Antimicrobials for Bacterial Bioterrorism Agents

Mitali Sarkar-Tyson; Helen S Atkins


Future Microbiol. 2011;6(6):667-676. 

In This Article


The circumstances associated with the potential use of biological agents for terrorism are unlike those associated with conventional attacks. For example, the detection of an attack may not be immediate and may not occur until significant numbers of people are diagnosed with a disease. Secondary transmissions and the occurrence of infections at locations other than the attack location may make confirming the details of the attack difficult. Infection control measures may be important in limiting the outbreak of disease and the implementation of available medical countermeasures (vaccines and antimicrobials) may be used to minimize the effect of the attack on individuals. Circumstances will be influenced by the biological agent used, particularly in terms of its infectivity and transmissability, virulence and lethality.

Bioterrorism Agents

The US CDC has listed biological agents into three principle categories: A–C [101]. Category A agents are the highest priority agents to address and are those considered the most dangerous agents because they are easily disseminated or transmitted from person to person, and have the potential to cause high mortality and for major public health impact. Category B agents are the second highest priority agents. They are considered moderately easy to disseminate and, although considered likely to cause low mortality rates, many are incapacitating and infection would result in moderate morbidity rates. Finally, category C agents are considered emerging pathogens that may be engineered for mass dissemination in the future due to their availability, ease of production and potential morbidity and mortality.

The development of effective antimicrobials for use against the potential bioterrorism agents presents unique and particular challenges. A key issue is that the traditional drug development route is not applicable, given the relatively small numbers of naturally occurring human cases of disease caused by the agents. Thus, in order to have scientific evidence of a drug's effectiveness, animal models and in vitro models of infection are relied upon. It is therefore critical that suitable models of infection are developed and that results obtained in animal studies accurately predict outcomes in the human population. In addition, the potential use of antimicrobials for bioterrorism agents in the event of an attack is likely to be widespread, so considerations regarding the availability, distribution and safety of the antimicrobials for large populations need to be addressed (Box 1).

The CDC list of bioterrorism agents includes viruses, bacteria and bacterial-derived toxins. The category A and category B bacterial terrorism agents included are listed in Box 2. Category A includes three pathogenic bacteria that have the highest potential for use in large-scale bioterrorist attacks: Bacillus anthracis, Francisella tularensis and Yersinia pestis. Category B includes Brucella species, Burkholderia mallei, Burkholderia pseudomallei, Chlamydia psittaci, Coxiella burnetii and Rickettsia prowazekii. Category B also includes threats to food (e.g., Salmonella species, Shigella and Escherichia coli O157:H7) and water (e.g., Vibrio cholera and Cryptosporidium), which are not included in Box 2.

Bacillus anthracis

B. anthracis is a Gram-positive spore-forming bacillus and the etiological agent of the zoonotic disease anthrax. The bacterium survives outside of the mammalian host in a dormant spore form, which is stable for many years. B. anthracis causes cutaneous, gastrointestinal or inhalational anthrax in humans, depending on the route of infection. Most cases occur by cutaneous infection via inoculation through the skin of material from infected animals or their products. Inhalational anthrax is the most acute form of the disease, associated with a high mortality rate. The infection is not known to spread from person to person, but outbreaks of inhalational anthrax, which have been well documented, demonstrate that infective spores can be effectively disseminated via aerosol. In 1979, an outbreak of inhalational anthrax occurred in Svedlorsk, Russia, where B. anthracis spores were released accidentally from a bioweapons manufacturing facility, resulting in 66 deaths from inhalational anthrax.[1] More recently, in September 2001, B. anthracis spores sent through the US postal system resulted in 22 confirmed cases of anthrax infection.[2]

At present, the only licensed vaccine for anthrax is BioThrax Anthrax Vaccine Adsorbed (AVA), which stimulates the development of antibodies against a protein produced by B. anthracis that binds to cellular receptors and facilitates the actions of toxins known to be key virulence factors for B. anthracis. In addition, B. anthracis is susceptible in vitro to a wide range of antimicrobial agents and many have been used successfully for the treatment of anthrax in humans. Most strains are sensitive to penicillin, as well as macrolides, aminoglycosides, tetracyclines and chloramphenicol.[3] However, although patients with inhalational anthrax from the September 2001 outbreak were typically given multiple antibiotics to which the organism was susceptible, five of 11 individuals died. Those that recovered had presented in what was considered the initial stages of illness, suggesting that early antimicrobial therapy is essential for survival.

