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THE OTHER BLACKGUARDS - RISING TO THE CHALLENGE
Year : 2017  |  Volume : 4  |  Issue : 1  |  Page : 67-74

Nontuberculous mycobacterial diseases: Current diagnosis and treatment


Department of Pulmonology and Critical Care Medicine, Fortis Hospital, Kolkata, West Bengal, India

Date of Web Publication6-Nov-2017

Correspondence Address:
Raja Dhar
Department of Pulmonology and Critical Care Medicine, Fortis Hospital, Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/astrocyte.astrocyte_54_17

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  Abstract 


There has been an ever-expanding list of isolation of organisms in the genus Mycobacterium. Leprosy and tuberculosis are specific diseases caused by mycobacteria; there are now several other mycobacteria that cause human diseases and can be widely found in the environment. These other mycobacteria are called as nontuberculous mycobacteria (NTM) or mycobacteria other than tubercle bacilli (MOTT) or atypical mycobacteria. They cause various human infections in the lungs, lymph glands, skin, wounds, or bone. They may also produce disseminated disease, especially in the immunocompromised. Various molecular, biochemical, and chemical techniques have been developed for rapid identification of these species. While it might be difficult to treat these infections, with duration of treatment longer than that for tuberculosis or leprosy, many drugs such as rifampicin, rifabutin, ethambutol, clofazimine, amikacin, new generation quinolones, and macrolides effective against mycobacterial infections are available that can be used in appropriate combinations and dosage to treat the NTM.

Keywords: Atypical mycobacteria, MOTT, nontuberculous mycobacteria


How to cite this article:
Sharma S, Dhar R. Nontuberculous mycobacterial diseases: Current diagnosis and treatment. Astrocyte 2017;4:67-74

How to cite this URL:
Sharma S, Dhar R. Nontuberculous mycobacterial diseases: Current diagnosis and treatment. Astrocyte [serial online] 2017 [cited 2020 Jun 2];4:67-74. Available from: http://www.astrocyte.in/text.asp?2017/4/1/67/217655




  Introduction Top


Nontuberculous mycobacteria [or mycobacteria other than tubercle bacilli (MOTT)/atypical/environmental mycobacteria] are ubiquitous, aerobic, nonmotile, acid fast bacteria commonly found in soil and water. When they infect humans, they commonly affect the lungs, lymph nodes, skin, and soft tissue.[1] The recent rise in interest in diseases caused by NTM can be attributed to increasing association of NTM with acquired immunodeficiency disease (AIDS) as well as increasing isolation in non-AIDS population. This increase in the detection rate is a result of improved awareness and laboratory methodology which has resulted in more accurate identification of NTM species from clinical specimens.

There were approximately 50 NTM species known till the 1990s. However, with recent advances in molecular techniques, over 125 NTM species have been identified. Most importantly, 16S rRNA gene sequencing has become a standard for new species cataloguing.[2] Mycobacterial species differ in virulence and may present characteristic antimicrobial patterns, hence, correct species identification may be considered appropriate as it may also aid in treatment decision.


  Epidemiology Top


NTM are ubiquitous organisms and are most commonly found in soil and water. They can occur in both natural and treated water sources.[3] This ubiquity and their disinfectant and antibiotic resistance can be attributed to their biofilm production.[4]

The most common nontuberculous species causing human disease in the United States are the slowly growing species of the Mycobacterium avium complex (MAC) and M. kansasii. Less common human pathogens include the slowly growing species M. marinum, M. xenopi, M. simiae, M. malmoense, and M. ulcerans, and the rapidly growing species M. abscessus, M. fortuitum, and M. chelonae. The overall isolation rate of NTM in India has been reported to range from 0.5% to 8.6%. In seronegative patients an NTM isolation rate of 3.5% has been reported,[5] most common isolates being M. fortuitum and M. intracellulare.[6]


  Taxonomy Top


First classification of NTM organisms was proposed by Runyon in 1959. This system divided human isolates of NTM into four groups [Table 1] on the basis of growth rates, colony morphology, and pigmentation in the presence and absence of light.[7]
Table 1: Classification of nontuberculous mycobacteria

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Recently, with the availability of 16S ribosomal DNA sequencing, high performance liquid chromatography (HPLC), polymerase chain reaction, and restriction length polymorphism analysis (PRA), the total number of new species and clinically significant species of NTM has risen dramatically.[8] Consequently, many species do not find a place in the original classification described by Runyon. However, for all classification purposes, the NTM can be broadly classified into slow growers and rapid growers.


