Chapter 7

Anthrax is an acute infectious disease caused by the spore-forming bacterium Bacillus anthracis. Anthrax most commonly occurs in wild and domestic lower vertebrates (cattle, sheep, goats, camels, antelopes, and other herbivores), but it can also occur in humans when they are exposed to infected animals or to tissue from infected animals or when anthrax spores are used as a bioterrorist weapon.

What is the difference between exposure to anthrax and disease caused by anthrax?

A person can be said to be exposed to anthrax when that person comes in contact with the anthrax bacteria and a culture taken from that person is positive for anthrax. A person can be exposed without having disease. A person who might have come in contact with anthrax, but without a positive culture would be said to be potentially exposed. Disease caused by anthrax occurs when there is some sign of illness, such as the skin lesion that occurs with cutaneous anthrax.

Anthrax is not contagious; the illness cannot be transmitted from person to person. B. anthracis spores can live in the soil for many years, and humans can become infected with anthrax by handling products from infected animals or by inhaling anthrax spores from contaminated animal products. Anthrax can also be spread by eating undercooked meat from infected animals. It is rare to find infected animals in the United States. Anthrax spores can be used as a bioterrorist weapon, as was the case in 2001, when Bacillus anthracis spores had been intentionally distributed through the postal system, causing 22 cases of anthrax, including 5 deaths.

Anthrax infection can occur in three forms: cutaneous (skin), inhalation, and gastrointestinal.

Early treatment of cutaneous anthrax is usually curative, and early treatment of all forms is important for recovery. Patients with cutaneous anthrax have reported case fatality rates of 20% without antibiotic treatment and less than 1% with it. Although case-fatality estimates for inhalational anthrax are based on incomplete information, the rate is extremely high, approximately 75%, even with all possible supportive care including appropriate antibiotics. Estimates of the impact of the delay in postexposure prophylaxis or treatment on survival are not known. For gastrointestinal anthrax, the case-fatality rate is estimated to be 25%-60% and the effect of early antibiotic treatment on that case-fatality rate is not defined.

Many human illnesses begin with what are commonly referred to as "flu-like" symptoms, such as fever and muscle aches. However, in most cases anthrax can be distinguished from the flu because the flu has additional symptoms. In previous reports of anthrax cases, early symptoms usually did not include a runny nose, which is typical of the flu and common cold.

Can I get screened or tested to find out whether I have been exposed to anthrax?

There is no screening test for anthrax; there is no test that a doctor can do for you that says you’ve been exposed to or carry it. The only way exposure can be determined is through a public health investigation. Nasal swabs and environmental tests, are not tests to determine whether an individual should be treated. These kinds of tests are used only to determine the extent of exposure in a given building or workplace.

CDC is engaging its partners in the Laboratory Response Network (LRN) in states all across the United States. The LRN is a collaborative partnership and multilevel system linking state and local public health laboratories with advanced capacity laboratories–including clinical, military, veterinary, agricultural, water, and food-testing laboratories– to rapidly identify threat agents, including anthrax. Local clinical laboratory testing is confirmed at state and large metropolitan public health laboratories. CDC conducts the definitive or highly specialized testing for major threat agents. There are 100 laboratories in the network; none of them are commercial labs.

When an area is tested for the presence of Bacillus anthracis , how long does it take to get the results?

Before testing can begin, samples must be collected in a form suitable for testing. The length of time it takes to get test results depends on both the kind of test to be performed and the laboratory’s workload. Some tests may take only a short time to perform, but confirmation takes longer. It may take many days to get the test results.

Testing is a two-step process. The first test, a screening test, may be positive within 2 hours if the sample is large and contains a lot of Bacillus anthracis, the organism that causes the disease anthrax. However, a positive reading on this first test must be confirmed with a second, more accurate test. This confirmation test, conducted by a more sophisticated laboratory, takes much longer. The length of time needed depends in part on how fast the bacteria grow, but results are usually available 1 to 3 days after the sample is received in the laboratory.

Hand-held assays (sometimes referred to as "Smart Tickets") are sold commercially for the rapid detection of Bacillus anthracis . These assays are intended only for the screening of environmental samples. First responder and law enforcement communities are using these as instant screening devices and should forward any positive samples to authorities for more sensitive and specialized confirmatory testing. The results of these assays should not be used to make decisions about patient management or prophylaxis. The utility and validity of these assays are unknown.

At this time, CDC does not have enough scientific data to recommend the use of these assays. The analytical sensitivity of these assays is limited by the technology, and data provided by manufacturers indicate that a minimum of 10,000 spores is required to generate a positive signal. This number of spores would suggest a heavy contamination of the area (sample). Therefore a negative result does not rule out a lower level of contamination. Data collected from field use also indicate specificity problems with some of these assays. Some positive results have been obtained with spores of the non-anthrax Bacillus bacteria that may be found in the environment.

For these reasons, CDC has been asked to evaluate the sensitivity and specificity of the commercially available, rapid, hand-held assays for B. anthracis. When this study is completed, results will be made available. Conclusions from this study are not expected in the near future.

All state health departments are capable of obtaining results of tests on suspected infectious agents. Laboratories are usually classified as Level A, B, C, or D. Level A laboratories are those typically found in community hospitals, and these laboratories should be able to perform initial testing on all clinical specimens (usually blood or some other body fluid). Public health laboratories are usually Level B; these laboratories are valuable for confirming or refuting preliminary test results and can usually perform antimicrobial susceptibility tests on bacteria and viruses. Level C laboratories, which are reference facilities and can be public health laboratories, can perform more rapid identification tests. Level D laboratories are designed to perform the most sophisticated tests and are located in federal facilities such as CDC. Every state has a Laboratory Response Network (LRN) contact. The LRN links state and local public health laboratories with advanced-capacity laboratories, including clinical, military, veterinary, agricultural, water, and food-testing laboratories. Laboratorians should contact their state public health laboratory to identify their local LRN representative. CDC’s public bioterrorism Web site provides access to CDC’s Centers for Public Health Preparedness, a national network of academic institutions and local health departments whose goal is to ensure that local public health workers are fully prepared to respond to current and emerging health threats, including bioterrorism.

There are many kinds of tests, and the reliability of each has not been determined. In general, findings from culturing environmental samples are specific; that is, a positive result reflects the true presence of Bacillus anthracis, and a negative result likely means that no B. anthracis is present.

Subtyping is a laboratory process to identify different subtypes of organisms, which is not possible with standard microbiological testing. Most Bacillus anthracis subtyping is done by examining the organism’s molecular structure for certain genetic characteristics that can then be compared with those of other B. anthracis organisms to determine whether they are the same or different. Differences between these two organisms would indicate different strains.

Polymerase chain reaction (PCR) is a laboratory method used to detect and amplify genetic material from organisms. It can be used to diagnose disease by identifying genetic material (DNA) commonly found in all Bacillus anthracis strains or it can be used to subtype the organism by amplifying specific genetic material and comparing it with known strains of B. anthracis to see if it matches or if it is different. When PCR is used for subtyping, the amplified genetic material is usually further analyzed by other molecular methods, such as DNA sequencing.

CDC uses a method called MLVA, which is the acronym for multi-locus variable-number of tandem (consecutive) repeat analysis .

MLVA examines a number of DNA segments within the chromosome or plasmids of Bacillus anthracis that have specific repeat patterns of nucleotides (fundamental DNA units). These repeats may differ by sequence and length, as well as the number of times that they are repeated. Different types of these repeats and the number of times that they are repeated provide a specific pattern that will identify different strains of the organism. More than 100 different strains of B. anthracis have been identified using this method.

Environmental sampling is the sampling of the air, soil, dust, water, and physical surfaces to identify the presence or absence of bacteria, chemicals, and radiological materials (see "Procedures for Collecting Surface Environmental Samples for Culturing Bacillus anthracis"). In the case of anthrax, this is used to identify its location and presence in the environment. Environmental sampling would be conducted if there were a threat or possibility of Bacillus anthracis contamination. However, the presence of B. anthracis in an environmental sample does not mean the person will get the disease.

Before testing can begin, samples must be collected and arrive in a form suitable for testing. The length of time necessary to get results of tests depends on transportation to the laboratory and the specific tests to be done. Testing is a two-step process. Initial screening tests (such as Gram stain) may be positive within two hours if the sample is large and the concentration of bacteria is high. These tests are used to narrow the definition of the sample. The confirmation tests take much longer, depending in part on how fast the bacteria grow, but are usually available 24-48 hours after the sample is received by the laboratory. (See "Basic Laboratory Protocols for the Presumptive Identification of Bacillus anthracis".)

This is not a "new test." The Laboratory Response Network (LRN) has been using a validated real-time polymerase chain reaction (PCR) assay on the LightCycler for some time. CDC has also developed and validated real-time PCR assays for Bacillus anthracis for the SmartCycler™, ABI/PE 7700 and 5700. In addition, Idaho Technology has a real-time PCR assay for B. anthracis that can be used with the R.A.P.I.D.™, which is similar to the LightCycler™. SmartCycler is a trade name of Cepheid; R.A.P.I.D. is a trade name of Idaho Technology; LightCycler is a trade name of Roche; Idaho Technology is the name of a company.

N o. The Mayo Clinic assay targets the Lethal Factor (lef) gene on the virulence plasmid p0X1 and the Protective Antigen gene (pag) on p0X2. This assay has been tested with DNA from 32 strains of Bacillus anthracis, 26 Bacillus species, and 21 different bacterial genera commonly encountered in human specimens. The Mayo Clinic assay has not been validated in multiple laboratories.

The CDC assay uses targets on p0X1, p0X2, and the chromosome. A total of 100 Bacillus anthracis isolates were used to evaluate the sensitivity of the assay. Of the 100, 77 were selected to provide the best possible representation with respect to geographic origin and date isolated. The strains were obtained from infected animals, humans, and from industrial sites associated with anthrax outbreaks; they span 58 years (1939-1997) and are from various countries. In addition, five p0X1-cured strains (including the Sterne strain) and one p0X2-cured strain (Pasteur strain) were included. For evaluation of the specificity of the assay, 54 Bacillus species were used (B. subtilis , 9; B. cereus, 23; B. thuringiensis , 12; and B. megaterium, 10) as well as 250 other DNAs of various viruses and bacteria from human, animal, and insect sources. The assay was validated in a multicenter study by using state public health laboratories that had the specific platform.

