ABSTRACT
The timely evaluation of new drugs that can be used to shorten tuberculosis (TB) treatment will require surrogate markers for relapse. This study examined bactericidal activity against intracellular Mycobacterium tuberculosis in whole blood culture (whole blood bactericidal activity; WBA) during TB treatment. In the absence of chemotherapy, immune mechanisms in patient blood resulted in bacteriostasis, whereas administration of oral chemotherapy resulted in bacillary killing. Total WBA per dose was greater during the intensive phase of treatment than during the continuation phase (mean, -2.32 vs. -1.67 log(10) cfu-days, respectively; P<.001). Cumulative WBA throughout treatment was greater in subjects whose sputum cultures converted to negative by the eighth week of treatment than in those for whom conversion was delayed (mean, -365 vs. -250 log(10) cfu-days; P=.04) and correlated with the rate of decrease of sputum colony-forming unit counts during the first 4 weeks of treatment (P=.018), both of which are indicative of prognosis. These findings indicate that measurement of WBA may have a role in assessing the sterilizing activity of new anti-TB drugs.
Subject(s)
Antitubercular Agents/therapeutic use , Blood Bactericidal Activity/immunology , Mycobacterium tuberculosis/drug effects , Mycobacterium tuberculosis/immunology , Tuberculosis, Pulmonary/drug therapy , Tuberculosis, Pulmonary/immunology , Adolescent , Adult , Antitubercular Agents/administration & dosage , Antitubercular Agents/blood , Area Under Curve , Drug Evaluation, Preclinical , Female , Humans , Male , Microbial Sensitivity Tests , Middle Aged , Recurrence , Sputum/microbiology , Tuberculosis, Pulmonary/blood , Tuberculosis, Pulmonary/microbiologyABSTRACT
Sputum and serum from patients with active pulmonary tuberculosis (TB), healthy purified protein derivative-positive adults, and patients with bacterial pneumonia were collected to simultaneously assess local immunity in the lungs and peripheral blood. To determine whether cytokine profiles in sputum from TB patients and control subjects were a reflection of its cellular composition, cytospin slides were prepared in parallel and assessed for the presence of relative proportions of epithelial cells, neutrophils, macrophages, and T cells. Gamma interferon (IFN-gamma) in sputum from TB patients was markedly elevated over levels for both control groups. With anti-TB therapy, IFN-gamma levels in sputum from TB patients decreased rapidly and by week 4 of treatment were comparable to those in sputum from controls. Further, IFN-gamma levels in sputum closely followed mycobacterial clearance. Although detected at fourfold-lower levels, IFN-gamma immunoreactivities in serum followed kinetics in sputum. TNF-alpha, interleukin 8 (IL-8) and IL-6 also were readily detected in sputum from TB patients at baseline and responded to anti-TB therapy. In contrast to IFN-gamma, however, TNF-alpha and IL-8 levels also were elevated in sputum from pneumonia controls. These data indicate that sputum cytokines correlate with disease activity during active TB of the lung and may serve as potential early markers for sputum conversion and response to anti-TB therapy.
