The accidental or hostile exposure of individuals to ionizing irradiation is of great public and military concern. Radiation sickness (acute radiation syndrome, or ARS) occurs when the body is exposed to a high dose of penetrating radiation within a short period of time. Systemic infection is one of the serious consequences of ARS. There is a direct relation between the magnitude of radiation exposure and the risk of developing infection. The risk of systemic infection is higher whenever there is a combined injury such as burn or trauma. Ionizing radiation enhances infection by allowing translocation of oral and gastrointestinal flora, and reducing the threshold of sepsis due to endogenous and exogenous microorganisms. The potential for concomitant accidental or terrorism-related exposure to bio-terrorism agents such as anthrax and radiation also exists.

This site is made of a home page that presents new developments and updates on the management of acute radiation syndrome including concomitant exposure to radiation and anthrax. Separate pages are dedicated to the treatment modalities.

Susceptibility and treatment of anthrax in the irradiated host


Anthrax is a zoonotic disease caused by the spore-forming organism Bacillus anthracis  (Brook I. The prophylaxis and treatment of anthrax. Int J Antimicrob Agents. ;20:320-5. 2002). Human infections normally result from contact with contaminated animals or animal products; human to human transmission has never been reported. Recently, however, anthrax spores were deliberately spread through the mail system in the United States causing an outbreak of bioterrorism-related infections (Dewan PK, Fry AM, Laserson K, et al. Inhalational anthrax outbreak among postal workers, Washington, D.C., 2001. 2002) Emerging Infectious Diseases 8:1066.)




Bacillus anthracis is considered to be a likely biological warfare and terrorist agent because of the high mortality associated with inhaled anthrax spores and the excellent stability of anthrax spores (Pile JC, Malone JD, Eitzen EM, et al .Anthrax as a potential biological warfare agent. Arch Intern Med 158:429-34. 1998).

In addition to biological threats, the potential for concomitant accidental or terrorism-related exposure to sublethal gamma or mixed-field (gamma and neutrons) radiation exists. Ionizing radiation damages the hematopoietic and the gastrointestinal systems. Prompt, sublethal irradiation increases susceptibility to bacterial infections by decreasing the number of circulating mature white blood cells and by decreasing the number of epithelial cells in the intestine (Alper T. Cellular Radiobiology. New York: Cambridge University Press. 1979)
Brook et al (Brook, I., Elliott, T.B., Harding, R.A., et al.  Susceptibility of irradiated mice to Bacillus anthracis sterne by the intratracheal route of infection. J Med Microbiol.;50:702-11. 2001.) demonstrated that sublethally irradiated mice have an increased susceptibility to B. anthracis Sterne and endogenous bacteria infections with corresponding increases in mortality.         



Gram stain of Bacillus anthracis
 
When mice were given a sublethal dose of gamma-photon radiation and then challenged with B. anthracis Sterne spores by the intratracheal or subcutaneous route a polymicrobial sepsis was induced. A biphasic mode of mortality was observed, with a constant response of up to 3 or 4 Gy (up to 18% mortality), after which a sharp increase in mortality occurred (up to 100%). When irradiation was delayed beyond 15 days after inoculation, the susceptibility to B. anthracis infection and subsequent mortality disappeared. B. anthracis was recovered from the organs and blood of up to 89% of the animals. However, organisms of enteric origin were also isolated mixed with B. anthracis from up to 36% of the animals exposed to 3, 5 or 7 Gy. Inoculation of B. anthracis delta-Sterne-1 that lacks lethal toxin and oedema toxin also induced infection with B. anthracis, but not translocation of enteric micro-organisms. The synergic adverse effect of exposure to gamma-radiation followed by intratracheal challenge with B. anthracis was observed above 4 Gy. The lethal toxin of B. anthracis may enhance the emergence of polymicrobial infection with B. anthracis and enteric micro-organisms. This B. anthracis-induced polymicrobial infection after sublethal doses of radiation is unique and similar to the polymicrobial sepsis that occurs only after lethal doses of radiation but does not occur, when other bacteria are used as the exogenous challenge inoculum. 

Elliott et al (Elliott TB, Brook I, Harding RA, et al. Antimicrobial therapy for B. anthracis-induced polymicrobial infection in (60)Co gamma-irradiated mice. Antimicrob Agents Chemother.;46:3463-71. 2002.) investigated the effect of antimicrobial therapy on the survival of mice who developed polymicrobial infection after irradiation and intratracheal challenge with B. anthracis Sterne spores 4 days after irradiation.. The mice were treated with either penicillin G procaine, ofloxacin, trovafloxacin, or gatifloxacin. Survival was prolonged, but not ensured, when the mice were treated with either ofloxacin or narrow 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 the second generation quinolones, 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%.

The authors concluded that the mixed infection induced by B. anthracis in irradiated mice makes effective therapy difficult narrow spectrum 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.

Brook et al (Brook I, Giraldo DE, Germana A, et al Comparison of clarithromycin and ciprofloxacin therapy for Bacillus anthracis Sterne infection in mice with or without 60Co gamma-photon irradiation. J Med Microbiol. 2005 ;54(Pt 12):1157-62.) found that ciprofloxacin and clarythromycin therapies in non-irradiated animals in Neither creased survival from 49 % (17/35 mice) control animals to 94 % (33/35) and 100 %, respectively (P < 0.001). However, neiither drugs was able to increase survival in gamma-irradiated animals. 

Brook et al (Brook I, Germana A, Giraldo DE, et al. Clindamycin and quinolone therapy for Bacillus anthracis Sterne infection in 60Co-gamma-photon-irradiated and sham-irradiated mice. J Antimicrob Chemother. 2005; 56: 1074-80.) investigated the efficacy of clindamycin, ciprofloxacin and moxifloxacin alone or in combination in irradiated and nonirradiated mice after intratracheal challenge with B. anthracis Sterne spores. The combination of quinolones and clindamycin is recommended by the CDC for treatment of anthrax infection because of clindamycin in vitro activity against B. anthracis and potential for inhibition of B. anthracis toxin production. Although all single therapies were effective in non irradiated and irradiated animals, antagonism between clindmycin and ciprofloxacin was present in mainly in irradiated mice and no evidence of in vivo toxin suppression was observed with clindamycin therapy. The mechanism for this antagonism is unclear, and it’s predominance in irradiated mice suggest that it may be due to the combined effect in the irradiation damaged host. Remarkably, despite the clinical success of antimicrobial therapy, B. anthracis Sterne was still present in the organs of treated nonirradiated and irradiated animals. These findings do not support the CDC recommendation to treat B. anthracis infections with the combination of clindmycin and ciprofloxacin.