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contaminants, have the same staining properties. Therefore, it is critical to determine whether acid-fast bacilli seen on smear represent M. tuberculosis or nontuberculous mycobacteria. This distinction can be made either by certain growth characteristics on culture or molecular biologic techniques.

For a single tubercle bacillus to be seen on smear, large numbers of organisms must be present in the lungs. Thus, even in the setting of active disease, if relatively few organisms are present in the lungs, the smear results may be negative, although culture results will often be positive. In general, the infectiousness of a patient with tuberculosis correlates with the number of organisms the patient is harboring and the presence of organisms on smear. Patients whose sputum is positive by smear tend to be much more infectious than patients whose sputum is positive by culture but negative by smear.

Because of the insensitivity of sputum smears and the time required for M. tuberculosis to grow in culture, rapid and more sensitive methods for establishing the diagnosis of tuberculosis have been developed. Nucleic acid amplification assays have been developed that can detect M. tuberculosis in respiratory specimens in less than 12 hours and with greater sensitivity and specificity than are generally available by staining techniques. Another technique involves detecting radiolabeled CO2 after incubation of the specimen with radiolabeled palmitic acid, a metabolic substrate for mycobacteria. Results can be obtained much more quickly with this technique than by conventional cultures.

Functional assessment of the patient with tuberculosis often shows surprisingly little impairment of pulmonary function. Such testing is useful primarily for the patient who already has compromised pulmonary function, when there is concern about how much of the patient’s reserve has been lost. However, a patient who is potentially contagious should not be evaluated with pulmonary function testing because of the possibility of infecting others during the testing maneuvers. Arterial blood gases are often relatively preserved, with normal or decreased PO2, depending on the amount of ventilation–perfusion mismatch that has resulted.

Principles of therapy

Effective chemotherapy is available for almost all cases of tuberculosis. Before the 1950s, treatment for tuberculosis was only marginally effective, involving prolonged hospitalization (usually in a sanatorium) or a variety of surgical procedures, whereas now most cases are curable with appropriate drug therapy. However, the rise in incidence of multidrug-resistant tuberculosis is again threatening the ability to effectively treat the disease. Patients are treated for a prolonged period, generally with a minimum of two effective antituberculous agents to which the organisms are sensitive. There are numerous different recommended drug regimens depending on the probability of resistant organisms and patient tolerability. In areas where the concern for drug resistance is low, the traditional regimen includes an intensive phase of four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol) for the first 2 months followed by 4 more months of two drugs. If susceptibility data become available, the initial choice of drugs is adjusted accordingly.

A common treatment of pulmonary tuberculosis is isoniazid and rifampin given for 6 months, supplemented by pyrazinamide for the first 2 months and ethambutol until the organism’s antimicrobial sensitivity is known.

Treatment can be administered in an outpatient setting unless the patient is sufficiently ill to require hospitalization. Patients whose sputum smears initially were positive are usually considered no longer infectious after they have demonstrated a clinical response to antituberculous therapy and their sputum has become smear-negative on three successive samples. A critical issue determining the success of

antituberculous therapy is the patient’s adherence to the medical regimen. Erratic or incomplete therapy is associated with a risk of treatment failure and the emergence of resistant organisms, with potentially disastrous consequences. As a result, the use of directly observed therapy, in which adherence is monitored in the outpatient setting with either video or in-person observation of the patient taking their medicines, has become an important component of treatment for most cases of tuberculosis. Hepatotoxicity can occur with antituberculous medications, necessitating appropriate monitoring of patients during therapy.

Treatment of active tuberculosis in patients with concomitant HIV/AIDS presents unique challenges. Such patients are at increased risk for drug interactions and adverse reactions to antituberculous medications. In addition, immune reconstitution inflammatory syndrome can develop if combination antiretroviral therapy is started concurrent with treatment of tuberculosis. With antiretroviral treatment, as the depleted immune system recovers and confronts the tuberculosis infection, intense inflammation may develop causing transient higher fever, malaise, weight loss, and worsening respiratory symptoms. This syndrome may be difficult to clinically differentiate from tuberculosis treatment failure.

Thus, effective therapy for tuberculosis requires long-term chemotherapy for all patients and directly observed therapy for as many as possible. Treatment is labor intensive, and it is most successful with a well-funded and effective public health system. Even in industrialized nations, this presents difficulties. Many parts of the world are under-resourced and this type of public health system is nonexistent.

In addition to multiple-drug therapy administered for active tuberculosis, therapy is indicated for select patients with latent tuberculous infection that is detected via tuberculin skin testing or IGRA. Currently, the Centers for Disease Control and Prevention (CDC) recommends a rifampin-based regimen for 3–4 months, as this is safe and effective with higher completion rate than the older regimen of isoniazid for 6 to 9 months. Such therapy substantially decreases the chances of developing active tuberculosis, especially in individuals who are at particularly high risk.

