Chicago—Bioterrorism is on the minds of infectious disease specialists these days. And as many gathered here at the Interscience Conference on Antimicrobial Agents and Chemotherapy, the topic took on a new urgency in the wake of recent deaths and illness caused by anthrax-laced mail.
Smallpox Vaccine Potency Tested
One of the most feared potential bioterrorist agents is smallpox, which was declared eradicated in nature in 1980. Because routine vaccinations ended in the United States in 1972, leaving the vast majority of people vulnerable to a deliberate release of smallpox by bioterrorists, the federal government has ordered 209 million doses of smallpox vaccine from a British company.
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Growing concerns that smallpox virus—the cause of these lesions on a patient in Bangladesh in 1973—could become a bioterrorist weapon has health experts scrambling to expand vaccine supplies. (Photo credit: CDC/James Hicks)
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But the vaccine is not expected to be available until early to late this fall. Scientists had suggested that it might be possible to expand the current supply of 15 million doses by diluting the vaccine and still obtain adequate protection against infection.
Preliminary data indicated that a 5:1 dilution of vaccine would work. To further examine this question, researchers affiliated with the National Institute of Allergy and Infectious Diseases (NIAID) Vaccine Treatment and Evaluation Unit at St Louis University in Missouri carried out a pilot study involving 60 healthy volunteers to test whether more diluted doses of the vaccine, which has been stored for nearly two decades, could stimulate a protective immune response against smallpox. Participants, healthy individuals between 18 and 30 years of age who had not previously been vaccinated against smallpox, were randomly assigned to be vaccinated with undiluted vaccine or a 1:10 or 1:100 dilution.
The vaccine, which was produced in 1982, is very viscous—the consistency of maple syrup and filled with particles and other debris—and is thus difficult to work with, said Robert Belshe, MD, head of the NIAID unit at St Louis University. (Belshe noted that he and his colleagues subsequently developed a better way to dilute the viscous vaccine by diluting it inside the vial in which the vaccine was stored—a technique that is being used in a large follow-up trial.)
Undiluted vaccine produced a 95% "take rate," or immune response, as indicated by the formation of a vaccinia vesicle, which correlated with an increase in levels of neutralizing antibodies—a response comparable with that seen in a 1977 test of a similar vaccine. For diluted vaccine, the take rate was only 15% for the 1:100 dilution. The 1:10 dilution produced a 70% response rate—better, but one that would leave too many people vulnerable to infection. "Seventy percent is not an acceptable response rate; you need a take rate of 90% to 95%," said Belshe.
Based on these findings, the investigators designed a large clinical trial involving more than 600 volunteers to test the effectiveness of vaccinia vaccine given in 1:5 and 1:10 dilutions. In addition, volunteers who fail to develop a vesicle at the vaccine site will be revaccinated—a strategy that the investigators believe could boost the overall response rate to more than 90%. Results of the trial were expected to be available early this year.
Antianthrax Antibiotics
The recent threat posed by anthrax-laced letters and the high-profile use of antibiotics—mostly ciprofloxacin—to ward off possible illness in postal workers and others exposed to the pathogen prompted many of the worried well to demand prescriptions of the antibiotic. But while anxiety about anthrax may have ebbed for the moment, another worry has not, say infectious disease experts: Potential misuse and overuse of ciprofloxacin provides a golden opportunity for microbes to develop resistance.
Researchers at the Armed Forces Radiobiology Research Institute in Bethesda, Md, have been studying the development of antibiotic resistance in anthrax bacteria and how to prevent resistance-related treatment failure of anthrax infections, said Itzhak Brook, MD. Using a veterinary vaccine strain of Bacillus anthracis, the investigators cultured and subcultured the microbe many times, all the while exposing it to subinhibitory concentrations of a number of antibiotic agents that are considered effective therapy for anthrax infection: doxycycline, quinolones (ciprofloxacin, alatrofloxacin, gatifloxacin, and ofloxacin), and macrolides (erythromycin, azithromycin, and clarithromycin).
"We saw the emergence of resistance to many, but not all, antibiotics," noted Brook. "There were also differences in the rate at which resistance developed."
They found that B anthracis developed increasing resistance to the quinolones and macrolides but minimal resistance to doxycycline. The study also revealed that bacteria resistant to one quinolone were also resistant to the other three.
The finding that long-term treatment of anthrax with any of the quinolones may induce resistance to many, if not all, drugs in the class is worrisome, they noted, because a 60-day course of ciprofloxacin is one of the recommended therapies for anthrax infection. Because the increase in resistance to doxycycline was relatively modest—at least in this in vitro study—the drug "might be useful for long-term therapy or prophylaxis against anthrax," the researchers said.
However, in cases of inhalation anthrax, because of the high mortality rate associated with pulmonary infection—and the potential for treatment failure caused by the development of antibiotic resistance—the Centers for Disease Control and Prevention advises using two or more antimicrobial agents predicted to be effective, although controlled studies to support using combination therapy are not available.
Researchers know that anthrax bacteria are capable of developing resistance against doxycycline because Russian scientists succeeded in genetically engineering doxycycline-resistant strains of B anthracis, cautioned Brook.
"We still don't have a perfect solution to the anthrax problem," he said. "We need to keep searching for more drugs."