Because the Mayo Clinic assay uses only two plasmid targets, it cannot identify Bacillus anthracis strains such as Sterne or Pasteur that may be present in environmental specimens. This would not be a problem if the assay were used to confirm the identity of a gram-positive, non-motile, non-hemolytic rod.

CDC is testing samples from the current anthrax outbreak. When we have sufficient time, we will study this and other anthrax assays.

On the basis of the data provided by the Mayo Clinic, the assay appears to be sensitive and specific. However, the results are only as good as the method used to prepare the sample for analysis. There have been no data provided to indicate the types of samples that can be assayed or how they are to be processed. The Food and Drug Administration (FDA) has not seen the package insert for this test. The CDC assay has been validated for different types of samples and sample processing methods.

T hrough the bioterrorism cooperative agreement, CDC has funded the purchase of platforms for real-time polymerase chain reaction (PCR) assays for the Laboratory Response Network (LRN). To date, 61 instruments have been purchased or ordered. Among these are 17 LightCyclers,™ 23 SmartCyclers™, 13 7700s, and 5 5700s. Reagents for real-time anthrax assays are made at CDC and placed in inventory. They are available at no charge to LRN laboratories. Currently, reagents for the LightCycler™ anthrax assay are available; reagents for the other platforms will be available soon. All of the assays have undergone the same rigorous validation procedure.

The Food and Drug Administration (FDA) considers this an investigational assay. As such it should be used only in conjunction with other tests, such as culture tests. Currently, polymerase chain reaction (PCR) assays are not considered confirmatory assays.

Currently, polymerase chain reaction (PCR) assays are not considered confirmatory tests for anthrax. PCR-positive specimens (or cultures) should be forwarded to the nearest LRN laboratory for confirmation.

A nthrax is diagnosed by isolating B. anthracis from the blood, skin lesions, or respiratory secretions or by measuring specific antibodies in the blood of persons with suspected cases.

In patients with symptoms compatible with anthrax, providers should confirm the diagnosis by obtaining the appropriate laboratory specimens based on the clinical form of anthrax that is suspected (i.e., cutaneous, inhalational, or gastrointestinal).

Inhalational - blood, cerebrospinal fluid (if meningeal signs are present) or chest X-ray

For more information, read Update: Investigation of Bioterrorism-Related Anthrax and Interim Guidelines for Clinical Evaluation of Persons with Possible Anthrax.

Presumptive identification to identify to genus level ( Bacillus family of organisms) requires Gram stain and colony identification.

Presumptive identification to identify to species level (B. anthracis) requires tests for motility, lysis by gamma phage, capsule production and visualization, hemolysis, wet mount and malachite green staining for spores.

Confirmatory identification of B. anthracis carried out by CDC may include phage lysis, capsular staining, and direct fluorescent antibody (DFA) testing on capsule antigen and cell wall polysaccharide.

A nasal swab involves placing a swab inside the nostrils and taking a culture. The CDC and the U.S. Department of Health and Human Services do not recommend the use of nasal swab testing by clinicians to determine whether a person has been exposed to Bacillus anthracis, the bacteria responsible for anthrax, or as a means of diagnosing anthrax. At best, a positive result may be interpreted only to indicate exposure; a negative result does not exclude the possibility of exposure. Also, the presence of spores in the nose does not mean that the person has inhalational anthrax. The nose naturally filters out many things that a person breathes, including bacterial spores. To have inhalational anthrax, a person must have the bacteria deep in the lungs, and also have symptoms of the disease. Another reason not to use nasal swabs is that most hospital laboratories cannot fully identify anthrax spores from nasal swabs. They are able to tell only that bacteria that resemble anthrax bacteria are present.

Nasal swabs and screening may assist in epidemiologic investigations, but should not be relied upon as a guide for prophylaxis or treatment. Epidemiologic investigation in response to threats of exposure to B. anthracis may employ nasal swabs of potentially exposed persons as an adjunct to environmental sampling to determine the extent of exposure.

The nasal swab test was used as a screening tool because, following initial recognition of the case of confirmed inhalational anthrax, there were no known sources of exposure. Determining whether anyone else associated with the case-patient might have been exposed was important. In this setting, the nasal swab method was used for a rapid assessment of exposure among people, and as a tool for rapid environmental assessment. When the source of exposure is not known, nasal swabs can help investigators determine that information. They are not used for diagnosing people with anthrax, and they are not 100 percent effective in determining all who may have been exposed. See also http://www.bt.cdc.gov/documentsapp/faqanthrax.asp#Q602.

A chest X-ray can be used to help diagnose inhalation anthrax in people who have symptoms. It is not useful as a test for determining anthrax exposure or for people with no symptoms.

Interim recommendations for postexposure prophylaxis for prevention of inhalational anthrax after intentional exposure to B. anthracis may be found in the MMWR at http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5041a1.htm.

A protective vaccine has been developed for anthrax; however, it is primarily given to military personnel. Vaccination is recommended only for those at high risk, such as workers in research laboratories that handle anthrax bacteria routinely. The antibiotics used in post exposure prophylaxis are very effective in preventing anthrax disease from occurring after an exposure.

A vaccine has been developed for anthrax that is protective against invasive disease, but it is currently only recommended for high-risk populations. CDC and academic partners are continuing to support the development of the next generation of anthrax vaccines.

T he Advisory Committee on Immunization Practices (ACIP) has recommended anthrax vaccination for the following groups:

Treatment protocols for cases of inhalational and cutaneous anthrax associated with this bioterrorist attack are found in the MMWR , 10/26/2001; 50(42), 909-919. (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm)

There is no need to buy or store antibiotics, and indeed, it can be detrimental to both the individual and to the community. First, only people who are exposed to anthrax should take antibiotics, and health authorities must make that determination. Second, individuals may not stockpile or store the correct antibiotics. Third, under emergency plans, the Federal government can ship appropriate antibiotics from its stockpile to wherever they are needed.

Ciprofloxacin and doxycycline are FDA-approved for PEP, and ciprofloxacin, doxycycline, and amoxicillin are FDA-approved for treatment. In the current situation of intentional anthrax distribution, doxycycline and ciprofloxacin are the recommended drugs for prophylaxis.

Inhalational anthrax treatment protocol for cases associated with this bioterrorism attack: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm - (table 1)

Cutaneous anthrax treatment protocol for cases associated with this bioterrorism attack: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm - (table 2)

People at risk for inhalational anthrax should receive 60 days of antibiotics. These people include the following:

Direct person-to-person spread of anthrax is extremely unlikely and anthrax is not contagious. Therefore, there is no need to quarantine individuals suspected of being exposed to anthrax or to immunize or treat contacts of persons ill with anthrax, such as household contacts, friends, or coworkers, unless they also were also exposed to the same source of infection.

If you develop side effects from the antibiotic, call your healthcare provider immediately. Depending on the type of side effects, you may be able to continue taking the medicine, or may be switched to an alternative antibiotic. If necessary, your physician may contact your State Department of Health for consultation on possible alternate antibiotics.

Yes. Antibiotic sensitivity testing performed at CDC has determined that the strain of anthrax was sensitive to a wide range of antibiotics, including penicillin and ciprofloxacin, giving public health officials important treatment information.

What are the risks of using tetracyclines and fluoroquinolones in children? Are alternatives available?

Risks of using tetracyclines and fluoroquinolones in children must be weighed carefully against the risk for developing a life-threatening disease due to B. anthracis. Both agents can have adverse health reactions in children. If adverse reactions are suspected, therapy may be changed to amoxicillin or penicillin.

As with all antibiotics, take the medication according to the schedule you were instructed, and even if you begin to feel better, continue taking it for the full number of days. If you need an extension of the antibiotic at the end of your prescribed number of days, local emergency healthcare workers or your healthcare provider will inform and tell you how to get more medicine. They may also tell you to discontinue the antibiotic, or will change the type of antibiotic, depending on results of laboratory tests.

After I have started taking ciprofloxacin to protect me from developing anthrax, what side effects could I get from taking this antibiotic?

Side effects which sometimes occur include nausea, mild diarrhea, stomach pain, headache and dizziness. Talk with your doctor if you have any of these problems while you are taking the antibiotic. Certain foods and medications should not be taken with ciprofloxacin; this should be discussed at the time the antibiotic is prescribed, so that side effects will not occur from the combinations. Ciprofloxacin also can cause sun sensitivity which increases the chances of sunburn. More serious side effects include central nervous system side effects such as confusion, tremors, hallucinations, depression, and increased risk of seizures. High blood pressure and blurred vision are also possible. Allergic reactions could cause difficulty breathing; closing of the throat; swelling of the lips, tongue, or face; hives or severe diarrhea. Pain, inflammation, or rupture of a tendon are possible and also severe tissue inflammation of the colon could occur. Call your doctor or seek medical advice right away if you are having any of these side effects. This list is NOT a complete list of side effects reported with ciprofloxacin. Your healthcare provider can discuss with you a more complete list of side effects.

After I have started taking doxycycline to protect me from developing anthrax, what side effects could I get from taking this antibiotic?

Less serious side effects include diarrhea, upset stomach, nausea, sore mouth or throat, sensitivity to sunlight, vaginal yeast infection or itching of the mouth lasting more than 2 days. You should talk with your doctor if you have any of these problems while taking doxycycline. Certain foods and medications should not be taken with doxycycline, and this should be discussed with your healthcare provider at the time the antibiotic is prescribed, so that side effects will not occur from the combinations. Doxycycline also causes sun sensitivity which increases the chances of sunburn. Serious side effects of doxycycline that are possible but uncommon include: life-threatening allergic reaction (symptoms are trouble breathing; closing of the throat; swelling of the lips, tongue, or face; hives), blood problems (symptoms are unusual bleeding or bruising), liver damage (symptoms are yellowing of the skin or eyes, dark urine, nausea ,vomiting, loss of appetite, abdominal pain), irritation of the esophagus. Call your doctor or seek medical attention right away if you are having any of these side effects. This list is NOT a complete list of side effects reported with doxycycline. Your healthcare provider can discuss with you a more complete list of side effects.

Why is CDC recommending doxycycline instead of ciprofloxacin for the treatment and prevention of anthrax?

