Ciprofloxacin, doxycycline, and penicillin G procaine have been approved by the Food and Drug Administration (FDA) for prophylaxis of inhalational Bacillus anthracis infection, on the basis of efficacy data in monkeys and pharmacokinetic, pharmacodynamic, and safety considerations (1–3). During the recent bioterrorist attacks, interim CDC recommendations for anthrax prophylaxis include ciprofloxacin or doxycycline; amoxicillin (in three daily doses) is an option for children and pregnant or lactating women exposed to strains susceptible to penicillin (4–6), to avoid potential toxicity of quinolones and tetracyclines. Amoxicillin is not widely recommended as a first-line prophylactic agent, however, because of lack of FDA approval, lack of data regarding efficacy, and uncertainty about the drug’s ability to achieve adequate therapeutic levels at standard doses.

The optimal duration of prophylaxis is uncertain; however, 60 days was recommended, primarily on the basis of animal studies of anthrax deaths and spore clearance after exposure. The possible need for longer prophylaxis and vaccine use was discussed. In monkeys after aerosol challenge, an estimated 0.5%-1% of spores remained at 75 days and traces were present at 100 days; delaying prophylaxis up to 20 days after exposure prolonged the incubation period without reducing disease risk (7). In one human case during the Sverdlovsk outbreak (former Soviet Union, 1979), anthrax developed 43 days after spores were released into the atmosphere (time of exposure unknown) (2,8). When prophylaxis is delayed or intermittent, several experts recommended a total of 60 days of therapy. (On December 18, the Department of Health and Human Services announced additional options for prophylaxis of inhalational anthrax for persons who wish to take extra precautions, especially those whose exposure may have been high. Three options are now offered: 1) 60 days of antibiotic prophylaxis; 2) 100 days of antibiotic prophylaxis, and 3) 100 days of antibiotic prophylaxis, plus anthrax vaccine as investigational postexposure treatment [3 doses over a 4-week period] [9].)

The need for prophylaxis is determined by public health officials on the basis of an epidemiologic investigation. Prophylaxis is indicated for persons exposed to an airspace contaminated with aerosolized B. anthracis. Prophylaxis is not indicated for health-care and mortuary workers who care for patients or attend to corpses using standard precautions, for persons who handle or open mail in the absence of a credible threat, or for prevention of cutaneous anthrax (10).

Successful implementation of mass prophylaxis requires clarity of public health intent and communication, as well as coordination and collaboration. A well-communicated policy on who receives prophylaxis and with which drugs is essential. Agency spokespersons, local health-care providers, employers, and employee organizations (e.g., labor unions) should be familiar with the policy. Local or regional task forces may be helpful in planning and communicating public health policy, and resolving jurisdictional issues. Prophylaxis teams should be predesignated to function around the clock. Team members should have contingency plans for personal needs (e.g., child care). Issues for the point of prophylaxis distribution include layout and managing of traffic flow; security; availability of medical and office supplies, antibiotic and disease fact sheets, multilingual staff, and mental health counselors; legal needs (e.g., for a physician to write orders); and plans for follow-up, including assessment of adherence, illness, and possible drug adverse effects. Collaboration among health departments, health-care delivery organizations, and clinicians is important. In the 2001 outbreak, some patients with possible drug side effects were refused appointments by their private physicians and were referred back to the health department.

Anthrax prophylaxis issues needing further consideration or research include efficacy of additional drugs, optimal duration of prophylaxis, usefulness of a loading dose, safety of prolonged drug use (especially in children and pregnant women), concomitant use of vaccine or antitoxin, level of infectious dose, and definition of high-risk exposure (e.g., according to particle size or degree of environmental contamination).

Twenty-two confirmed or suspected cases (11 confirmed inhalational; 7 confirmed and 4 suspected cutaneous) were identified in the 2001 outbreak of bioterrorism-related anthrax. Cases were reported from Florida, New York, New Jersey, the District of Columbia, and Connecticut.

Treatment recommendations for anthrax infections have been based on historical information and limited data from animals (nonhuman primates), as well as in vitro findings. Susceptibility testing of 65 historical isolates was performed at CDC. In the absence of published guidelines for testing for B. anthracis, the standard National Committee for Clinical Laboratory Standards broth microdilution method was used with staphylococcal breakpoints. These 65 isolates and all those associated with the 2001 outbreak were sensitive to the quinolones, rifampin, tetracycline, vancomycin, imipenem, meropenem, chloramphenicol, clindamycin, and the aminoglycosides. The isolates have intermediate-range susceptibility to the macrolides but are resistant to extended-spectrum cephalosporins, including third-generation agents (e.g., ceftriaxone), and to trimethoprim-sulfamethoxazole (12).

The decision regarding the use of penicillins, the drugs historically used for treatment and prophylaxis of anthrax, is complicated. An inhibition assay shows beta-lactamase activity at low levels in the isolates. Genomic sequence data show two beta-lactamases: a potential penicillinase (class A) and a cephalosporinase (class B), which is expressed. Concern about the use of penicillin arises because an inducible penicillinase could be activated in the face of treatment with beta-lactams, particularly if the number of organisms present is high, as appears typical with inhalational disease. Concerns have also been raised about the poor penetration of beta-lactams into macrophages, the site where B. anthracis spores germinate.

Ciprofloxacin has been recommended on the basis of in vivo (animal) findings; other quinolones have not been studied in the primate model. Doxycycline, another first-line agent, should not be used if meningitis is suspected because of its lack of adequate central nervous system penetration. Bacteremic patients are often initially treated with a multidrug regimen to which an offending organism is presumed sensitive; this treatment allows empiric coverage for other pathogens. Thus, the recommendation for initial treatment of inhalational anthrax is a multidrug regimen of either ciprofloxacin or doxycycline along with one or more agents to which the organism is typically sensitive. After susceptibility testing and clinical improvement, the regimen may be altered. The drugs of choice for treatment of cutaneous disease are also ciprofloxacin or doxycycline. A penicillin such as amoxicillin or amoxacillin/clavulanic acid may be used to complete the course if susceptibility testing is supportive.

On the basis of risk for the inhalational form of the disease, cases of both inhalational and cutaneous anthrax associated with the 2001 outbreak are being treated with 60 days of antibiotics. Although zoonotic cutaneous anthrax is treated with a 7- to 10-day regimen, inhaled spores can remain latent for extended periods.

Two months after the 2001 outbreak, 6 of 11 patients with inhalational anthrax had survived. Keys to successful management appear to be early institution of antibiotics and aggressive supportive care. Chest tube drainage of the recurrent pleural effusions, which are typically hemorrhagic, often leads to dramatic clinical improvement. Because these effusions tend to reaccumulate rapidly, insertion of a chest tube or tubes has been beneficial.

Anthrax treatment issues meriting further consideration relate to adjunctive therapies. Clindamycin has been suggested to have antitoxin properties (as in the treatment of toxic shock associated with group A streptococci, Staphylococcus aureus, and Clostridium infections). Steroids have been used to control the edema of cutaneous disease and have been suggested for the treatment of meningitis or substantial mediastinal edema (13). Other antitoxin agents investigated in vitro include angiotensin-converting enzyme inhibitors, calcium channel blockers, and tumor necrosis factor inhibitors. Specific anthrax IgG antisera, collected from military or other vaccinees, may be an adjunct, as well as administration of the vaccine itself.