cell count has been >100/μL for at least 6 months. If immune reconstitution is not achieved, indefinite treatment is recommended.

Mycobacetriun kansasii:

The recommended treatment is similar to that of pulmonary.

M. abscessus, M. chelonae, and M. fortuitum.

The treatment should be guided by susceptibility testing. Recommended treatment duration is at least 6 months.

Cutaneous

M. marinum:

Clarithromycin 1000 mg/day, ethambutol (15 mg/kg/day). Addition of rifampin should de done if osteomyelitis is suspected. The ulcerated wound may require surgical debridement. Suggested indication is about 3-4 months, which should include 1-2 months following resolution.

M. ulcerans:

Antibacterial treatment alone is ineffective and surgical debridement with or without plastic reconstruction is indicated.

M. abscessus, M. chelonae, and M. fortuitum:

Clarithromycin 500 mg po bid may be sufficient to treat localized infections due to these NTM agents. Due to high degree of macrolide resistance, M. fortuitum treatment should be guided by susceptibility testing.

B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.

Like with treatment for mycobacterial infections the common pitfalls and side effects of management pertain to the antimicrobial agents used in the treatment of these conditions. Isoniazid or INH is one of the common causes of elevated liver enzymes and hepatitis. Caution should be exercised when using INH in the treatment of mycobacterial infections. The onset of INH induced hepatitis occurs early on during treatment and a close surveillance should be done to identify such an adverse effect. INH hepatitis may warrant cessation of treatment with INH. INH may also promote peripheral neuropathy and hence, pyridoxine should be used when starting patients on INH. If possible, concomitant drugs that impair hepatic function should not used while the patient is on INH.

Ethambutol also can lead to hepatitis. Another clinically relevant pitfall one should be careful of when using Ethambutol is optic neuritis. Changes in visual acuity and other visual changes should be taken seriously and usually warrant cessation of ethambutol. Elevated LFTs and hepatitis are seen not infrequently with rifampicin/rifabutin as well. These agents should never be used by themselves as resistance against them is easily attained. Rifampin can also lead to the development of Clostridium difficile infection.

Not commonly seen but several conditions may warrant changes in the treatment. In particular, disseminated infection may present as endocarditis, osteomyelitis, tenosynovits and may warrant longer duration of treatments.

Cessation of immunosuppression is not always feasible. This is especially true when the patient is receiving immunosuppression following transplantation.

Hospitalist should also be abreast with development of immune reconstitution syndrome while on treatment. This may occur both in HIV negative ad HIV positive patients. One common scenario is worsening lymphadenopathy while on treatment or shortly after treatment with anti mycobacterial and treatment of HIV infection.

IV. What's the evidence?

Griffith, DE, Aksamit, T, Brown-Elliott, BA, Catanzaro, A, Daley, C, Gordin, F. "An official ATS/IDSA statement: diagnosis, treatment, and prevention of nontuberculous mycobacterial diseases". Am J Respir Crit Care Med.. vol. 175. 2007 Feb 15. pp. 367-416.

Taiwo, B, Glassroth, J.. "Nontuberculous mycobacterial lung diseases". Infect Dis Clin North Am.. vol. 24. 2010 Sep. pp. 769-89.

Nontuberculous Mycobacterial Infections. Harrison’s Principles of Internal Medicine.

Johnson, MM, Waller, EA, Leventhal, JP.. "Nontuberculous mycobacterial pulmonary disease". Curr Opin Pulm Med.. vol. 14. 2008 May. pp. 203-10.

Glassroth, J.. "Pulmonary disease due to nontuberculous mycobacteria". Chest. vol. 133. 2008 May. pp. 1291-51.

Horsburgh, CR, Gettings, J, Alexander, LN, Lennox, JL.. "Disseminated Mycobacterium avium complex disease among patients infected with human immunodeficiency virus, 1985-2000". Clin Infect Dis.. vol. 33. 2001 Dec 1. pp. 1938-43.

Daley, CL.. "Nontuberculous mycobacterial disease in transplant recipients: early diagnosis and treatment". Curr Opin Organ Transplant. vol. 14. 2009 Dec. pp. 619-24.

These two references show possible sequelae of pulmonary NTM:

Yeh, JJ, Wang, YC, Sung, FC, Chou, CY, Kao, CH.. "Nontuberculosis mycobacterium disease is a risk factor for chronic obstructive pulmonary disease: a nationwide cohort study". Lung.. vol. 192. 2014. pp. 403-11.

Yeh, JJ, Wang, YC, Lin, CL, Chou, CY, Yeh, TC, Wu, BT, Sung, FC, Kao, CH.. "Nontuberculous mycobacterial infection is associated with increased respiratory failure: a nationwide cohort study". PLoS One. vol. 9. 2014. pp. e99260.

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