The long-term objective of this project is to improve the treatment of tuberculosis in HIV-infected and HIV-uninfected patients and to develop pharmacologic data that will facilitate further tuberculosis research. There is one specific aim - to determine and compare the intrapulmonary pharmacokinetics of INH, RlF, and PZA in TB-infected patients with and without AIDS by quantitating drug concentrations in bronchoalveolar lavage (BAL) fluid, alveolar cells (AC) and epithelial lining fluid (ELF). The re-emergence of tuberculosis has become one of our most important public health problems. In the US, co-infection with M. tuberculosis and HIV is estimated to occur in 100,000 individuals and the annual risk for the development of tuberculosis in coinfected individuals is 8%. The pathogenicity of M. tuberculosis is dependent upon its ability to survive within macrophages. However, despite the obligate intracellular location of M. tuberculosis, and the propensity of the organism to cause pulmonary infection, the in vivo intracellular and intrapulmonary pharmacokinetics of antituberculous agents have not been studied in patients with tuberculosis. Significant abnormalities in the gastrointestinal tract of AIDS patients have been demonstrated and have been shown to interfere with drug absorption. By performing bronchoscopy and bronchoalveolar lavage (BAL) in patients with pulmonary tuberculosis and measuring drug levels using highly specific and sensitive chromatographic techniques (HPLC), the intrapulmonary pharmacokinetics of these drugs will be defined and compared in HIV- infected and HIV-uninfected men and women. Alveolar cell separation using the FACSTAR cell sorter, determination of drug concentrations in peripheral blood mononuclear cells after Ficoll-Hypaque separation, tri-lobar lavage and the determination of concentrations of albumin in ELF have been added to the original proposal.