Both doxycycline and ciprofloxacin are effective in treating Bacillus anthracis that we are dealing with in these investigations. Although CDC first recommended the use of either drug for postexposure prophylaxis for the prevention of inhalational anthrax, we are now recommending doxycycline in order to prevent other bacteria from developing resistance to ciprofloxacin. Ciprofloxacin is part of the fluoroquinolone family of drugs, a relatively new class of antibiotics used to treat infections caused by organisms for which doctors do not have information about antimicrobial susceptibility. This kind of treatment is known as empiric therapy. Ciprofloxacin and other fluoroquinolones are used for empiric treatment for a variety of serious and common infections in the United States, including pneumonia, gastrointestinal infections, and urinary tract infections. The number of people who have been exposed to B. anthracis and need antibiotics has increased dramatically since CDC first issued guidelines for treatment. If all those people take ciprofloxacin, other bacteria they carry in their bodies may develop resistance to fluoroquinolones, potentially limiting the usefulness of these drugs as empiric therapy. Doxycycline is less frequently used for empiric treatment than ciprofloxacin; therefore, we have fewer concerns regarding this drug and the emergence of new resistant bacteria.

Why are people who have been exposed to B. anthracis being given antibiotics for different amounts of time?

The initial number of people placed on prophylaxis may reflect conservative estimates with wide safety margins based on limited preliminary information. As the investigation progresses, and a clearer picture of exposure develops, the number of people advised to continue prophylaxis may be reduced. As of the last week of October 2001, when preliminary tests show that people have been exposed to Bacillus anthracis, those exposed may be provided with a starter packet of antibiotics; the number of days for which antibiotics are prescribed can vary according to the specific situation and person. Additional tests are then conducted of the area where exposure occurred and to determine the extent of exposure. Based on the results of these additional tests, those exposed may be instructed to return to a centralized location for additional care or to seek additional care from their primary care providers; additional antibiotics may be prescribed based on the particular situation and person. Lastly, it is recommended that people found to be at risk of inhalation anthrax be prescribed 60 days of antibiotics. These general procedures may change at any time as new information is gathered.

Are there different strains of B. anthracis ? Do they all respond to antibiotics?

Yes, there are different strains of Bacillus anthracis . Some strains of B. anthracis may be naturally resistant to certain antibiotics and not others. In addition, there may be biologically mutant strains that are engineered to be resistant to various antibiotics. A laboratory analysis can help to define which strain of B. anthracis is present and which antibiotic would be the most effective in treating the resulting anthrax.

What is the FDA telling physicians and other health professionals about prescriptions for ciprofloxacin?

Although FDA does not regulate the practice of medicine, the agency is strongly recommending that physicians not prescribe ciprofloxacin for individual patients to have on hand for possible use against inhaled anthrax. Indiscriminate and widespread use of ciprofloxacin could hasten the development of drug-resistant organisms and lessen the effects of these agents against many infections.

Can other fluoroquinolones be used instead of ciprofloxacin for postexposure prophylaxis (PEP)/treatment?

Other fluoroquinolones, such as ofloxacin and levofloxacin, are not specifically recommended as alternatives to ciprofloxacin because of a lack of sufficient data on their efficacy. However, if first-line drugs were not available, these other fluoroquinolones may be effective.

Anthrax spores grow like plant seeds. If you plant seeds and give them sun and water, they will grow into plants. If you give anthrax spores the right environment, such as the human body, they can grow into the harmful form of the bacteria that can cause anthrax disease. It takes anthrax spores an average of 7 days to grow into the harmful form of the bacteria, but it can take longer. For this reason, you must continue taking preventive antibiotics for the full 60 days.

What happens if I take ciprofloxacin, doxycycline, or amoxicillin for a few days, stop, and then restart the antibiotics?

You should complete the 60-day course of antibiotics that you were given. It is best to take antibiotics as prescribed and not to skip any doses.

The ciprofloxacin I am taking gives me headaches. Is there anything I can do to help this?

If you don’t have a history of headaches, then your headache may be related to the medicine. Changing the time of day that you take the ciprofloxacin or eating after you take the medicine may help. Pain relievers such as acetaminophen may help your headache. If your headache does not go away, you should consult your doctor.

The ciprofloxacin, doxycycline, or amoxicillin I am taking makes me feel sick to my stomach. Is there anything I can do to help this?

Taking your antibiotic with food may help reduce this sick feeling. Ciprofloxacin and doxycycline should not be taken within 2 hours of taking antacids. Ciprofloxacin and doxycycline should not be taken with dairy or calcium-fortified products (such as ice cream or calcium-fortified orange juice).

The ciprofloxacin, doxycycline, or amoxicillin I am taking gives me diarrhea. Is there anything I can do to help this?

Antibiotics may disrupt bacteria in the gastrointestinal tract, causing diarrhea. Food may help relieve the diarrhea. If the diarrhea does not go away, your doctor may recommend another antibiotic. If you develop severe, long-lasting diarrhea, you may have a serious condition and should consult your doctor.

If taking one of the recommended antibiotics makes me feel terrible, can I switch to another of these antibiotics?

If you have tried taking the medicine with food or changing the time of your dose but still feel terrible, you should ask your doctor about switching antibiotics.

I am having terrible yeast infections while taking ciprofloxacin, doxycycline, or amoxicillin. Is there anything I can take for this?

Occasionally, women develop yeast infections while taking amoxicillin. You may treat the infection with over-the-counter medicines such as clotrimazole. If the symptoms do not go away, you should consult your doctor.

I feel much better if I take only one pill of ciprofloxacin, doxycycline, or amoxicillin each day. Is that okay?

No. The drug must be taken twice a day to kill the bacteria. If your body contains anthrax bacteria and you do not take the full dose, the bacteria may start to grow again and become harder to kill.

My prescription says to take one pill every 12 hours. If 15 hours have passed since my last dose, is it still okay to take the pill?

Yes. It is okay to take the next pill even if 15 hours have elapsed. However, you should not make a habit of this. The medicine works best when taken every 12 hours.

Any side effect that forces you not to take your medicine is serious enough that you should consult or see your doctor.

Serious side effects of ciprofloxacin include seizures, mental confusion, rash that does not go away, or excessive diarrhea.

Serious side effects of doxycycline include jaundice (yellow eyes or skin), rash that does not go away, or excessive diarrhea. If you have any of these effects, call your doctor.

Any reaction that causes a rapid swelling of the lips and face, shortness of breath, or hives is a medical emergency. You should call 911. These types of reactions are extremely rare.

Can I drink alcohol if I am taking ciprofloxacin, doxycycline, or amoxicillin?

Social drinking of alcohol (fewer than 2 drinks a day) should not cause any side effects unless you already have a liver problem. However, drinking too much alcohol can cause the medicine to leave your body faster, which will decrease the effectiveness of the medicine. If you drink more than two drinks a day, you should tell your doctor so that different medicines can be prescribed.

The ciprofloxacin, doxycycline, or amoxicillin I am taking makes me feel itchy all over. Is there anything I can do to help this?

Rashes that appear suddenly or do not go away after a few days may be signs of an allergic reaction. You should see your doctor immediately.

If the allergic reaction was severe or rapid, you should notify your doctor before taking another antibiotic. Your doctor will prescribe a different antibiotic that will kill the bacteria without causing an allergic reaction. Remember: you should complete the entire 60 days of treatment even if you change antibiotics.

Why can’t I take a shot, wear a patch, or take one large dose of the medicine instead of taking it for 60 days?

Spores can stay in your body for some time before they start growing and causing you to become ill. When the spores are not growing, antibiotics are not effective. Only after the spores start to grow can the antibiotics work. Therefore, you need a constant level of antibiotic in your body for 60 days to make sure that when the spores start to grow, the antibiotic is there to kill them.

Ciprofloxacin and doxycycline look different and come in different doses. Is one better than the other?

Ciprofloxacin 500 mg and doxycycline 100 mg both have the same killing power in your bloodstream and are equally effective against anthrax bacteria. Doxycycline is available in both tablet and capsule form. Both will give you the same amount of medicine in your bloodstream to kill the bacteria.

No. CDC does not recommend treating all patients who have flu-like illness with antibiotics. Antibiotics do not kill viruses, which cause the flu. If the patient is not at risk for developing anthrax, antibiotics are not recommended because the person may experience serious side effects. Also, taking antibiotics can increase the chance that the medicine will not be as effective against other bacterial infections.

We do not have enough data at this time to make this determination. However, it is theoretically possible to gain post-infection immunity.

How do doctors treat inhalational anthrax to reduce the risk of death in patients?

When inhalational anthrax is suspected, physicians prescribe antibiotics to treat the disease. To be effective, antibiotic therapy should be initiated as soon as possible after exposure. Other treatment includes supportive care in hospital. B. anthracis usually responds effectively to several antibiotics including penicillin, doxycycline, and fluoroquinolones (such as ciprofloxacin).

I was told that I had been exposed to Bacillus anthracis and prescribed antibiotics. I took the medicine for a couple weeks. Wouldn’t that weaken any anthrax that’s in my body?

You should take the full 60 days of antibiotics even if you feel better. Inhaled anthrax spores become lodged in the body and may activate after initial exposure. Antibiotics have little or no effect when the spores are inactive. To be effective in preventing inhalational anthrax, the antibiotics must be in your system when the spores activate. It is necessary to take the medicine for at least 60 days to ensure the best protection against inhalational anthrax.

At the beginning of the recent anthrax outbreak, investigators did not know which drugs would kill the strains of Bacillus anthracis responsible for the outbreak. They used ciprofloxacin because very few bacteria are resistant to it. Recent laboratory tests using all of the B. anthracis strains from the recent outbreak have indicated that all the strains are susceptible to ciprofloxacin, doxycycline, and other antibiotics.

Besides anthrax, what else is ciprofloxacin prescribed for? Has there been resistance to ciprofloxacin when used in other instances (historically)?

Ciprofloxacin is a broad-spectrum, highly effective antibiotic that has been part of the "international traveler’s" kit at CDC for at least a year. It can be used against most bacterial infections. However, ciprofloxacin is frequently overused for many diseases that can be treated with less powerful, narrower-spectrum drugs. Right now, most bacteria are susceptible to ciprofloxacin, which is why we want to be cautious about its use. Overuse of ciprofloxacin could lead to the development of resistance.

I’m taking medication to prevent anthrax, and I just found out that I’m pregnant. What should I do?

