Antimicrobial Therapy forBacillus anthracis-Induced Polymicrobial Infection in⁶⁰Co γ-Irradiated Mice

Abstract

Challenge with both nonlethal ionizing radiation and toxigenic Bacillus anthracis spores increases the rate of mortality from a mixed bacterial infection. If biological weapons, such as B. anthracis spores, and nuclear weapons were used together, casualties could be more severe than they would be from the use of either weapon alone. We previously discovered that a polymicrobial infection developed in B6D2F 1 /J mice after nonlethal (7-Gy) 60 Co ␥ irradiation and intratracheal challenge with B. anthracis Sterne spores 4 days after irradiation. In this present study, we investigated the survival of mice and the response of the polymicrobial infection during the course of antimicrobial therapy with penicillin G procaine, ofloxacin, trovafloxacin, or gatifloxacin. Survival was prolonged, but not ensured, when the mice were treated with either broad-spectrum ofloxacin or narrow-spectrum penicillin G for 7 days beginning 6 or 24 h after challenge. Survival was not prolonged when therapy was delayed more than 24 h after challenge. When these two antimicrobial agents were given for 21 days, the survival rate was increased from 0% for the controls to 38 to 63% after therapy. Therapy with trovafloxacin or gatifloxacin reduced the incidence of mixed infection and improved the rate of survival to 95% (trovafloxacin) or 79% (gatifloxacin), whereas the rate of survival for the controls was 5%. We conclude that the mixed infection induced by B. anthracis in irradiated mice complicates effective therapy with a single antimicrobial agent. To limit mortality following nonlethal irradiation and challenge with B. anthracis spores, antimicrobial therapy needs to be initiated within a few hours after challenge and continued for up to 21 days.Accidental or war-related exposure to ionizing radiation, if combined with accidental or intended infection with Bacillus anthracis spores, could cause combined injuries that would be more severe than the injuries caused by either agent alone. Nonlethal doses of ionizing radiation increase susceptibility to exogenous bacterial infections (18). As a potential biological weapon, B. anthracis spores are a source of exogenous infection by inhalation (36). Inhalational anthrax is rare but usually fatal in humans because the disease progresses rapidly with few clinical signs or symptoms until just prior to death (1, 17), as demonstrated in several species of laboratory animals (16,27).It is likely that such combined injuries would be presented to civilian as well as military emergency medical services. Effective preventive and therapeutic measures need to be developed for such combined injuries. To do so, it is essential that the threats posed by the biological effects of ionizing radiation in combination with the effects of biological weapons, such as B. anthracis spores, or endemic infectious diseases be assessed in a practical laboratory animal model.We needed a laboratory animal model that would not only demonstrate differences in responses to combined doses of both ␥ radiation and bacterial spore...

Histopathology in a murine model of anthrax

“…In summary, we found that subcutaneous infection was a consistent and simple way to establish systemic anthrax in a mouse model. Because, unlike in humans, the skin in mice does not appear to be a significant barrier to systemic disease, we did not need more complex or invasive infection procedures used in other models such as aerosolization chambers or intratracheal injection (Albrink 1961;Dalldorf et al 1971;Fritz et al 1995;Elliott et al 2002;Vasconcelos et al 2003). Similarly, we did not need to use previously described intraperitoneal infection routes (Karginov et al 2004;Popov et al 2004), thereby avoiding direct and potentially confounding interactions of bacteria with intraperitoneally dosed anaesthetics and therapeutic compounds under study in our laboratory.…”

Cooperation and the evolutionary ecology of bacterial virulence: TheBacillus cereusgroup as a novel study system

“…Could long distance secretion facilitate cheating within anthrax infections? The existence of any mixed infections of B. anthracis and other toxin null Bc group bacteria remain unclear although polymicrobial infections involving B. anthracis are not unknown [84]. Loss of toxin-bearing plasmids also occurs quite readily in culture [85].…”

Determination of Antibiotic Efficacy against Bacillus anthracis in a Mouse Aerosol Challenge Model

“…Many of these models have used subcutaneous challenges and have been used primarily for vaccine development studies (7,25). Two recent reports did involve respiratory route challenges followed by antibiotic treatment, using a guinea pig intranasal challenge model (2) and an irradiated mouse intratracheal challenge model (16). The guinea pig model is limited due to the safety spectrum of antibiotics that can be tested in this model (32).…”