Tuberculosis therapy: past, present and future.

The major historical landmarks of tuberculosis (TB) therapy include: the discovery of effective medications (streptomycin and para-aminosalicylic acid) in 1944; the revelation of "triple therapy" (streptomycin, para-aminosalicylic acid and isoniazid) in 1952, which assured cure; recognition in the 1970s that isoniazid and rifampin could reduce the duration of treatment from 18 to 9 months; and the observation in the 1980s that adding pyrazinamide to these drugs allowed cures in only 6 months. To combat noncompliance, intermittent regimens, twice or thrice weekly, have been proven to cure even far-advanced TB in as few as 62-78 encounters over 26 weeks. However, these regimens are not sufficiently short or convenient to facilitate effective treatment in resource-poor countries. Therefore, drug-resistant strains have emerged to threaten TB control in various areas of the world, including India, China, Russia and the former Soviet Union. For these reasons, it is vital that new medications are developed to shorten the duration of therapy, increase the dosing interval of intermittent regimens and replace agents lost to resistance. Other special considerations include identifying optimal therapy for persons with acquired immune deficiency syndrome, particularly noting the problems of drug/drug interactions for those receiving antiretroviral treatment. Finally, the Alchemist's Dream of tuberculosis should be pursued: modulating the immune response to shorten treatment and/or overcome drug resistance.

Vertebral osteomyelitis due to infection with nontuberculous Mycobacterium species after blunt trauma to the back: 3 examples of the principle of locus minoris resistentiae.

Osteomyelitis due to infection with nontuberculous mycobacterial organisms is unusual, especially in the absence of nonpenetrating trauma. We describe 3 patients with vertebral osteomyelitis due to infection with nontuberculous mycobacterial organisms that was precipitated by blunt trauma; these 3 unusual cases illustrate the principle of locus minoris resistentiae.

Novel treatment of meningitis caused by multidrug-resistant Mycobacterium tuberculosis with intrathecal levofloxacin and amikacin: case report.

We report the case of a 25-year-old HIV-negative man with disseminated multidrug-resistant tuberculosis (MDRTB), who-on a retreatment regimen-experienced total resolution of TB miliary disease, but progressive TB meningitis. Therefore, intrathecal treatment with amikacin and levofloxacin was instituted, with successful clinical and microbiological results.

Immunologic diagnosis of tuberculosis: a review.

The diagnosis of tuberculosis (TB) principally rests on the sputum examination and culture. However, the sensitivity of sputum smear for acid-fast bacteria is only approximately 50% and sputum culture has a relatively long turnaround time. As a result, a number of studies have been conducted in an attempt to find a rapid and accurate diagnostic test for TB. They include serological assays against various mycobacterial antigens. Here we review the merits and deficiencies of the serological tests for TB. In general, serological assays have a high negative predictive value, making them potentially useful as a screening test to rule out active TB although in HIV-positive individuals, low sensitivity and low negative predictive value compromises the accuracy of the seroassays in this group of individuals. In populations where the prevalence of latent TB infection is high, the relatively low positive predictive value of the tests reduces their specificity for active TB. Furthermore, the higher costs and greater training required in performing these tests makes it important that future studies also assess whether their use affects patient outcomes in management of TB.

Management of multidrug-resistant tuberculosis.

Drug-resistant tuberculosis (TB) originally is the product of inadequate therapy; this may entail noncompliance with treatment, interrupted drug supplies, or inappropriate prescription. Patients may sequentially acquire resistance to several drugs through repetition of this process. Loss of activity of the major drugs greatly compromises the treatment process; most problematic is resistance to both isoniazid and rifampicin, so-called 'multidrug-resistant tuberculosis' (MDR-TB). Recent evidence indicates that MDR-TB is being transmitted to others, and particularly to persons with HIV infection/AIDS. Other situations in which epidemic spread of MDR-TB occurs include hospitals and prisons. In several areas of the world, ominous levels of MDR-TB have been identified in a recent WHO survey. Treatment of MDR-TB entails the use of poorly tolerated, second-line medications that are often toxic, and the duration of treatment must be extended to the range of two years. Resectional surgery may be required to effect cures in patients with advanced disease in which most of the first-line agents have been lost to resistance.

Treatment and implications of multidrug-resistant tuberculosis for the 21st century.

Drug-resistant tuberculosis fundamentally reflects inadequate chemotherapy. To prevent increases in the prevalence of resistance, physician education and more structured treatment programs are needed. In one recent series, 80% of patients with multidrug-resistant tuberculosis (MDR-TB) had been previously managed with clear breaches of standard practice. These errors included adding a single drug to a failing regimen, failing to identify initial or acquired resistance, using an inadequate regimen, and not recognizing (and coping with) non-adherence to therapy. Both medical and surgical management should be considered in optimizing treatment of patients with MDR-TB. Optimal treatment strategies for MDR-TB are outlined in this paper. The use of susceptibility testing is strongly advised, but in situations where such laboratory services are not available, empirical management regimens are discussed.

Potential association between calcified thoracic lymphadenopathy due to previous Histoplasma capsulatum infection and pulmonary Mycobacterium avium complex disease.

BACKGROUND: Among patients with pulmonary disease due to Mycobacterium avium complex (MAC) seen recently at our center, a substantial number have had extensive calcified mediastinal, hilar, and peribronchial lymphadenopathy, a finding historically inconsistent with pulmonary MAC disease. METHOD: We retrospectively studied the frequency of calcified lymphadenopathy in the chest and prevalence of known risk factors for MAC infection in 79 patients with pulmonary MAC disease who were referred to our hospital over a 1-year period. RESULTS: Calcified intrathoracic adenopathy was present in 25 of the 79 patients (32%). Residential histories revealed that 20 of the 25 patients (80%) with such calcified chest adenopathy reported living for substantial periods in the regions indigenous for Histoplasma capsulatum. In contrast, the residences of patients without calcified chest adenopathy were more evenly distributed throughout the country. Nineteen of these 25 patients (76%) with calcified chest adenopathy had no known predisposing risk factor for the infection; in contrast, the proportion of patients with no calcified adenopathy who also had no identifiable classic risk factor tended to be lower (32/54, 59%). CONCLUSION: In this retrospective study, we observed that (1) a large number of patients with pulmonary MAC disease had no identifiable risk factor, (2) calcified chest adenopathy was present in one third of the patients, (3) the residential history of those with calcified adenopathy mirrored the endemic region of histoplasmosis, and, (4) conversely, those patients with pulmonary MAC who lived outside the histoplasmosis belt had no such adenopathy. Thus, we hypothesize that previous fungal infection may predispose the lungs of certain patients to subsequent invasion by MAC, presumably by airway distortion and/or parenchymal damage.