Ciprofloxacin (or a similar fluoroquinolone) is currently recommended as prophylaxis or early treatment for those considered at greatest risk of exposure following a large-scale release of anthrax spores in a deliberate attack. Studies in small animal models of inhalational B. anthracis infection have demonstrated the in vivo efficacy of ciprofloxacin and levofloxacin for postexposure prophylaxis of anthrax.[4–6] In addition, ciprofloxacin was shown to be effective for postexposure prophylaxis of anthrax in nonhuman primates.[7] Accordingly, the US FDA has provided an indication for ciprofloxacin for the prophylaxis of infection with B. anthracis. The FDA also approved levofloxacin for anthrax postexposure prophylaxis, an indication supported by in vitro hollow-fiber infection studies that replicate the pharmacokinetic profile of levofloxacin observed in humans or animals[8] and efficacy studies in nonhuman primates using a humanized antibiotic dosing regimen.[9] Doxycycline is the preferred tetracycline as a result of its proven efficacy in mice[4,5] and primates,[7] as well as its ease of administration.

Although cases of inhalational anthrax may be controlled by antibiotics, the treatment regimen has to be followed continuously for 60 days to ensure any residual spores are eliminated. Thus, protecting a civilian population against a bioterrorism attack with anthrax is difficult. Advance stockpiling of antibiotics would be required to ensure there is sufficient supply for a 60-day regimen per person. As a result, there is a clear need for cost-effective antimicrobials for anthrax.

Francisella tularensis

F. tularensis is a facultative intracellular bacterium and the etiological agent of the zoonotic disease tularemia. Human tularemia is endemic in North America and some parts of Northern Europe, where F. tularensis is usually transmitted to humans by the bite of a tick vector or through handling or eating infected carcasses. Thus, the most common form of tularemia in humans is ulceroglandular tularemia. The species is classified into four biovars on the basis of virulence and differences in 16S ribosomal DNA sequences: F. tularensis biovar tularensis (previously known as type A), holartica, mediaasiatica and novicida. The inhalation of F. tularensis results in the most severe form of tularemia in humans. Only low doses of F. tularensis are required for infection by this route and, without antibiotic treatment, a fatality rate of up to 30% occurs.[10] These properties of F. tularensis previously led to weaponization of the pathogen[11] and contribute to its classification by CDC as category A.

At present, no licensed vaccine is available for tularemia. F. tularensis is generally considered treatable with antibiotics. However, some antibiotics are unsuitable for tularemia, including β-lactams and macrolides.[11] Aminoglycosides, specifically streptomycin, are traditionally the postexposure prophylaxis of choice, although streptomycin is now avoided due to limited availability and toxicity, and gentamycin is now recommended by the UK Health Protection Agency (HPA).[102] However, gentamycin is parenterally administered. Thus, in the event of a deliberate release HPA currently recommends postexposure prophylaxis with oral ciprofloxacin or doxycycline for 14 days.[12] Early studies in a murine model of F. tularensis infection showed that ciprofloxacin and doxycycline were equally effective for postexposure prophylaxis, although neither antibiotic prevented relapse.[13]

Fluoroquinolones are appealing because of their activity against Gram-negative bacilli and their intracellular penetration, which is particularly useful for the facultatively intracellular F. tularensis. In humans, the use of ciprofloxacin has generally been successful, although a 50% relapse rate has been reported.[13] Other studies have indicated that relapse following therapy with ciprofloxacin is less likely than with streptomycin and doxycycline.[14–17] More recently, levofloxacin has also been shown to be effective as postexposure prophylaxis against highly virulent strains of F. tularensis in mice[6] and nonhuman primates,[18] providing supporting efficacy data for the future indication of this antibiotic for tularemia.

