Use of immunotherapy to enhance the efficacy of ceftazidime for the treatment of acute pulmonary Burholderia pseudomallei infection
Date
2010
Authors
Kellihan, Lisa M., author
Dow, Steven W., advisor
Schweizer, Herbert P., committee member
Gentry-Weeks, Claudia R., committee member
Journal Title
Journal ISSN
Volume Title
Abstract
B. pseudomallei is a soil bacterium endemic to Southeast Asia and northern Australia and is the causative agent of melioidosis. This organism is capable of causing acutely lethal pneumonia in humans when inhaled and is inherently resistant to many commonly used antimicrobials, thus making pulmonary B. pseudomallei infection difficult to treat. Effective treatment requires prolonged antibiotic therapy and, even with appropriate treatment, relapse is common. With increasing incidence of this disease in endemic regions and renewed interest in this bacterium as a potential biowarfare agent, more effective treatment approaches are needed. We investigated the ability of immunotherapy to enhance the effectiveness of antimicrobial therapy for the treatment of pulmonary B. pseudomallei infection. Immunotherapy with cationic liposome-DNA complexes (CLDC), potent stimulators of innate immunity and pro-inflammatory cytokine production, combined with ceftazidime antimicrobial therapy elicited synergistic inhibition of intracellular B. pseudomallei replication in infected alveolar macrophages and protected mice from acutely lethal i.n. challenge with B. pseudomallei. Mice treated with CLDC and ceftazidime also had significantly reduced organ bacterial burdens. We determined in vitro that IFN-y elicited by CLDC administration was the predominant cytokine responsible for the synergistic interaction with ceftazidime. Treatment of alveolar macrophages and mice with recombinant IFN-y as a substitute for CLDC also significantly increased the efficacy of ceftazidime in the treatment of B. pseudomallei infection. As a result, we concluded that immuno-antimicrobial therapy consisting of an IFN-y-inducing immunotherapeutic and a conventional antimicrobial may improve the treatment of B. pseudomallei infection via augmentation of antimicrobial efficacy.
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Print version deaccessioned 2022.
Print version deaccessioned 2022.
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Subject
Burkholderia pseudomallei
Cephalosporins
Immunotherapy