It is very important that you continue to take as directed the medication you have been prescribed. You should also contact your doctor or local public health officials right away to let them know that you are pregnant. They will want to discuss which medicine would be the best choice for you—to prevent anthrax and to be safe for both you and the fetus.

You should take medication to prevent anthrax only if a public health official confirms that you have had a potential exposure to anthrax. You and your doctor will want to discuss the risks and benefits of the various antibiotics that can be used to prevent anthrax. Which medicine is most appropriate for you will depend on the specific place and situation of your exposure and on your general medical history (including other medicines you may be taking and any medication allergies you may have). Currently, there are three main antibiotics used to prevent anthrax: ciprofloxacin, amoxicillin, and doxycycline. Ciprofloxacin is effective against anthrax and is unlikely to cause major problems for the fetus, but there is not enough experience or data involving ciprofloxacin during pregnancy to say for certain that there is no risk to the fetus. Doctors are more confident about the safety of amoxicillin for the fetus, but amoxicillin may not always be effective against anthrax. Before prescribing amoxicillin for you, your doctor would want to make sure that the anthrax you were exposed to is not resistant to amoxicillin. Doxycycline can sometimes cause tooth and bone problems in the fetus. Therefore, you should not take doxycycline unless there is a specific reason why you cannot take either ciprofloxacin or amoxicillin.

I’ve heard that doctors don’t generally prescribe ciprofloxacin to pregnant women. Why is that? Why are they recommending it for anthrax prevention?

Ciprofloxacin is not likely to cause major problems for a fetus, but there is not enough experience and data involving ciprofloxacin during pregnancy to say for certain that there is no risk to the fetus. Ciprofloxacin is not commonly used during pregnancy because most infections that pregnant women get can be treated with other drugs whose safety for pregnant women and their fetuses is better documented. However, because anthrax is a life-threatening disease, the benefits of using ciprofloxacin may outweigh potential risks to the fetus.

I was started on ciprofloxacin to prevent anthrax. I’ve heard that amoxicillin may be a safer drug for me to take during my pregnancy. How do I know if I can be switched to amoxicillin?

Doctors are often more confident about using amoxicillin than ciprofloxacin in pregnancy because they have more information on the safety of amoxicillin for the mother and the fetus. But in some situations, amoxicillin may not be effective against anthrax; this is because the bacteria that cause anthrax can sometimes develop resistance to penicillins such as amoxicillin. Before prescribing amoxicillin for you, your doctor will want to learn more about the specific place and situation of your exposure to anthrax and also about your general medical history. (For instance, some women cannot take amoxicillin because they are allergic to it.)

Doxycycline is being recommended for my coworkers who aren’t pregnant . Is doxycycline a better medicine against anthrax than ciprofloxacin?

No. There are no data to suggest that doxycycline is better than ciprofloxacin for preventing anthrax.

No. Antacids should not be taken at the same time as ciprofloxacin because they may make ciprofloxacin less effective. (They can interfere with the absorption of ciprofloxacin.) You should not take antacids in the 6 hours before you take a ciprofloxacin pill or for 2 hours after you take ciprofloxacin.

Whether to try to become pregnant while taking medication to prevent anthrax is your personal decision. When making this decision, you should discuss the possible risks and benefits with your family and your doctor. Some women may prefer to wait until after completing the full course of antibiotics before becoming pregnant. If you decide not to wait, it may be best not to take doxycycline unless there is a specific reason why you cannot take either ciprofloxacin or amoxicillin.

I just recently found out I’m pregnant, and I was exposed to anthrax at work. I want to take the best medication for my fetus and me, but I don’t yet want my employer to know that I’m pregnant. What should I do?

It is very important that you tell your doctor or local public health officials that you are pregnant. They will not be required to tell your employer.

What is the risk for an individual if he or she is treated with antibiotics and is exposed to Bacillus anthracis again?

Because inhalational anthrax in humans is so rare, we cannot be certain about the risk of reinfection; therefore, CDC recommends that another course of antibiotic treatment be given promptly if a person is reexposed to Bacillus anthracis. In animal studies of inhalational anthrax, animals given anthrax vaccine and antibiotics after exposure did not develop anthrax when reexposed 4 months after the original exposures, while animals treated with antibiotics alone became ill when reexposed.

Can the spores that cause anthrax multiply outside of a human or animal host?

What are the odds of my getting anthrax? (What is the average risk of contracting anthrax in the United States?)

In an average year, the chance that any one individual in the United States will contract anthrax is extremely low - about one case in nearly 300 million. In 2001, even with the intentional release of Bacillus anthracis spores in some environments, the nationwide risk was still extremely low - about 23 cases in nearly 300 million people.

Can anthrax affect pregnancy? Should pregnant women exposed to anthrax take antibiotics?

Anthrax is a serious illness in all humans, including pregnant women. Inhalational anthrax has a high fatality rate, and cutaneous (skin) anthrax also is serious, but less frequently fatal. Because these infections are potentially fatal, it has been recommended that ciprofloxacin, or similar antibiotic drugs, be prescribed for pregnant women believed to have been exposed to anthrax. Clinical studies of the use of the ciprofloxacin in pregnant women have not been conducted, so ciprofloxacin and related drugs are not generally recommended for pregnant women with less serious illnesses.

The Department of the Treasury sponsored a study to investigate this risk, and it revealed no evidence that anthrax can be spread by handling money.

What is the risk for anthrax in employees of a facility with a positive environmental sample?

The risk would depend on where the environmental sample was, the amount (quantity) of material, and if it was collected in an air sample or on a surface. The risk would also depend on the person’s contact with the type of sample in terms of breathing or touching the sample.

Finding a positive surface or air sample does not mean that employees of a facility are at risk for anthrax. Heavily contaminated surfaces may pose a small risk for cutaneous anthrax, which can be minimized by clean-up. Laboratory test results of environmental surface samples should not be the only criterion for starting, continuing, or stopping preventive antibiotic therapy for inhalational disease.

Influenza (flu) and inhalation anthrax can have similar symptoms. Does CDC recommend that I get a flu shot to help diagnose anthrax?

You should get a flu shot only to prevent the flu. CDC does not recommend you get the flu shot so doctors can tell whether you have the flu or anthrax. Many illnesses (including anthrax) begin with flu-like symptoms, which include fever, body aches, tiredness, and headaches. In fact, most illnesses with flu-like symptoms are not either the flu or anthrax. The flu vaccine is the best protection you can get to prevent the flu and its severe complications, especially among those who are at the highest risk (e.g., people older than 65 years old or younger people with chronic disease such as diabetes or heart disease). The flu shot can prevent 70%-90% of flu infections, but it will not prevent illnesses with flu-like symptoms caused by anything other than influenza.

Early inhalational anthrax symptoms can be similar to those of much more common infections. However, a runny nose is a rare feature of anthrax. This means that a person who has a runny nose along with other common influenza-like symptoms is by far more likely to have the common cold than to have anthrax.

In addition, most people with inhalational anthrax have high white blood cell counts and no increase in the number of lymphocytes. On the other hand, people with infections such as flu usually have low white blood cell counts and an increase in the number of lymphocytes. Chest X-rays are also critical diagnostic tools. Chest X-rays showed that all patients with inhalational anthrax have some abnormality, although for some patients, the abnormality was subtle. CT scans can confirm these abnormalities.

Is there a quick test that doctors can do to tell whether I have anthrax or an illness like the flu?

Some influenza detection tests give results fairly quickly. However, these tests are not perfect and are not appropriate for every patient. Rapid influenza tests can provide results within 24 hours; viral culture provides results in 3-10 days. However, as many as 30% of samples that test positive for influenza by viral culture may give a negative rapid test result. And, some rapid test results may indicate influenza when a person is not infected with influenza.

CDC does not have specific studies to address this, however, cross-contamination of the mail could occur during the processing, sorting, and delivery of mail when an envelope comes in contact with an envelope, piece of equipment (e.g., an electronic sorting machine), or other surface that is contaminated with Bacillus anthracis spores. In addition, airborne spores in contaminated postal facilities before they were cleaned might play a role.

Can the presence of Bacillus anthracis spores be detected by a characteristic appearance, odor, or t aste?

Bacillus anthracis spores do not have a characteristic appearance (e.g., color), smell, or taste. Spores themselves are too small to be seen by the naked eye, but have been mixed with powder to transport them. The U.S. Postal Service advises that individuals be suspicious of letters or packages with any powdery substance on them, regardless of color.

Genetic information about B. anthracis, particularly to determine genetic similarity among strains, is an important part of a disease investigation, but it is not immediately required for taking action to prevent or treat anthrax in those who may have been exposed to or infected by B. anthracis. Genetic information is often used to determine the similarity of strains if a common source is suspected.

The strains of anthrax identified in Florida, New York, and Washington, D.C., are similar and consistent with a naturally occurring strain that shows no evidence of genetic alteration or bioengineering. All are sensitive and susceptible to the antibiotics recommended by CDC for those who have been exposed to or infected with B. anthracis.

When there is a known incident, how can I prevent anthrax exposure from cross- contaminated mail?

There are no scientifically proven recommendations for preventing exposure. However, there are some common-sense steps people can take:

Some characteristics of suspicious packages and envelopes include the following:

* These recommendations were published on October 26, 2001, in "Update: Investigation of bioterrorism-related anthrax and interim guidelines for exposure management and antimicrobial therapy" MMWR 2001; 50(42):909-919. (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5042a1.htm)

If there is a risk for inhalational anthrax associated with exposure to cross-contaminated mail, it is very low. For example, about 85 million pieces of mail were processed on the few days in 2001 after envelopes containing Bacillus anthracis (addressed to two U.S. senators) passed through the New Jersey and District of Columbia sorting facilities until they were closed. Despite the fact that both of these facilities had evidence of widespread environmental contamination with B. anthracis spores and the fact that public health officials had been aggressively looking for anthrax cases, no new cases of anthrax were identified during that time.

As a postal employee, am I at risk for getting anthrax from handling mail on the job when there is an anthrax cross-contaminated mail event?

If there is a risk for inhalational anthrax associated with exposure to cross-contaminated mail, it is very low, even for postal employees and persons who work in company mailrooms. CDC has published interim recommendations that are intended to assist personnel responsible for occupational health and safety in developing a comprehensive program to reduce potential cutaneous or inhalational exposures to Bacillus anthracis spores among workers in work sites where mail is handled or processed. Detailed guidelines may be found on these Web sites:

When the possibility of cross-contamination of the mail exists, should I take antibiotics?

