Experimental investigations of the optimal therapy of systemic BCG infection in vivo

Abstract

Hematogenous spread of BCG after intravesical instillation against bladder cancer is rare, but may result in systemic infection and hypersensitivity reaction. We investigated fluoroquinolones and steroids in an animal model to improve the therapeutic options in local and systemic BCG infection. Furthermore, we tested the antitumor effectiveness of intravesical BCG with simultaneous application of fluoroquinolones and/or steroids. After systemic BCG infection, experiments were performed with quinolones as antimicrobial agent. Trimethoprim/sulfamethoxazole (TMS) was also tested in comparison to quinolones as a non-specific antimicrobial agent. To evaluate the hyperergic reaction after repeated BCG infection (hypersensitivity model), re-infection was performed seven days after primary infection with accompanying oral antimicrobial therapy with and without steroids. Intravesical tumor therapy was carried out with BCG in orthotopic murine bladder tumor model MB 49 together with simultaneous antimicrobial therapy. After primary infection, quinolones led to a significant prolonged survival independent of steroid administration. Steroids alone after primary BCG infection reduced the survival. In contrast to these experiments, only steroid-treated mice had a significant improvement in survival after a second challenge with BCG. Therapeutic efficacy of BCG was not affected by antibacterial therapy with quinolones. Steroids alone induced a significantly increased death rate during intravesical BCG therapy. Quinolones have a positive effect on survival in acute systemic BCG infection in mice. Re-infection with BCG led to severe hyperergic reaction that can only be influenced by steroids. Thus, quinolones can be used in primary systemic BCG infection after topical application as a sufficient alternative to common tuberculostatics. Repeated BCG instillation may lead to hyperergic reaction, making additional administration of steroids essential. In this animal model, therapeutic efficacy of BCG obviously was not affected by additional administration of antimicrobials.