Abstract:
Moxifloxacin is considered to be a broad-spectrum fluoroquinolone due to its activity against both gram positive and gram negative bacteria. Importantly this agent is currently being evaluated in ongoing clinical trials in South Africa and South America as a treatment for Moxifloxacin is considered to be a broad-spectrum fluoroquinolone due to its activity against both gram positive and gram negative bacteria. Importantly this agent is currently being evaluated in ongoing clinical trials in South Africa and South America as a treatment for pulmonary tuberculosis, with the specific objective of decreasing the duration of chemotherapy. However, relatively little is known about the effects of moxifloxacin on host defenses, particularly innate protective mechanisms, involving neutrophils. The primary theme of the laboratory research presented in this dissertation was to investigate the role of moxifloxacin in modulating the host immune system, specifically neutrophil protective functions, as well as lymphocyte proliferation and cytokine production (IL-1, IL-2, IL-4, IL-5, IL-6, IL-7, IL-10, IL-12, IL13, IL-17, IFN-γ, GM-CSF, G-CSF, TNF-α, and MCP-1). The generation of reactive oxidants and elastase release by neutrophils activated with the chemoattractant, fMLP, or the phorbol ester, PMA, were assayed using luminol- and lucigenin-enhanced chemiluminescence (LECL) and colorimetric procedures, while alterations in cytosolic Ca2+ concentrations were monitored by radiometric (45Ca2+) procedures. Moxifloxacin (1-20 ㎍/ml) was found to have no significant priming or inhibitory effects on oxidant generation by human neutrophils activated with fMLP or PMA, while elastase release was increased at the highest concentrations of the antibiotic. The magnitude of efflux or store-operated Ca2+ influx was unaffected following activation of neutrophils with fMLP. Moxifloxacin at all concentrations tested, did not affect either lymphocyte proliferation or CD25 expression by PHA-activated mononuclear leukocytes (MNLs). Similarly, none of the cytokines measured were significantly affected by moxifloxacin, either in the absence or presence of PHA, compatible with a lack of effect of this agent on Th1 and Th2 lymphocytes. In conclusion, this study suggests that moxifloxacin, at therapeutic doses, does not affect the protective functions of human neutrophils and lymphocytes.