  Transmission and Pathogenesis Top


As stated earlier, NTM are ubiquitous and can be found in water (natural as well as treated), biofilms, soil, and aerosols.[9] Human to human transmission is rare, and thus, it is presumed that transmission is from these sources, which is also proved by isolation of same strains of NTM from infected patients and their environments.

NTM infections can be classified into four distinct syndromes [Figure 1], with pulmonary disease being the most common.
Figure 1: Various clinical syndromes of NTM infection in humans.

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Pulmonary infection caused by nontuberculous mycobacteria

Pulmonary infection by NTM is presumed to be contracted by aerosol inhalation from natural surface water or from domestic and institutional hot water systems. The chain of events in the pathogenesis is similar to those described for tuberculosis. There should be an index of suspicion for NTM infection in patients suspected to have tuberculosis. NTM isolation rates as high as 8% were found in a study evaluating patients clinically suspected to have tuberculosis, with M. fortuitum being the most common isolate followed by M. avium.[10] In the BCG trial of Chingleput, Madras, MAC was the most common isolate.[11]

Mycobacterium Avian Complex (MAC) infection – After being inhaled, MAC survive their initial run into alveolar macrophages. Bloodborne host defences are then called into play (lymphocytes and monocytes) that differentiate into macrophages. Ultimately, MAC is taken up by macrophages and survives as an intracellular pathogen and proliferates within vacuoles in the cytoplasm. Interaction of lymphocytes with infected macrophages then leads to intracellular destruction of the mycobacteria or the infected macrophage itself. This pathway of interaction between macrophage, lymphocyte, and the NTM organism is the central point in the pathogenesis and leads to granuloma formation, successful control of the infection, or clinical disease.

These events lead to two major forms of pulmonary MAC disease in adults:fibrocavitary and fibronodular.

Fibrocavitary disease

Fibrocavitary disease occurs most commonly in older male smokers with chronic pulmonary symptoms due to underlying lung disease and affects the upper lobes more commonly. Symptoms and radiographic changes may be a reflection of the underlying lung disease, thus making it difficult to differentiate from the underlying disease. Bacteriologically, MAC is often easily recovered from the respiratory samples of these patients. These patients are often initially diagnosed to be affected with pulmonary tuberculosis.

Fibronodular disease

Predisposing factors for fibronodular disease include:

  1. Body morphotype is believed to predispose to the fibronodular form of disease as it is seen that patients with fibronodular NTM lung disease have similar clinical characteristics and body types. In few studies, it was found that patients with fibronodular disease caused by NTM infection are taller and leaner than controls, with high rates of scoliosis, pectus excavatum, mitral valve prolapse, and cystic fibrosis.[12],[13] The mechanism by which the body morphotype predisposes to pulmonary mycobacterial infection remains unknown.
  2. Bronchiectasis is also known to predispose to NTM lung disease. Some potential etiologies for bronchiectasis in this population include:


    1. Gastroesophageal reflux with chronic aspiration
    2. Alpha 1 antitrypsin deficiency
    3. Cystic fibrosis
    4. Primary ciliary dyskinesia
    5. Connective tissue disorders
    6. Heritable connective tissue disorders – Marfan's syndrome, hyper IgE syndrome, etc


    Lady Windermere Syndrome – this condition named after Oscar Wilde's play Lady Windermere's Fan refers to a pattern of pulmonary MAC infection seen typically in elderly white women who chronically suppress the normal cough reflex. Suppression of the cough is thought to predispose to lung infection by allowing secretions to collect in the airways, especially in the right middle lobe, which has the longest and narrowest of the lobar bronchi.

  3. Hereditary predispositions are known to result in familial clusters of patients with pulmonary NTM lung disease.[14]


Radiographically, the fibronodular form is characterized by multiple small nodules and fibrosis, associated with cylindrical bronchiectasis, typically affecting the midlung fields as seen on HRCT. This combination of nodules, fibrosis, and mid lung affection by bronchiectasis is highly suggestive of MAC infection. One study found that CT prediction of cultures positive for MAC in bronchiectatic patients with multiple small lung nodules has a sensitivity of 80%, specificity of 87%, and an accuracy of 86%.[15] Pathologically, these nodules represent granulomatous inflammation. Shedding of MAC into the respiratory secretions in these patients is less consistent than that in the fibrocavitary form of the disease. Sputum may be intermittently positive and/or positive with low numbers of organisms. Therefore, prior to the advent of HRCT, isolation of MAC from the sputum of such patients was frequently dismissed as “colonization.” Another study, however, has demonstrated that this condition may progress to respiratory failure.