Preventive antibiotics are not recommended for persons who routinely open or handle mail, either at home or at the workplace. Antimicrobial prophylaxis is recommended only in certain specific situations such as for persons exposed to an air space known to be contaminated with aerosolized Bacillus anthracis or for persons in a postal sorting facility in which an envelope containing B. anthracis spores was processed. CDC’s complete recommendations on antimicrobial prophylaxis are contained in the November 9, 2001 MMWR. (http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5044a1.htm)

What should I do to protect my family and myself if a dangerous chemical agent were released in my community?

Emergency management teams would lead efforts in the event of a chemical attack and would let you know if you need to evacuate the area or seek some type of shelter.

Should I purchase a gas mask as protection from any chemical agent release such as anthrax?

No, CDC does not recommend purchasing gas masks. The likelihood that you would be involved in a chemical attack is low, and your protection is the responsibility of state and federal law enforcement officials. They are on high alert to ensure that such an event does not happen. In addition, CDC believes that purchasing a gas mask causes a false sense of security and can do more harm than good. Masks that aren’t used properly or that do not fit well will not give you adequate protection.

The recommendations are divided into four categories. They are engineering controls, administrative controls, housekeeping controls, and personal protective equipment for workers. The guidelines describe measures that should be implemented in mail-handling/processing sites to prevent potential exposures to B. anthracis spores.

If these recommendations are followed does it mean workers will stop getting sick with anthrax?

The interim recommendations that have been developed are based on the limited information available on ways to avoid infection and the effectiveness of various prevention strategies. As new information becomes available the guidelines will be updated. These recommendations do not address instances where a known or suspected exposure has occurred. Workers should be trained in how to recognize and handle a suspicious piece of mail (www.bt.cdc.gov/documentsapp/anthrax/10312001/han51.asp). In addition, each work site should develop an emergency plan describing appropriate actions to be taken when a known or suspected exposure to B. anthracis occurs.

Is CDC telling all mail handling operations to adopt these anthrax worker safety guidelines immediately?

Every facility is different and should be evaluated based on the recommendations in the guidelines, and the recommendations implemented should be selected on the basis of an initial evaluation of the work site. This evaluation should focus on determining which processes, operations, jobs, or tasks would be most likely to result in an exposure should a contaminated envelope or package enter the work site. Many of these measures (e.g., administrative controls, use of HEPA filter-equipped vacuums, wet-cleaning, use of protective gloves) can be implemented immediately; implementation of others will require additional time and efforts.

What kinds of engineering controls should mail-handling/processing operations consider implementing for detecting anthrax spores?

B. anthracis spores can be aerosolized during the operation and maintenance of high-speed, mail-sorting machines, potentially exposing workers and possibly entering heating, ventilation, or air-conditioning (HVAC) systems. Engineering controls can provide the best means of preventing worker exposure to potential aerosolized particles, thereby reducing the risk for inhalational anthrax, the most severe form of the disease. In settings where such machinery is in use, the following engineering controls should be considered:

What administrative controls should mail-handling/processing sites consider implementing to protect workers from exposure to B. anthracis spores?

Strategies should be developed to limit the number of people working at or near sites where aerosolized particles may be generated, such as mail-sorting machinery and places where mailbags are unloaded or emptied. In addition, restrictions should be in place to limit the number of people including support staff and nonemployees entering areas where aerosolized particles may be generated. This recommendation applies to contractors, business visitors, and support staff.

What housekeeping controls in mail-handling/processing sites are recommended to protect workers from exposure to B. anthracis spores?

In the mail-handling worksite, dry sweeping and dusting should be avoided. Instead, the area should be wet-cleaned and vacuumed with HEPA-equipped vacuum cleaners.

What personal protective equipment for workers in mail-handling/processing sites is recommended to protect workers from exposure to B. anthracis spores?

Personal protective equipment for workers in mail-handling/processing work sites must be selected on the basis of the potential for cutaneous or inhalational exposure to B. anthracis spores. Handling packages or envelopes may result in skin exposure. In addition, because certain machinery such as electronic mail sorters can generate aerosolized particles, people who operate, maintain, or work near such machinery may be exposed through inhalation. People who handle or sort mail or work at other sites where airborne particles may be generated such as where mailbags are unloaded or emptied may also be exposed through inhalation.

What are some examples of personal protective equipment and clothing that could be used to protect workers who handle mail from exposure to B. anthracis spores?

Are there some areas in the postal setting that present a greater risk to some workers than others for anthrax exposure?

Only specially trained personnel can distinguish between a real bioterrorism attack and a false one. If you suspect that a package, letter, or anything else contains a harmful biological agent, call 911 to activate the local emergency response system; in communities without 911 systems, notify local law enforcement authorities. Guidance on identifying suspicious packages and letters and what to do until the authorities arrive are available on CDC’s Web site at www.bt.cdc.gov/documentsapp/anthrax/10312001/han50.asp.

What can the consumer buy to protect against germ or chemical warfare such as anthrax?

Currently, the CDC does not recommend consumers buy any particular product to protect against biological or chemical attacks.

What should be done with clothing contaminated with anthrax? Is washing in a regular home washer and dryer ok? Does CDC recommend adding bleach to the wash?

Contact your state or local public health department for advice. Clothing can be decontaminated using soap and water, and 0.5% hypochlorite solution (one part household bleach to 9 parts water).

Are other solutions used at hospitals for cleaning blood spills also effective against anthrax?

(Source: Interim Recommendation for Firefighters and other First Responders) The recommendation for decontaminating equipment is a 0.5% hypochlorite solution (1 part household bleach to ten parts water). www.bt.cdc.gov/documentsapp/anthrax/protective/10242001protect.asp.

What actions need to be taken if a facility is found to have an environmental sample positive for anthrax?

The number and location of positive environmental samples will be used to guide clean-up efforts. Positive environmental samples alone do not indicate the need for antibiotics or the need to close a facility. Employees, visitors, and family members of employees at these facilities are advised to monitor their own health carefully and report any unusual symptoms to a physician.

If tests confirm that I was potentially exposed to Bacillus anthracis or have anthrax, how will it be reported to the proper authorities?

Your doctor should immediately report any suspected isolate of Bacillus anthracis or any suspected case of anthrax to your local or state public health department. The state public health department is available to your doctor for consultation 24 hours a day. If local or state health department officials suspect that cases of illness may be due to a bioterrorist incident, they will notify CDC and an investigation will be conducted. If the investigation confirms that a bioterrorist incident has occurred or is thought probable, the FBI will be notified. Public health officials will also involve other response partners using a preestablished notification list. The CDC bioterrorism Web site displays the protocol that health officials will use for further reporting:

How should healthcare workers respond to suspected exposure to a bioterrorist agent? Who should healthcare workers call first, second, third? CDC, FBI, local police, local health department?

Healthcare providers, clinical laboratory personnel, and infection control professionals who notice illness patterns and diagnostic clues that might indicate an unusual infectious disease outbreak associated with intentional release of a biologic agent should report any clusters or findings to their local or state health department. (Guidelines for recognizing a number of biologic agents, including anthrax, plague, botulism, smallpox, inhalational tularemia, and hemorrhagic fever, are described in CDC’s Morbidity and Mortality Weekly Report, Vol. 50, No. 41, dated October 19, 2001.)

Of the numerous biological agents that may be used as weapons, the Working Group on Civilian Biodefense has identified a limited number of organisms that could cause disease and deaths in sufficient numbers to cripple a city or region. Anthrax is one of the most serious of these diseases.

High hopes were once vested in the Biological Weapons and Toxins Convention, which prohibited offensive biological weapons research or production and was signed by most countries. However, Iraq and the former Soviet Union, both signatories of the convention, have subsequently acknowledged having offensive biowarfare programs; a number of other countries are believed to have such programs, as have some autonomous terrorist groups. The possibility of a terrorist attack using bioweapons would be especially difficult to predict, detect, or prevent, and thus, it is among the most feared terrorist scenarios.¹

Biological agents have seldom been dispersed in aerosol form, the exposure mode most likely to inflict widespread disease. Therefore, historical experience provides little information about the potential impact of a biological attack or the possible efficacy of postattack measures such as vaccination, antibiotic therapy, or quarantine. Policies and strategies must therefore rely on interpretation and extrapolation from an incomplete knowledge base. The Working Group on Civilian Biodefense reviewed the available literature and expertise and developed consensus recommendations for medical and public health measures to be taken following such an attack.

For centuries, anthrax has caused disease in animals and, uncommonly, serious illness in humans throughout the world.² Research on anthrax as a biological weapon began more than 80 years ago.³ Today, at least 17 nations are believed to have offensive biological weapons programs⁴; it is uncertain how many are working with anthrax. Iraq has acknowledged producing and weaponizing anthrax.⁵

Most experts concur that the manufacture of a lethal anthrax aerosol is beyond the capacity of individuals or groups without access to advanced biotechnology. However, autonomous groups with substantial funding and contacts may be able to acquire the required materials for a successful attack. One terrorist group, Aum Shinrikyo, responsible for the release of sarin in a Tokyo, Japan, subway station in 1995,⁶ dispersed aerosols of anthrax and botulism throughout Tokyo on at least 8 occasions. For unclear reasons, the attacks failed to produce illness.⁷

The accidental aerosolized release of anthrax spores from a military microbiology facility in Sverdlovsk in the former Soviet Union in 1979 resulted in at least 79 cases of anthrax infection and 68 deaths and demonstrated the lethal potential of anthrax aerosols.⁸ An anthrax aerosol would be odorless and invisible following release and would have the potential to travel many kilometers before disseminating.^9-10 Evidence suggests that following an outdoor aerosol release, persons indoors could be exposed to a similar threat as those outdoors.¹¹

In 1970, a World Health Organization (WHO) expert committee estimated that casualties following the theoretical aircraft release of 50 kg of anthrax over a developed urban population of 5 million would be 250,000, 100,000 of whom would be expected to die without treatment.⁹ A 1993 report by the US Congressional Office of Technology Assessment estimated that between 130,000 and 3 million deaths could follow the aerosolized release of 100 kg of anthrax spores upwind of the Washington, DC, area—lethality matching or exceeding that of a hydrogen bomb.¹² An economic model developed by the Centers for Disease Control and Prevention (CDC) suggested a cost of $26.2 billion per 100,000 persons exposed.¹³

