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Feature Articles : Apr 1, 2009 ( )
Unearthing More Effective Therapies for Anthrax
Bioterrorism Attacks Remain a Real Threat, and Resources Are Needed to Respond Effectively
Anthrax has been designated as the number one biological warfare threat to the U.S. military and the American homeland. It is likely to be the weapon of choice based on its weaponization potential, ease of production, ease of delivery as aerosolized spores, and the lethality of the inhalational form of the disease.
The Department of Health and Human Services has adopted a scenario planning model based on research conducted at Stanford University. The model illustrates what would occur in a large-scale anthrax attack. It has been determined that a one kilogram release of anthrax spores would affect an urban area of over 30 kilometers, exposing 11.5 million people to anthrax and infecting 1.5 million people. Of those infected, more than 120,000 would be expected to die. In addition, the economic impact of such an attack would be tremendous. The total economic impact of the 15 grams of anthrax used in the 2001 anthrax attacks has been estimated at more than $6 billion.
Anthrax is particularly virulent due to its ability to evade and impair the immune system. Once inhaled, spores less than 5 mm can become deposited in the lung’s alveoli where they are ingested by macrophages and transported to mediastinal lymph nodes. These spores then germinate into viable bacteria, typically causing a hemorrhagic mediastinitis and subsequent bacteremia. A poly-D-glutamic acid capsule inhibits phagocytosis of the bacterium, while two toxins (lethal toxin and edema toxin) further impair the immune system by killing macrophages and inhibiting phagocytosis. With an impaired immune system, bacteria replicate freely and toxin production results in hemorrhage, edema, and necrosis.
Interventions against anthrax include a preventive vaccine that is approved for use prior to any exposure and several antibiotics that have been approved for use after exposure to anthrax spores, but prior to demonstrating signs or symptoms of inhalational anthrax (designated PEP or post-exposure prophylaxis).
Administration of vaccine is also recommended following exposure to augment the patient’s immune response, but no anthrax vaccine has yet been approved for this indication. In addition, there are no therapies that are specifically approved for treating patients with signs/symptoms of inhalational anthrax (IA). Patients with IA are treated with antibiotics and supportive care, but even with modern aggressive interventions, the survival rate for IA was only 55% (6/11) in the anthrax attacks of 2001.
Clearly, current interventions for IA are not ideal. After initial anthrax vaccine administration, it takes several weeks before immunity is detectable, and multiple injections over an 18-month period with annual boosters are required to maintain protection. Antibiotics do not address the toxemia associated with infection. Once there is a critical concentration of the toxin within an infected individual, death may ensue even if the replicating bacteria are eradicated through the administration of antibiotics. Further, there is concern about bacterial resistance to antibiotics, both natural and genetically engineered.
It has been reported that the Soviet Union successfully created an anthrax strain resistant to multiple antibiotics without a loss of virulence. In the PEP setting, there have been issues with adherence to prolonged antibiotic regimens, as documented among those for whom 60 days of antibiotic prophylaxis was initially recommended in the 2001 anthrax attacks. This could decrease the effectiveness of such therapy.
Because of these issues, there has been active research into anthrax antitoxins, particularly monoclonal antibodies (mAbs). These mAbs would immediately interact with anthrax toxin, as antimicrobials address bacteremia and as the body is generating a natural immune response against anthrax. Monoclonal antibodies directed against the protective antigen (PA) of the anthrax toxin have demonstrated safety in clinical trials and efficacy in animal models.
In New Zealand white rabbits, up to 100% survival has been demonstrated when these animals were treated at the first evidence of circulating PA in their blood or an elevated temperature. In cynomolgus monkeys, survival of greater than 64% has been described when mAbs were given at the time of the first signs of IA. When evaluated in human volunteers, anti-anthrax mAbs have demonstrated that they are generally safe and well tolerated, and they do not appear to have adverse interactions with ciprofloxacin, one of the commonly used antibiotics to treat IA. This suggests that anthrax anti-toxin mAbs may be used in conjunction with antibiotics against anthrax.
The paradigm for combining antitoxins with antimicrobials is not unique to anthrax. There are a number of infectious diseases where toxins play a significant role in causing morbidity and/or mortality, including Clostridium difficile-associated diarrhea (CDAD), Shiga toxin-induced hemolytic uremic syndrome (STHUS), and toxic shock syndrome associated with Staphyloccus aureus.
While antibiotics play a role in the treatment of these diseases, they have not been completely effective, and in the setting of STHUS, there have been reports of antimicrobials exacerbating the syndrome. As in the setting of IA, recent research has focused on therapies to neutralize the toxins, including the use of monoclonal antibodies.
This has proven promising, as shown in a double-blind, placebo-controlled Phase II trial where two anti-Clostridium difficile toxin antibodies used in combination with standard of care antibiotics decreased recurrence rates of CDAD by approximately 70% when compared to antibiotics alone.
The need for anthrax antitoxin therapies is apparent and consistent with experience in other infectious diseases. A number of compounds are being evaluated, including small molecule drugs, small therapeutic proteins, and mAbs. Of these, mAbs are the most advanced, having demonstrated safety in human volunteers and efficacy in animal models. By February, the first delivery of 20,000 doses of an anthrax antitoxin mAb to the U.S. Strategic National Stockpile (SNS) had occurred. Other anthrax antitoxin mAbs continue to receive government funding for development in an effort to provide additional therapeutic options to the SNS. It is imperative that such research continues so that we have sufficient resources to respond to the next bioterrorist attack.
Matthew Meldorf, M.D. (matt.meldorf@ pharmathene.com), is senior program director for Valortim® at PharmAthene. Web: www.pharmathene.com.
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