M. kansasii infection — lung infections resemble TB clinically and radiographically. Older age, male sex, smoking, and underlying lung disease are predisposing factors.

Rapidly growing mycobacteria — Rapid growers, especially M. abscessus, can also infect lungs. Affected patients tend to be non-smoker females without any pre-existing lung disease.


  Clinical Presentation and Diagnosis Top


Chronic pulmonary disease is the most common clinical manifestation of NTM.

Symptoms and signs

The symptoms of NTM pulmonary disease are variable and nonspecific. Virtually, all patients have chronic or recurring cough with or without sputum production. Other symptoms include fatigue, malaise, dyspnea, fever, hemoptysis, chest pain, and weight loss. Symptoms are progressively more prevalent with worsening NTM lung disease. It is important to suspect an NTM infection as initial evaluation is often complicated by symptoms caused by coexisting lung diseases such as bronchiectasis, COPD, cystic fibrosis, and pneumoconiosis. Physical findings are nonspecific and usually only reflect underlying pulmonary pathology, such as bronchiectasis and chronic obstructive lung disease. On chest auscultation, findings may include rhonchi, crackles, wheezes, and squeaks. Patients with fibronodular MAC disease tend to be postmenopausal women many of whom also have a characteristic morphotype with a thin body habitus and may also have scoliosis, pectus excavatum, and mitral valve prolapse.[12],[13]

Radiography

A plain chest radiograph may be adequate for evaluating patients with fibrocavitary disease. However, to demonstrate the characteristic abnormalities of nodular/bronchiectatic NTM lung disease, HRCT of the chest is now routinely indicated [Figure 2].
Figure 2: HRCT characteristics of NTM infection; (a) Tree in bud, (b) Bronchiectasis, (c) Cavity, nodules, and (d) Consolidation.

Click here to view


Radiographically, NTM disease can be separated into predominantly cavitary and nodular/bronchiectatic. Cavitary disease, similar to pulmonary tuberculosis, chiefly affects the upper lung zones and is seen in approximately 90% of patients with M. kansasii infection and almost 50% of M. avium complex infection. These cavities have thinner walls and surrounding parenchymal opacities are less than those caused by M. tuberculosis.[16]

Almost 50% of patients with MAC lung disease have radiographic abnormalities characterized by clusters of small nodules associated with bronchiectasis or nodular/bronchiectatic disease. The nodules and bronchiectasis are usually present within the same lobe and occur most frequently in the middle lung fields.[17] This radiographic pattern can also be seen with other NTM pathogens including M. abscessus, M. simiae, and M. kansasii. Solitary nodules and dense consolidation have also been described. Pleural effusions are uncommon, but reactive pleural thickening can be seen.

Microbiologic evaluation

Chest radiography and skin testing are nonspecific and these modalities fail to differentiate pulmonary tuberculosis from NTM infection. Hence, microbiologic confirmation for presence of NTM infection is recommended.

There should be a high index of suspicion for possible presence of NTM infection in a patient with a chronic pulmonary infiltrate with or without a cavity and persistence of one of the symptoms as mentioned earlier. The diagnostic evaluation should consist of smear and culture of at least three separate expectorated sputum specimens obtained in the morning. In an event of any uncertainty, a bronchoalveolar lavage (BAL) and/or transbronchial biopsies can be performed.

Positive sputum cultures for NTM must be interpreted cautiously as these organisms can be recovered from the respiratory tract without causing progressive infection, and additionally, NTM are common in the natural environment and may contaminate laboratory specimens. It is important to distinguish between transient infection or contamination and true infection. But, as it happens to be, most lung diseases caused by NTM are slowly progressive and careful assessment over time is possible.