Naturally occurring anthrax is a disease acquired following contact with anthrax-infected animals or anthrax-contaminated animal products. The disease most commonly occurs in herbivores, which are infected by ingesting spores from the soil. Large anthrax epizootics in herbivores have been reported; during a 1945 outbreak in Iran, 1 million sheep died.¹⁴ Animal vaccination programs have reduced drastically the animal mortality from the disease.¹⁵ However, anthrax spores continue to be documented in soil samples from throughout the world.^16-18

In humans, 3 types of anthrax infection occur: inhalational, cutaneous, and gastrointestinal. Naturally occurring inhalational anthrax is now a rare cause of human disease. Historically, wool sorters at industrial mills were at highest risk. Only 18 cases were reported in the United States from 1900 to 1978, with the majority occurring in special-risk groups, including goat hair mill or goatskin workers and wool or tannery workers. Two of the 18 cases were laboratory associated.¹⁹

Cutaneous anthrax is the most common naturally occurring form, with an estimated 2000 cases reported annually.¹⁸ Disease typically follows exposure to anthrax-infected animals. In the United States, ²² 4 cases of cutaneous anthrax were reported between 1944 and 1994.²⁰ The largest reported epidemic occurred in Zimbabwe between 1979 and 1985, when more than 10,000 human cases of anthrax were reported, nearly all of them cutaneous.²¹

Gastrointestinal anthrax is uncommonly reported^{.18, 22-23} However, gastrointestinal outbreaks have been reported in Africa and Asia.²⁴ Gastrointestinal anthrax follows ingestion of insufficiently cooked contaminated meat and includes 2 distinct syndromes, oral-pharyngeal and abdominal.^{22, 24-27} In 1982, there were 24 cases of oral-pharyngeal anthrax in a rural northern Thailand outbreak following the consumption of contaminated buffalo meat.²⁴ In 1987, there were 14 cases of gastrointestinal anthrax reported in northern Thailand with both oral-pharyngeal and abdominal disease occurring.²⁵

No case of inhalational anthrax has been reported in the United States since 1978,^19-20 making even a single case a cause for alarm today. As was demonstrated at Sverdlovsk in 1979, inhalational anthrax is expected to account for most morbidity and essentially all mortality following the use of anthrax as an aerosolized biological weapon.^{8, 28} In the setting of an anthrax outbreak resulting from an aerosolized release, cutaneous anthrax would be less common than inhalational anthrax, easier to recognize, simpler to treat, and associated with a much lower mortality. In the Sverdlovsk experience, there were no deaths in patients developing cutaneous anthrax.⁸ There is little information available about the risks of direct contamination of food or water with anthrax spores. Although human infections have been reported, experimental efforts to infect primates by direct gastrointestinal instillation of anthrax spores have not been successful.²⁹

Figure 1. Gram Stain of Bacillus anthracis. Gram-positive anthrax bacilli in a peripheral blood smear from a rhesus monkey that died of inhalational anthrax. Reprinted with permission from Zajtchuk and Bellamy.²³

Bacillus anthracis derives from the Greek word for coal, anthrakis, because the disease causes black, coal-like skin lesions. Bacillus anthracis is an aerobic, gram-positive, spore-forming, nonmotile Bacillus species. The nonflagellated vegetative cell is large (1-8 µm in length, 1-1.5 µm in breadth). Spore size is approximately 1 µm. Spores grow readily on all ordinary laboratory media at 37°C, with a "jointed bamboo-rod" cellular appearance and a unique "curled-hair" colonial appearance, and display no hemolysis on sheep agar (Figure 1). This cellular and colonial morphology theoretically should make its identification by an experienced microbiologist straightforward, although few practicing microbiologists outside the veterinary community have seen anthrax colonies other than in textbooks.³⁰

Anthrax spores germinate when they enter an environment rich in amino acids, nucleosides, and glucose, such as that found in the blood or tissues of an animal or human host. The rapidly multiplying vegetative anthrax bacilli, on the contrary, will only form spores after local nutrients are exhausted, such as when anthrax-infected body fluids are exposed to ambient air.^16-17 Full virulence requires the presence of both an antiphagocytic capsule and 3 toxin components (i.e., protective antigen, lethal factor, and edema factor).³⁰ Vegetative bacteria have poor survival outside of an animal or human host; colony counts decline to undetectable within 24 hours following inoculation into water.¹⁷ This contrasts with the environmentally hardy properties of the B. anthracis spore, which can survive for decades.³⁰

Inhalational anthrax follows deposition of spore-bearing particles of 1 to 5 µm into alveolar spaces.^31-32 Macrophages ingest the spores, some of which undergo lysis and destruction. Surviving spores are transported via lymphatics to mediastinal lymph nodes, where germination may occur up to 60 days later.^28-29,33 The process responsible for the delayed transformation of spores to vegetative cells is poorly understood but well documented. In Sverdlovsk, cases occurred from 2 to 43 days after exposure.⁸ In experimental monkeys, fatal disease occurred up to 58 days²⁸ and 98 days³⁴ after exposure. Viable spores have been demonstrated in the mediastinal lymph nodes of monkeys 100 days after exposure.³⁵

Once germination occurs, disease follows rapidly. Replicating bacteria release toxins leading to hemorrhage, edema, and necrosis.^{23, 36} In experimental animals, once toxin production has reached critical threshold, death occurs even if sterility of the bloodstream is achieved with antibiotics.¹⁹ Based on primate data, it has been estimated that for humans the LD 50 (lethal dose sufficient to kill 50% of persons exposed to it) is 2500 to 55,000 inhaled anthrax spores.³⁷

The term inhalational anthrax reflects the nature of acquisition of the disease. The term anthrax pneumonia is misleading. Typical bronchopneumonia does not occur. Postmortem pathological study of patients who died because of inhalational anthrax in Sverdlovsk showed hemorrhagic thoracic lymphadenitis and hemorrhagic mediastinitis in all patients. In up to half of the patients, hemorrhagic meningitis also was seen. No patients who underwent autopsy had evidence of a bronchoalveolar pneumonic process, although 11 of 42 patients undergoing autopsy had evidence of a focal, hemorrhagic, necrotizing pneumonic lesion analogous to the Ghon complex associated with tuberculosis.³⁸ These findings are consistent with other human case series and experimentally induced inhalational anthrax in animals.^{33, 39-40}

Early diagnosis of inhalational anthrax would be difficult and would require a high index of suspicion. Clinical information is available from only some of the 18 cases reported in the United States in this century and from the limited available information from Sverdlovsk. The clinical presentation has been described as a 2-stage illness. Patients first developed a spectrum of nonspecific symptoms, including fever, dyspnea, cough, headache, vomiting, chills, weakness, abdominal pain, and chest pain.^{8, 19} Signs of illness and laboratory studies were nonspecific. This stage of illness lasted from hours to a few days. In some patients, a brief period of apparent recovery followed. Other patients progressed directly to the second, fulminant stage of illness.^{2, 19, 41}

This second stage developed abruptly, with sudden fever, dyspnea, diaphoresis, and shock. Massive lymphadenopathy and expansion of the mediastinum led to stridor in some cases.^42-43 A chest radiograph most often showed a widened mediastinum consistent with lymphadenopathy (Figure 2).⁴²Up to half of patients developed hemorrhagic meningitis with concomitant meningismus, delirium, and obtundation. In this second stage of illness, cyanosis and hypotension progress rapidly; death sometimes occurs within hours.^{2, 19, 41}

Figure 2. Chest radiograph of a patient with inhalational anthrax. Chest radiograph of a 51-year-old laborer with occupational exposure to airborne anthrax spores taken on day 2 of illness. Lobulated mediastinal widening (arrowheads) is present, consistent with lymphadenopathy, with a small parenchymal infiltrate at the left lung base. Reprinted with permission from Zajtchuk and Bellamy.²³

The mortality rate of occupationally acquired cases in the United States is 89%, but the majority of cases occurred before the development of critical care units and, in some cases, before the advent of antibiotics.¹⁹ At Sverdlovsk, it is reported that 68 of the 79 patients with inhalational anthrax died, although the reliability of the diagnosis in the survivors is questionable.⁸ Patients who had onset of disease 30 or more days after release of organisms had a higher reported survival rate compared with those with earlier disease onset. Antibiotics, antianthrax globulin, and vaccine were used to treat some residents in the affected area some time after exposure, but which patients received these interventions and when is not known. In fatal cases, the interval between onset of symptoms and death averaged 3 days. This is similar to the disease course and case fatality rate in untreated experimental monkeys, which have developed rapidly fatal disease even after a latency as long as 58 days.²⁸

Modern mortality rates in the setting of contemporary medical and supportive therapy might be lower than those reported historically. However, the 1979 Sverdlovsk experience is not instructive. Although antibiotics, antianthrax globulin, corticosteroids, and mechanical ventilation were used, individual clinical records have not been made public.8 It is also uncertain if the B. anthracis strain to which patients were exposed was susceptible to the predominant antibiotics that were used during the outbreak.

Physiological sequelae of severe anthrax infection in animal models have been described as hypocalcemia, profound hypoglycemia, hyperkalemia, depression and paralysis of respiratory center, hypotension, anoxia, respiratory alkalosis, and terminal acidosis.^44-45 Those animal studies suggest that in addition to the rapid administration of antibiotics, survival might improve with vigilant correction of electrolyte disturbances and acid-base imbalance, glucose infusion, and early mechanical ventilation and vasopressor administration.