Single-drug therapy with rifampin or isoniazid is indicated for selected patients with latent tuberculous infection (with a positive tuberculin skin test or interferon-γ release assay but no evidence of active disease).

In addition to close contacts of patients with active tuberculosis, certain other patients with latent tuberculous infection documented by a positive tuberculin skin test reaction or IGRA but no evidence of active disease are considered candidates for treatment with a single-drug regimen. Specifically, this category includes patients who satisfy additional criteria that put them at high risk for reactivation of a dormant infection. Examples include the presence of stable radiographic findings of old active tuberculosis but no prior therapy, or the presence of underlying diseases or treatment that impairs host defense mechanisms. Although this form of single-drug therapy was often called “prophylactic” or “preventive,” it actually represents treatment aimed at eradicating a small number of dormant but viable organisms, and only a single drug is required because there is less concern about resistance when organism numbers are low. Treatment of latent tuberculosis is very effective in decreasing the rate of reactivation tuberculosis.

As noted, a recent major public health issue has been the development of organisms resistant to one or more of the commonly used antituberculous agents. When a strain is resistant to both isoniazid and rifampin, it is termed multidrug resistant (MDR). If a strain is resistant to isoniazid and rifampin plus any fluoroquinolone and at least one of the injectable drugs, it is termed extensively drug resistant (XDR). This problem underscores the importance of public health measures to limit person-to-person transmission of tuberculosis, as well as efforts to improve patient adherence with antituberculous

medication. When treating a patient with tuberculosis caused by MDR or XDR organisms, close

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coordination between the treating physicians and the public health authorities is essential. Molecular diagnostic techniques have been developed to immediately identify some drug resistance at the time tuberculosis is diagnosed, and they may significantly improve the management of these patients.

The goal of developing an effective vaccine against M. tuberculosis remains an important step toward achieving worldwide eradication of tuberculosis. Vaccination with BCG, a live, attenuated strain of Mycobacterium bovis, has been used for many years in various countries around the world, but it has not been recommended for use in the United States except in selected rare circumstances. Although BCG vaccination appears to decrease the risk of serious and potentially life-threatening forms of tuberculosis in children, its efficacy in preventing pulmonary tuberculosis in adults is questionable. Of note, patients treated with a BCG vaccination will at least initially have a positive response to a PPD test, although the accuracy of IGRAs for tuberculosis is unaffected in this setting.

Nontuberculous mycobacteria

A variety of nontuberculous mycobacteria, sometimes called atypical mycobacteria, are potential pulmonary pathogens. They are generally found in water and soil, which appear to be the sources of infection rather than person-to-person transmission. The most common organisms in this group are classified as belonging to the Mycobacterium avium complex (MAC), which includes Mycobacterium avium, Mycobacterium intracellulare and other genetically similar organisms. Nontuberculous organisms which may also cause lung disease include M. kansasii, M. abscessus, M. xenopi, and M. fortuitum.

The nontuberculous mycobacteria are primarily responsible for disease in two settings: (1) the patient with underlying structural lung disease, most commonly bronchiectasis, cystic fibrosis, or severe COPD, in whom local host defense mechanisms are impaired, and (2) the patient with acquired or inherited defects in the host immune response, including HIV/AIDS and genetic defects in the interferon-γ pathway. Importantly, treatment with immunosuppressive agents, especially glucocorticoids and biological therapy against TNF-α, is similarly associated with increased risk. However, nontuberculous mycobacteria may also cause disease in a small number of patients without any of these risk factors.

Nontuberculous mycobacteria are most frequently pathogens in patients with underlying lung disease or defects in host immune response.

Disease caused by nontuberculous mycobacteria can be localized to the lung, where it can mimic tuberculosis, or it can be found after hematogenous dissemination throughout the body, particularly in patients with AIDS or other immunodeficiencies. Confirmation of disease caused by these organisms is difficult. In patients with underlying lung disease, these organisms can colonize the respiratory system without being responsible for invasive disease and can be found as laboratory contaminants.

Unlike tuberculosis, where recovery of organisms is evidence for active disease that requires treatment, isolation of nontuberculous mycobacteria does not automatically mean treatment is indicated. Because treatment can be associated with side effects, the toxicity of treatment may outweigh its potential benefit. Consequently, the decision whether to treat is based on the presence and severity of disease, the risk of progression, and patient priorities. When treatment is given, it typically involves multiple agents for an extended period, usually longer than 1 year. The organisms are frequently resistant to some of the standard antimycobacterial drugs, so treatment regimens are complicated, difficult to tolerate, and often unsuccessful. All treatment should be based on drug sensitivity data. For patients with MAC, macrolide antibiotics (e.g., clarithromycin, azithromycin) are recommended as part of a three-drug regimen, depending on sensitivities. A more complete discussion of this topic is beyond the scope of this text, so

the reader is referred to the review articles in the references.

Principles of therapy

Nontuberculous mycobacteria

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