Diagnostic criteria

The American Thoracic Society (ATS) and Infectious Disease Society of America (IDSA) have jointly established specific criteria [Table 2] for the diagnosis of NTM lung disease.[18]
Table 2: Features of various types of NTM infections

Click here to view


Expert consultation should be obtained when NTM are recovered that are either infrequently encountered or that usually represent environmental contamination. Making a diagnosis of NTM infection may not necessitate the initiation of treatment.[18]


  Treatment of M. Avium Complex Lung Infection Top


MAC are the most common pulmonary NTM pathogens worldwide and predominantly human disease within this complex are caused by M. avium, M. intracellulare, and M. chimaera. Treatment of NTM infection of the lung depends on numerous factors, most important being the species of the infecting organism. Cavitary disease is rapidly progressive and warrants initiation of early treatment. In addition to cavitary disease, low body mass index (BMI) has been consistently identified as a risk factor for progressive disease and/or mortality. Other described factors include male gender, older age, presence of comorbidities, and the number of lung segments involved.[19]

Treatment is not indicated in all patients of MAC pulmonary disease at the time of diagnosis and anti-mycobacterial treatment is prolonged, with drugs that can be difficult to tolerate, and long-term response rates are variable and uncertain. Commonly, close observation instead of antibiotic treatment is advisable, however, NTM infection being indolent, most patients progress over time, and most of them eventually require treatment.

However, fibrocavitary disease may be associated with rapid progression and destructive disease, hence, initiation of treatment at the time of initial diagnosis is recommended.

On the other hand, for patients with nodular/bronchiectatic disease, observation is reasonable in the setting of minimal symptoms or radiographic findings. Eventually, the decision to observe or treat depends on the clinical presentation and the overall clinical status of the patient. Observation consists of regular clinical evaluation, sputum cultures, and serial radiographical evaluation for disease progression.

There are no set guidelines to determine the optimal frequency of monitoring for disease progression among patients who are being only observed without treatment initiation. Appropriate frequency depends on the extent of disease, and in general sputum cultures should be obtained every 2–3 months and repeat imaging every 6 months. Development of new radiographical features such as cavitation or worsening nodularity would be a sign of progressive disease and so would be the increasing bacterial load (change from smear negative to smear positive sputum or increasing quantitative culture results).[20]

These changes should alert the treating physician to initiate the treatment.

Pretreatment susceptibility testing

MAC organisms are usually susceptible to macrolides and clofazimine, with varying susceptibility to rifampin, rifabutin, ethambutol, fluoroquinolones, linezolid, and aminoglycosides.

At present, expert panels recommended drug susceptibility testing on a routine basis for clarithromycin only.[18] However, the role of DST is controversial because in-vitro susceptibility might not reflect the in-vivo outcome, with the exception of macrolides and amikacin.[21] However, given that intolerance to the first line drugs is common, testing for additional drugs may be useful information as it could aid in deciding for the use of alternative agents for treatment.

Initiating therapy

Macrolides are the most important drugs in the treatment of MAC based primarily on observational studies. Sputum conversion rates as high as 75–86% have been reported with macrolide containing regimens.[22] Azithromycin and clarithromycin are the primary macrolides used in the treatment of MAC but azithromycin is the preferred macrolide, considering its better side effect profile and fewer adverse reactions while maintaining the similar treatment outcomes as clarithromycin.

It is advisable to initiate one drug at a time, particularly in patients who are older and/or have a history of drug intolerance. Initiation with azithromycin followed by addition of ethambutol and then rifampin is recommended.

At initiation of therapy, the baseline laboratory evaluations listed in [Table 3] should be performed.
Table 3: Diagnostic criteria for NTM

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Initial treatment

Regimen selection depends, in part, on susceptibility to macrolides. Most MAC isolates are macrolide susceptible, particularly in patients who have not been treated before.

For initial treatment of patients with MAC lung disease, a three-drug regimen containing a macrolide, a rifamycin, and ethambutol is used. A parenteral aminoglycoside is also often used in the initial phase for patients who have severe or fibrocavitary disease.