Cutaneous anthrax occurs following the deposition of the organism into skin with previous cuts or abrasions especially susceptible to infection.^{21, 46} Areas of exposed skin, such as arms, hands, face, and neck, are the most frequently affected. There are no data to suggest the possibility of a prolonged latency period in cutaneous anthrax. In Sverdlovsk, cutaneous cases occurred only as late as 12 days after the original aerosol release.⁸ After the spore germinates in skin tissues, toxin production results in local edema (Figure 3). An initially pruritic macule or papule enlarges into a round ulcer by the second day. Subsequently, 1- to 3-mm vesicles may appear, which discharge clear or serosanguinous fluid containing numerous organisms on Gram stain. As shown in Figure 3, development of a painless, depressed, black eschar follows, often associated with extensive local edema. The eschar dries, loosens, and falls off in the next 1 to 2 weeks, most often leaving no permanent scar. Lymphangitis and painful lymphadenopathy can occur with associated systemic symptoms. Although antibiotic therapy does not appear to change the course of eschar formation and healing, it does decrease the likelihood of systemic disease. Without antibiotic therapy, the mortality rate has been reported to be as high as 20%; with antibiotics, death due to cutaneous anthrax is rare.²

Gastrointestinal anthrax occurs following deposition and subsequent germination of spores in the upper or lower gastrointestinal tract. The former results in the oral-pharyngeal form of disease.^24-26 An oral or esophageal ulcer leads to development of regional lymphadenopathy, edema, and sepsis.^24-26 The latter results in primary intestinal lesions occurring predominantly in the terminal ileum or cecum,³⁸ presenting initially with nausea, vomiting, and malaise and progressing rapidly to bloody diarrhea, acute abdomen, or sepsis.²² Massive ascites has occurred in some cases of gastrointestinal anthrax.²⁷ Advanced infection may appear similar to the sepsis syndrome occurring in either inhalational or cutaneous anthrax.² Some authors suggest that aggressive medical intervention such as would be recommended for inhalational anthrax may reduce mortality, although, given the difficulty of early diagnosis, mortality almost inevitably would be high.^{2, 22}

Given the rarity of anthrax infection and the possibility that early cases are a harbinger of a larger epidemic, the first suspicion of an anthrax illness must lead to immediate notification of the local or state health department, local hospital epidemiologist, and local or state health laboratory. By this mechanism, definitive tests can be arranged rapidly through a reference laboratory and, as necessary, the US Army Medical Research Institute of Infectious Diseases (USAMRIID), Fort Detrick, Md.

The first evidence of a clandestine release of anthrax as a biological weapon most likely will be patients seeking medical treatment for symptoms of inhalational anthrax. The sudden appearance of a large number of patients in a city or region with an acute-onset flulike illness and case fatality rates of 80% or more, with nearly half of all deaths occurring within 24 to 48 hours, is highly likely to be anthrax or pneumonic plague (Table 1). Currently, there are no effective atmospheric warning systems to detect an aerosol cloud of anthrax spores.⁴⁷

Rapid diagnostic tests for diagnosing anthrax, such as enzyme-linked immunosorbent assay for protective antigen and polymerase chain reaction, are available only at national reference laboratories. Given the limited availability of these tests and the time required to dispatch specimens and perform assays, rapid diagnostic testing would be primarily for confirmation of diagnosis and determining in vitro susceptibility to antibiotics. In addition, these tests will be used in the investigation and management of anthrax hoaxes, such as the series occurring in late 1998.⁴⁸ They would also be of value should suspicious materials in the possession of a terrorist be identified as possibly containing anthrax.

If only small numbers of cases present contemporaneously, the clinical similarity of early inhalational anthrax to other acute respiratory tract infections may delay initial diagnosis for some days. However, diagnosis of anthrax could soon become apparent through the astute recognition of an unusual radiological finding, identification in the microbiology laboratory, or recognition of specific pathologic findings. A widened mediastinum on chest radiograph (Figure 2) in a previously healthy patient with evidence of overwhelming flulike illness is essentially pathognomonic of advanced inhalational anthrax and should prompt immediate action.^{23, 42} Although treatment at this stage would be unlikely to alter the outcome of illness in the patient concerned, it might lead to earlier diagnosis in others.

Microbiologic studies can also demonstrate B. anthracis and may be the means for initial detection of an outbreak. The bacterial burden may be so great in advanced infection that bacilli are visible on Gram stain of unspun peripheral blood, as has been demonstrated in primate studies (Figure 1). While this is a remarkable finding that would permit an astute clinician or microbiologist to make the diagnosis, the widespread use of automated cell-counter technology in diagnostic laboratories makes this unlikely.⁴¹

The most useful microbiologic test is the standard blood culture, which should show growth in 6 to 24 hours. If the laboratory has been alerted to the possibility of anthrax, biochemical testing and review of colonial morphology should provide a preliminary diagnosis 12 to 24 hours later. Definitive diagnosis would require an additional 1 to 2 days of testing in all but a few national reference laboratories. It should be noted, however, that if the laboratory has not been alerted to the possibility of anthrax, B. anthracis may not be correctly identified. Routine laboratory procedures customarily identify a Bacillus species from a blood culture approximately 24 hours after growth, but most laboratories do not further identify Bacillus species unless specifically requested to do so. In the United States, the isolation of species most often represents growth of Bacillus cereus. The laboratory and clinician must determine whether its isolation represents specimen contamination.⁴⁹ There have been no B. anthracis bloodstream infections reported for more than 20 years. However, given the possibility of anthrax being used as a weapon and the importance of early diagnosis, it would be prudent for laboratory procedures to be modified so that B. anthracis is excluded after identification of a Bacillus species bacteremia.

Sputum culture and Gram stain are unlikely to be diagnostic, given the lack of a pneumonic process.³⁰ If cutaneous anthrax is suspected, a Gram stain and culture of vesicular fluid will confirm the diagnosis.

A diagnosis of inhalational anthrax also might occur at postmortem examination following a rapid, unexplained terminal illness. Thoracic hemorrhagic necrotizing lymphadenitis and hemorrhagic necrotizing mediastinitis in a previously healthy adult are essentially pathognomonic of inhalational anthrax.^{38, 43} Hemorrhagic meningitis should also raise strong suspicion of anthrax infection.^{23, 38, 43, 50} Despite pathognomonic features of anthrax on gross postmortem examination, the rarity of anthrax makes it unlikely that a pathologist would immediately recognize these findings. If the case were not diagnosed at gross examination, additional days would likely pass before microscopic slides would be available to suggest the disease etiology.

The US anthrax vaccine, an inactivated cell-free product, was licensed in 1970 and is produced by Bioport Corp, Lansing, Mich (formerly called the Michigan Biologic Products Institute). The vaccine is licensed to be given in a 6-dose series and has recently been mandated for all US military active- and reserve-duty personnel.⁵¹ The vaccine is made from the cell-free filtrate of a nonencapsulated attenuated strain of B. anthracis.⁵² The principal antigen responsible for inducing immunity is the protective antigen.^{18, 23} A similar vaccine has been shown in one small placebo-controlled human trial to be efficacious against cutaneous anthrax.⁵³ As of March 1, 1999, approximately 590,000 doses of anthrax vaccine have been administered to US Armed Forces (Gary Strawder, Department of Defense, Falls Church, Va, oral communication, April 1999); no serious adverse events have been causally related (Miles Braun, Food and Drug Administration, Rockville, Md, written communication, April 1999). In a study of experimental monkeys, inoculation with this vaccine at 0 and 2 weeks was completely protective against an aerosol challenge at 8 and 38 weeks and 88% effective at 100 weeks.⁵⁴

A human live attenuated vaccine is produced and used in countries of the former Soviet Union.⁵⁵ In the Western world, live attenuated vaccines have been considered unsuitable for use in humans.⁵⁵

Current vaccine supplies are limited and the US production capacity is modest. It will be years before increased production efforts can make available sufficient quantities of vaccine for civilian use. However, even if vaccine were available, populationwide vaccination would not be recommended at this time, given the costs and logistics of a large-scale vaccination program and the unlikely occurrence of a bioterrorist attack in any given community. Vaccination of some essential service personnel should be considered if vaccine becomes available. Postexposure vaccination following a biological attack with anthrax would be recommended with antibiotic administration to protect against residual retained spores, if vaccine were available.

Recommendations regarding antibiotic and vaccine use in the setting of a biological anthrax attack are conditioned by a limited number of studies in experimental animals, current understanding of antibiotic resistance patterns, and the possible requirement to treat large numbers of casualties. A number of possible therapeutic strategies have yet to be fully explored experimentally or submitted for approval to the FDA. For these reasons, the working group offers consensus recommendations based on the best available evidence. The recommendations do not represent uses currently approved by the FDA or an official position on the part of any of the federal agencies whose scientists participated in these discussions and will need to be revised as further relevant information becomes available.

Given the rapid course of symptomatic inhalational anthrax, early antibiotic administration is essential. A delay of antibiotic treatment for patients with anthrax infection even by hours may substantially lessen chances for survival.^56-57 Given the difficulty in achieving rapid microbiologic diagnosis of anthrax, all persons with fever or evidence of systemic disease in an area where anthrax cases are occurring should be treated for anthrax until the disease is excluded.

There are no clinical studies of the treatment of inhalational anthrax in humans. Thus, antibiotic regimens commonly recommended for empirical treatment of sepsis have not been studied in this setting. In fact, natural strains of B. anthracis are resistant to many of the antibiotics used in these empirical regimens, such as those of the extended-spectrum cephalosporins.^58-59 Most naturally occurring anthrax strains are sensitive to penicillin, and penicillin historically has been the preferred therapy for the treatment of anthrax. Penicillin is approved by the FDA for this indication,^{41, 56-57} as is doxycycline.⁶⁰ In studies of small numbers of monkeys infected with susceptible strains of B. anthracis, oral doxycycline has proved efficacious.⁴¹

Table 2. Working Group Recommendations for Medical Therapy for Patients With

              Clinically Evident Inhalational Anthrax Infection in the Contained Casualty

               Setting^{28,41,60,62,63†}

                                                                        Optimal Therapy if

                           Initial Therapy                                   Strain Is Proven Susceptible                    Duration, d ‡

Adults      Ciprofloxacin, 400 mg intravenously     Penicillin G, 4 million U intravenously       60

                every 12 h                                          every 12 h

                                                                        Doxycycline, 100 mg intravenously

                                                                          every 12 h§

Children Ciprofloxacin, 20-30 mg/kg per day   Age<12 y: penicillin G, 50 0000 U/kg    60

                divided into 2 daily doses,                   intravenously every 6 h

                 not to exceed 1 g/d                          Age ³12 y: penicillin G, 4 million U

                                                                          intravenously every 4 h

Pregnant women¶                                          Same for nonpregnant adults

Immunosuppressed persons               Same as for nonimmunosuppressed adults and children

* Most recommendations are based on animal studies or in-vitro studies and are not approved by the US Food and Drug Administration (FDA). These recommendations are not FDA approved but were reached by consensus the working group. See text for explanations and alternatives.

