The Centers for Disease Control and Prevention in Atlanta held a special meeting in Washington to talk about ensuring that people exposed to large numbers of spores -- such as those in Senate Majority Leader Tom Daschle's office and some U.S. Postal Service workers -- do not develop inhalational anthrax infection after taking the recommended 60-day regimen of antibiotics.
"We wonder if those who inhaled a great many spores might be at risk for a longer period of time," said D.A. Henderson, who heads up bioterrorism efforts at the Health and Human Services Department.
CDC, HHS and local health officials are frustrated and hampered by the lack of scientific data on inhalation anthrax, simply because there have been so few infections -- 18 in the 20th century with most occurring before antibiotics -- from which to derive case information.
Some studies on mice, rabbits, monkeys and guinea pigs are available, but no one is sure just how that data correlate with what happens in humans.
Without the scientific data, the idea is to err on the side of caution and most officials in Washington on Saturday were leaning toward making a recommendation to HHS Secretary Tommy Thompson early next week that would bring the somewhat controversial anthrax vaccine into play.
The recommendation likely will be that those at high risk of possibly developing anthrax infection, because of the amount of the pathogen they were exposed to, would be able to join an Investigational New Drug clinical trial program using the anthrax vaccine, made by Bioport Corp. for post-exposure protection.
The vaccine is not experimental, approved by the Food and Drug Administration in 1970 for pre-exposure vaccination purposes only. A so-called off-label use post-exposure, which perhaps not technically illegal, would raise problems with management and monitoring of quality and results unless done within the scope of the IND program, which would place it under federal regulatory requirements.
Also expected is the recommendation that those getting the vaccine also be given at least another 30 days of antibiotics to protect them during the three-dose stage of vaccination, prior to full effectiveness.
Dr. John Eisold, the Capitol Hill physician who attended many exposed to anthrax via the Daschle letter, said in earlier planning -- well before the current anthrax cases -- that he and representatives of other federal agencies had agreed post-exposure vaccination should be part of any anthrax response plan. The idea was shelved when officials realized what happened on Capitol Hill would have a far-reaching impact on many people beyond the Hill.
The anthrax scare, which began in early October in Boca Raton, Fla., has resulted in 22 cases of suspected and confirmed anthrax infection -- including 11 inhalation cases and five deaths. The bigger picture is the more than 10,000 people -- from staffers and officials on Capitol Hill to postal workers to the media -- who were prescribed preventive antibiotics for 10 to 60 days, depending on their exposure and potential risk of infection.
Just this week, those who began the first 60-day doses are coming off the medication, and officials wonder if they are out of the woods.
Dr. Janet Woodcock of FDA said the 60-day FDA antibiotic regimen recommendation "was considered a conservative recommendation."
Dr. Thomas Inglesby, of Johns Hopkins Center for Civilian Biodefense Perspective in Baltimore, Md., supported the vaccination and additional antibiotic recommendations because the issue of taking medication for 60 days is fraught with pitfalls. He said anthrax, in its early stages, presents like any number of other illnesses and there is no one quick test to determine exposure and infection.
"This is a big problem in terms of management," he said.
Also, compliance among those taking antibiotics ranges from around 45 percent to 50 percent in Florida to 88 percent among Daschle office workers. People sometimes forget to take the medication or stop taking it because of side effects. Follow-up monitoring shows up to 45 percent reporting severe side effects from the antibiotics, however none so serious to warrant a trip to the hospital.
Officials wonder if people who do not complete the drug regimen get the full protection or if they might be susceptible to infection from lingering anthrax spores still viable inside their lungs. Studies show spores can remain viable for weeks after an exposure, even beyond the 60-day antibiotic regimen.
Louise Pitt of the U.S. Army Medical Research Institute for Infectious Diseases, or USAMIRIID, where many animal anthrax studies are done, said they show that for guinea pigs, a lethal dose of anthrax for 50 percent of the animals given anthrax was 79,000 spores. The so-called LD-50 for rabbits was 110,000 and for rhesus monkeys it was 55,000. For humans, it's been debated whether infection can occur at between 8,000 and 10,000 spores. But it is unknown what constitutes a fatal dose or even at what point in an infection that antibiotics would not be effective.
"When we calculate inhaled doses, we make no assumption about retention in the lung," Pitt said.
Dr. Greg Martin, chief of infectious diseases at Bethesda Naval Hospital, said studies show animals given antibiotics were protected from infection at the time but when the medication was stopped, five of 29 developed fatal inhalation anthrax infection. One study showed 75 days after exposure 1 percent of animals still had spores in their systems and one died 98 days after exposure.
Martin said it was possible "high exposure people could be at risk longer" and he supported using the anthrax vaccine accompanied by an additional 30 days of antibiotics.
He said cultures of people exposed to anthrax at Daschle's office were so filled with anthrax bacteria colonies it was impossible to tell where one colony ended and another began. Others suggested that some postal workers, such as those working at the Brentwood mail distribution facility near Capitol Hill, which handled anthrax letters sent to lawmakers, also would have high spore exposure rates.
Dr. Arthur Friedlander, a senior military scientist for USAMRIID at Fort Detrick, Md., said studies show animals given antibiotics were protected from anthrax infection only for the duration of the drug regimen and only those given both antibiotics and the vaccine were protected from additional exposures or latent spores.
The vaccine, however, brings additional problems. Used mostly by the military, there are reports by soldiers of severe side effects and some in the military have refused to take the vaccine. CDC records as of Dec. 14 showed 1,818 total adverse events reported, 117 of them serious and six fatalities.
District of Columbia Health Department Deputy Director Larry Siegel said there still are many questions about the vaccine and the potential IND program.
"I personally would have a great deal of difficulty recommending to an individual patient taking antibiotics to take the vaccine," Siegel said.
Siegel said in talks with U.S. Postal Service officials they indicated they would be cautious as well, taking under advisement only any recommendation from HHS that postal workers participate in the IND vaccination program.
Studies show the vaccine, as approved by FDA in 1970, is highly effective -- 93 percent coverage --but there are questions about the quality of the vaccine supply currently available. Bioport is the only company that makes it, but the FDA closed the plant for violations of regulations governing manufacturing of drugs. Bioport has made changes and renovations to its facility and is awaiting FDA re-inspection.
Dr. Kathryn Zoon, director of FDA's Center for Drug Evaluation and Research, said most of the vaccine is under the control of the Department of Defense and used for the military. DOD, however, has made available to HHS 5 million doses from Bioport that have minor changes and manufacturing deviations but which could be used in an "emergency situation only."
DOD also has transferred to HHS 10,000 doses of new vaccine made by Bioport following its facility upgrades but which are not yet approved and 209,000 doses manufactured in 1992 that when recently tested met FDA quality and efficacy requirements.
The University of Iowa's Dr. Charles Helms, chairman of the Bioterrorism Working Group for the Advisory Committee on Immunization Practices, said ACIP supports a recommendation for the IND vaccination program accompanied by additional antibiotics, a change from the group's recommendations made one year earlier when it stated antibiotics alone would be sufficient.
For Helms and other clinical investigators and health officials, the IND program may be the only way to get solid scientific data on anthrax infection and prevention in humans, answering at least some of the questions that have turned this fall's response to the anthrax attacks a learn-as-you-go experience.