Daily versus intermittent therapy

In patients with nonsevere nodular bronchiectatic disease pattern, an intermittent regimen (i.e., dosing medications three times weekly versus daily) is recommended for initial therapy. Studies suggest that intermittent (thrice weekly) dosing is as effective as daily therapy and better tolerated in most patients.[23],[24] However, for patients with severe or cavitary disease or patients who have failed previous therapy intermittent medication dosing is not effective.[25] If sputum cultures remain positive after 12 months of intermittent therapy, switching over to daily therapy is recommended.[26]

Mild to moderate nodular bronchiectatic disease

A thrice weekly regimen of:

  • Azithromycin (500 mg three times per week) PLUS
  • Rifampin (600 mg three times per week) PLUS
  • Ethambutol (25 mg/kg three times per week)


Fibrocavitary or severe nodular bronchiectatic disease

A daily regimen of:

  • Azithromycin (250 to 500 daily) PLUS
  • Rifampin (10 mg/kg/day) PLUS
  • Ethambutol (15 mg/kg daily)
  • Parenteral streptomycin or amikacin (10 to 15 mg/kg thrice a week) for the first 8 to 16 weeks of therapy since treatment outcomes are worse in patients with cavitary disease


Macrolide resistant infection

In cases of macrolide resistance:

  • A macrolide should not be used
  • Additional drugs must be substituted in the antimycobacterial regimen
  • Consultation with an expert in treating MAC infections is warranted
  • Daily regimen consisting of ethambutol, rifampin (or rifabutin), and clofazimine, along with 2–6 months of intravenous amikacin (as long as the amikacin MIC ≤64 mcg/mL) administered three times a week
  • Assess for the feasibility of surgical resection


Improved treatment outcomes have been observed with use of parenteral aminoglycosides in patients with macrolide resistant disease.[27],[28] Newer drugs such as bedaquiline may have a role in the future.[29]

Duration of therapy

Treatment should be continued until sputum cultures are consecutively negative for at least 12 months. Because sputum conversion usually requires 3–6 months of treatment, a typical patient will be treated for 15–18 months.


  Surgical Management Top


Surgery may be useful in the following settings:

  • Localized disease, especially upper lobe cavitary disease
  • Failure to achieve sputum conversion to negative after 6 months of continuous treatment
  • Patients who cannot tolerate medical therapy
  • Macrolide-resistant MAC lung disease


In such patients, lung resection is effective in controlling infection and offers a greater chance of bacteriologic cure.

However, it is essential to note that ideally, for patients undergoing surgery for MAC infection, the procedure should be performed once sputum cultures are negative because positive cultures at the time of surgery may be associated with complications postoperatively.


  Adjunctive Measures Top


As it is clear by now that most patients with pulmonary MAC disease may have primary chronic lung disease such as bronchiectasis or COPD, adjunctive therapies are an important aspect of treatment. Improving airway clearance by using flutter valves, vests, and inhaled hypertonic saline, and preventing aspiration can result in better outcomes. Dietary consultation is also recommended because poor nutritional status is associated with poor response to therapy and increased adverse effects and drug intolerance.


  Treatment Failure or Relapse Top


It is defined as the failure to achieve culture conversion after 6 to 12 months of therapy.

Treatment failure warrants:

  1. Evaluation for adherence to the drug regimen
  2. Susceptibility testing to macrolides and other drugs that may be needed for treatment
  3. Serum drug concentrations assessment


In patients who respond clinically and radiographically but remain culture positive beyond 6 months, it is advised to continue the macrolide-based regimen if the isolate is still susceptible. However, if the patient remains culture positive after 12 months, it is likely to be treatment failure. Such patients, if on intermittent therapy, switch to daily administration and other interventions such as administration of an aminoglycoside and/or resectional surgery should be considered. Recurrent MAC growth in the sputum after achieving sustained sputum conversion (persistently negative cultures) can either be relapse of the original infection or reinfection with a new strain. Retreatment strategy would remain the same as that for initial treatment and would depend on macrolide sensitivity of the isolate. Macrolide resistance is more likely with relapsed disease. It is also essential to look for a possible environmental source in cases of reinfection.


  Treatment of Mac Lymphadenitis Top


  • Excisional surgery without chemotherapy is the recommended treatment [30]
  • Incisional biopsy alone or the use of anti-tuberculosis drugs alone is frequently followed by persistent clinical disease, including sinus tract formation and chronic drainage, and should be avoided
  • In difficult to operate cases, such as those where the risk of complications like facial nerve palsy is high, its is recommended to prescribe Clarithromycin based multidrug regimen like that used for the NTM pulmonary infections
  • For children with recurrent disease, a second surgical procedure is usually performed and anti-tubercular therapy administered



  Treatment of Disseminated M. Avium Disease Top


Disseminated MAC is an opportunistic infection in patients with AIDS.

