An extremely serious aspect of the TB problem in the United States is MDR-TB (i.e., TB resistant to at least isoniazid and rifampin). MDR-TB can usually be prevented by initially treating TB patients with four drugs and by administering TB medications on a directly observed basis. Persons at high risk for MDR-TB include persons who have been recently exposed to MDR-TB, especially if they are immunocompromised; TB patients who failed to take medications as prescribed; TB patients who were prescribed an ineffective treatment regimen; and persons previously treated for TB.

MDR-TB presents difficult treatment problems. Treatment must be individualized and based on the patient's medication history and drug susceptibility study results. Clinicians who are not familiar with the management of patients with MDR-TB disease or with patients infected with multidrug-resistant organisms should seek expert consultation.

For persons likely to have been infected with M. tuberculosis resistant to both isoniazid and rifampin, observation without preventive therapy is usually recommended because only isoniazid and rifampin have been evaluated for preventive therapy. However, for persons at an especially high risk for TB disease once infected (e.g., persons with HIV infection), preventive therapy with an alternative regimen should be strongly considered.