Yersinia pestis

Yersinia pestis is a Gram-negative bacterium and the causative agent of plague, a disease that is endemic in Africa, Asia, South America and in south-western USA. Y. pestis primarily causes bubonic plague in humans, usually a consequence of the transmission of bacteria to humans via bites from fleas that have previously fed on infected rodents. More rarely, cases of pneumonic plague are reported, resulting from the acquisition of the bacterium via aerosols generated, for example, by coughing and sneezing or from the spread of Y. pestis following the bite of an infected flea. Pneumonic plague follows a rapid course and is associated with high mortality, which is the likely consequence of the use of Y. pestis as an aerosolized biological weapon.[19]

A number of antibiotics are active against Y. pestis. Traditionally, streptomycin has been the antibiotic of choice for plague, given intramuscularly over 10 days; other regimens include oral tetracycline or intravenous chloramphenicol. Ciprofloxacin is also recommended for both therapeutic and prophylactic use. These recommendations are supported by in vitro studies[20,21] and efficacy in animal models of pneumonic plague.[22,23] However, mortality associated with pneumonic plague may be high even with antibiotic treatment. There is concern regarding the use of naturally occurring or genetically engineered strains of Y. pestis with increased antimicrobial resistance given the emergence of isolates from Madagascar containing transferable multidrug resistance plasmids,[24,25] and a quinolone-resistant strain is a potential risk.[20]

Burkholderia pseudomallei & Burkholderia mallei

Burkholderia pseudomallei and Burkholderia mallei are close phylogenetically related species. B. pseudomallei is a Gram-negative bacillus that is found predominantly in southeast Asia and northern Australia and is the causative agent of melioidosis. The infection of humans with B. pseudomallei may occur by various routes including via wounds and existing skin lesions, aspiration of contaminated water during near-drowning and inhalation of organisms. Melioidosis may present as an acute infection with pneumonia and septicemia and can be rapidly progressive with high mortality rates. However, sub-acute and chronic forms of melioidosis also exist and re-activation following sometimes lengthy latent periods is common.[26,27] In comparison, B. mallei is the causative agent of glanders, primarily an equine disease. Although B. mallei infections in humans are uncommon, it has been used as a biological weapon, both in World War I[28] and World War II.[29] As with B. pseudomallei, B. mallei is highly infectious by the respiratory route and has a high mortality rate if left untreated.[28]

The current recommended treatment for acute melioidosis infection is high-dose intravenous ceftazidime or a carbapenem, for at least 10–14 days, followed by oral eradication therapy.[30] Both organisms are susceptible to the tetracyclines, trimethoprim-sulfamethoxazole (co-trimoxazole), amoxicillin-clavulanate (co-amoxiclav), third generation cephalosporins and chloramphenicol.[30] Since there is little evidence available related to antibiotic treatment of glanders in humans it is recommended that cases should be treated with the same regimens used for melioidosis. There are few recommendations for postexposure prophylaxis in other circumstances, such as laboratory workers, although UK HPA guidance recommends co-trimoxazole (with or without doxycycline),[31] supported by activity of these antibiotics in murine models of infection.[32,33]

Multidrug resistance in B. pseudomallei is a significant problem in the treatment of melioidosis and there is no human vaccine currently licensed for protection against melioidosis or glanders. Furthermore, relapsing melioidosis can result from the re-activation of a latent infection of B. pseudomallei, often due to the withdrawal of antibiotics or the failure to complete prescribed courses of antibiotics. Thus, there is a requirement for safe and effective antibiotics for melioidosis and glanders, particularly to address the potential use of these pathogens as bioterror agents.


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