Daily regimen is preferred over intermittent therapy and includes:[18]

  • Clarithromycin 1000 mg/day or azithromycin 500 mg/day PLUS
  • Ethambutol (15 mg/kg/day) PLUS
  • Rifabutin (300 mg/day)


In cases of macrolide resistance, an injectable aminoglycoside and a quinolone, such as moxifloxacin, can be considered and should be given in addition to thambutol and rifabutin.

As patients with AIDS can have various adverse effects related to drug interactions with antiretroviral drugs, monitoring of treatment is highly recommended.


  Treatment of M. Kansasiiinfection Top


M. kansasii closely parallels the clinical disease pattern of M. tuberculosis and most patients have upper lobe fibrocavitary pattern while some present with nodular/bronchiectatic pattern.

Treatment includes a daily regimen of the following drugs and are administered for 12 months after achieving a negative sputum culture status:[18]

  • Rifampin (10 mg/kg/day) PLUS
  • Isoniazid (300 mg/day) PLUS
  • Ethambutol (15 mg/kg/day)


Patients with rifampicin resistance have shown response regimen consisting of high dose isoniazid (900 mg), ethambutol (25 mg/kg), and sulfamethoxazole (3 g) for 18–24 months. It can be combined with an injectable aminoglycoside daily for 2–3 months followed by intermittent dosing for further 6 months.

Treatment recommendation for disseminated disease remains the same as that for pulmonary disease.


  Treatment of M. Abscessus Pulmonary Disease Top


M. abscessus is a rapid grower and the third most common NTM infection in the United States.[31] The usual clinical presentation is similar to other NTM pulmonary infections [Table 4]. HRCT findings include bronchiectasis with multiple small nodules, similar to MAC lung disease.[32]
Table 4: Baseline laboratory evaluation at initiation of therapy for NTM

Click here to view


Skin, soft tissue, and bone diseases caused by M. abscessus usually follows accidental trauma or surgery in various clinical settings.[33]

M. abscessus is typically resistant to first-line anti-tubercular drugs and are susceptible to amikacin, sulphonamides, ciprofloxacin, cefoxitin, imipenem, tobramycin, erythromycin, and doxycycline.

For pulmonary infections, surgical resection of the involved lung lobe along with multidrug chemotherapy is recommended as the only curative option. The duration of therapy recommended is 12 months after achieving negative sputum cultures. However, because there is no standard medication strategy to reliably achieve this goal, alternative goals of therapy, such as symptomatic improvement, radiographic regression of infiltrates, or improvement in sputum culture positivity can be considered more realistic.[18]

Skin, soft tissue, and bone infections should be treated with a regimen same as that for pulmonary infections and for a duration of minimum 4 months for skin and soft tissue infections and 6 months for bone infections.[34]


  Conclusions Top


The incidence of tuberculosis in our country far exceeds that of NTM. However, there is still a sizeable load of NTM infection. The numbers are underestimated because many cases are missed. Infection can affect any organ, however, lung infections are by far the most common. M. avium, M. kansasii, and M. abcessus are the most common organisms which cause lung disease. The presence of the bacteria does not equate to active disease. A conglomeration of clinical, radiological, and microbiological parameters must be present to equate to active disease. Eradication of the bug and hence the disease process is often difficult and involves prolonged combination antibiotic treatment. Surgical resection is sometimes needed with drug resistant organisms or in some cases for failure of medical treatment.

There are knowledge gaps in the treatment of NTM pulmonary infections. Disease susceptibility is unclear (unlike TB), and hence, preventive measures are difficult to adapt. In addition, it is very difficult to eradicate NTM and there is a high recurrence rate, and selecting appropriate candidates for treatment and timing for initiation of treatment is a challenge. The pharmacotherapy for certain NTM such as M. abcessus is also unsatisfactory. Hence, especially in India, we have a long way to go before we manage effective identification and treatment of NTM.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Abstract
Introduction
Epidemiology
Taxonomy
Transmission and...
Clinical Present...
Treatment of M. ...
Surgical Management
Adjunctive Measures
Treatment Failur...
Treatment of Mac...
Treatment of Dis...
Treatment of M. ...
Treatment of M. ...
Conclusions
References
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