† In vitro studies suggest ofloxacin, 400 mg intravenously every 12 hours, or levofloxacin, 500 mg intravenously every 24 hours, could be substituted for ciprofloxacin.

‡ Oral antibiotics should be substituted for intravenous antibiotics as soon as clinical condition improves.

§ In vitro studies suggest tetracycline could be substituted for doxycycline.

| Doxycycline could also be used. For children heavier than 45 kg. use adult dosage. For children 45 kg or lighter, use 2.5 mg/kg doxycycline intravenously every 12 hours. Refer to management of pediatric population in text for details.

¶ Refer to section on management of pregnant women in text for details.

Table 3. Working Group Recommendations for Medical Therapy for Patients With

               Clinically Evident Anthrax Infection in the Mass Casualty Setting or for

                Postexposure Prophylaxis⁴¹ *

                                                                                              Optimal Therapy if
                           Initial Therapy†                                 Strain Is Proven Susceptible                         Duration, d‡

Adults         Ciprofloxacin, 500 mg             Amoxicillin, 500 mg every 8 hr                  60

                    intravenously every 12 h         Doxycycline, 100 mg by mouth

                                                                    every 12 h‡

Children§   Ciprofloxacin, 20-30 mg/kg        Weight ³ 20 kg: amoxicillin, 500 mg          60

                  per day by mouth divided into 2   by mouth every 8 hr

                  daily doses, not to exceed 1 g/d   Weight <20 kg: amoxicillin, 40 mg/kg

                                                                      divided into 3 doses to be taken every 8 h

Pregnant    Ciprofloxacin, 500 mg by mouth   Amoxicillin, 500 mg by mouth every 8 h    60

women||      every 12 h

Immunosuppressed persons            Same as for nonimmunosuppressed adults and children

* Most recommendations are based on animal studies or in-vitro studies and are not approved by the US Food and Drug Administration (FDA). These recommendations are not FDA approved but were reached by consensus of the working group. See text for explanations and alternatives.

† In vitro studies suggest ofloxacin, 400 mg intravenously every 12 hours, or levofloxacin, 500 mg by mouth every 24 hours, could be substituted for ciprofloxacin.

‡ In vitro studies suggest tetracycline, 500 mg by mouth every 6 hours, could be substituted for doxycycline.

§ Doxycycline could also be used. For children heavier than 45 kg. use adult dosage. For children 45 kg or lighter, use 2.5 mg/kg doxycycline by mouth every 12 hours. Refer to management of pediatric population in text for details.

| Refer to section on management of pregnant women in text for details.

Doxycycline is the preferred option from the tetracycline class of antibiotics because of its proven efficacy in monkey studies and its ease of administration. Other members of this class of antibiotics are suitable alternatives. Although treatment of anthrax infection with ciprofloxacin has not been studied in humans, animal models suggest excellent efficacy.^{28, 41, 61} In vitro data suggest that other fluoroquinolone antibiotics would have equivalent efficacy in treating anthrax infection, although no animal data exist for fluoroquinolones other than ciprofloxacin.⁵⁹

Reports have been published of a B. anthracis vaccine strain that has been engineered by Russian scientists to resist the tetracycline and penicillin classes of antibiotics.⁶² Although the engineering of quinolone-resistant B. anthracis may also be possible, to date there have been no published accounts of this.

Balancing considerations of efficacy with concerns regarding resistance, the working group recommends that ciprofloxacin or other fluoroquinolone therapy be initiated in adults with presumed inhalational anthrax infection. Antibiotic resistance to penicillin- and tetracycline-class antibiotics should be assumed following a terrorist attack until laboratory testing demonstrates otherwise. Once the antibiotic susceptibility of the B. anthracis strain of the index case has been determined, the most widely available, efficacious, and least toxic antibiotic should be administered to patients and persons requiring postexposure prophylaxis.

In a contained casualty setting (a situation in which a modest number of patients require therapy), the working group recommends intravenous antibiotic therapy, as shown in Table 2. If the number of persons requiring therapy is sufficiently high (i.e., a mass casualty setting), the working group recognizes that intravenous therapy will no longer be possible for reasons of logistics and/or exhaustion of equipment and antibiotic supplies, and oral therapy will need to be used (Table 3). The threshold number of cases at which parenteral therapy becomes impossible depends on a variety of factors, including local and regional health care resources.

In experimental animals, antibiotic therapy during anthrax infection has prevented development of an immune response.^{28, 62} This suggests that even if the antibiotic-treated patient survives anthrax infection, risk for recurrence remains for at least 60 days because of the possibility of delayed germination of spores. Therefore, the working group recommends that antibiotic therapy be continued for 60 days, with oral therapy replacing intravenous therapy as soon as a patient’s clinical condition improves. If vaccine were to become widely available, postexposure vaccination in patients being treated for anthrax infection might permit the duration of antibiotic administration to be shortened to 30 to 45 days, with concomitant administration of 3 doses of anthrax vaccine at 0, 2, and 4 weeks.

The treatment of cutaneous anthrax historically has been with oral penicillin. The working group recommends that oral fluoroquinolone or tetracycline antibiotics as well as amoxicillin in the adult dosage schedules described in Table 2 and Table 3 would be suitable alternatives if antibiotic susceptibility is proved. Although previous guidelines have suggested treating cutaneous anthrax for 7 to 10 days,^{23, 49} the working group recommends treatment for 60 days in the setting of bioterrorism, given the presumed exposure to the primary aerosol. Treatment of cutaneous anthrax generally prevents progression to systemic disease, although it does not prevent the formation and evolution of the eschar. Topical therapy is not useful.²

Other antibiotics effective against B. anthracis in vitro include chloramphenicol, erythromycin, clindamycin, extended-spectrum penicillins, macrolides, aminoglycosides, vancomycin hydrochloride, cefazolin, and other first-generation cephalosporins.^58-59,64 The efficacy of these antibiotics has not been tested in humans or animal studies. The working group recommends the use of these antibiotics only if the previously cited antibiotics are unavailable or if the strain is otherwise antibiotic resistant. Natural resistance of B. anthracis strains exists against sulfamethoxazole, trimethoprim, cefuroxime, cefotaxime sodium, aztreonam, and ceftazidime.^58-59,64 Therefore, these antibiotics should not be used in the treatment or prophylaxis of anthrax infection.

Guidelines regarding which populations would require postexposure prophylaxis following the release of anthrax as a biological weapon would need to be developed quickly by state and local health departments in consultation with national experts. These decisions require estimates of the timing and location of the exposure and the relevant weather conditions in an outdoor release.65 Ongoing monitoring of cases would be needed to define the high-risk areas, direct follow-up, and guide the addition or deletion of groups to receive postexposure prophylaxis.

There are no FDA-approved postexposure antibiotic regimens following exposure to an anthrax aerosol. For postexposure prophylaxis, the working group recommends the same antibiotic regimen as that recommended for treatment of mass casualties; prophylaxis should be continued for 60 days (Table 3).

Consensus recommendations for special groups as set forth herein reflect the clinical and evidence-based judgments of the working group and at this time do not necessarily correspond with FDA-approved use, indications, or labeling.

It has been recommended that ciprofloxacin and other fluoroquinolones should not be used in children younger than 16 to 18 years because of a link to permanent arthropathy in adolescent animals and transient arthropathy in a small number of children.⁶⁰ However, balancing these risks against the risks of anthrax caused by an engineered antibiotic-resistant strain, the working group recommends that ciprofloxacin be used in the pediatric population for initial therapy or postexposure prophylaxis following an anthrax attack (Table 2). If antibiotic susceptibility testing allows, penicillin should be substituted for the fluoroquinolone.

As a third alternative, doxycycline could be used. The American Academy of Pediatrics has recommended that doxycycline not be used in children younger than 9 years because the drug has resulted in retarded skeletal growth in infants and discolored teeth in infants and children.⁶⁰ However, the serious risk of infection following an anthrax attack supports the consensus recommendation that doxycycline be used in children if antibiotic susceptibility testing, exhaustion of drug supplies, or allergic reaction preclude use of penicillin and ciprofloxacin.

In a contained casualty setting, the working group recommends that children receive intravenous antibiotics (Table 2). In a mass casualty setting and as postexposure prophylaxis, the working group recommends that children receive oral antibiotics (Table 3).

The US vaccine is licensed for use only in persons aged 18 to 65 years because studies to date have been conducted exclusively in this group.⁵² No data exist for children, but based on experience with other inactivated vaccines, it is likely that the vaccine would be safe and effective.

Fluoroquinolones are not generally recommended during pregnancy because of their known association with arthropathy in adolescent animals and small numbers of children. Animal studies have discovered no evidence of teratogenicity related to ciprofloxacin, but no controlled studies of ciprofloxacin in pregnant women have been conducted. Balancing these possible risks against the concerns of anthrax due to engineered antibiotic-resistant strains, the working group recommends that ciprofloxacin be used in pregnant women for therapy and postexposure prophylaxis following an anthrax attack (Table 2 and Table 3). No adequate controlled trials of penicillin or amoxicillin administration during pregnancy exist. However, the CDC recommends penicillin for the treatment of syphilis during pregnancy and amoxicillin as a treatment alternative for chlamydial infections during pregnancy.⁶⁰

The working group recommends that pregnant women receive fluoroquinolones in the usual adult dosages. If susceptibility testing allows, intravenous penicillin in the usual adult dosages should be substituted for fluoroquinolones. As a third alternative, intravenous doxycycline could be used. The tetracycline class of antibiotics has been associated with both toxic effects in the liver in pregnant women and fetal toxic effects, including retarded skeletal growth.⁶⁰ Balancing the risks of anthrax infection with those associated with doxycycline use in pregnancy, the working group recommends that doxycycline be used in pregnant women for therapy and postexposure prophylaxis if antibiotic susceptibility testing, exhaustion of drug supplies, or allergic sensitivity preclude the use of penicillin and ciprofloxacin. If doxycycline is used in pregnant women, periodic liver function testing should be performed if possible.

Ciprofloxacin (and other fluoroquinolones), penicillin, and doxycycline (and other tetracyclines) are each excreted in breast milk. Therefore, a breast-feeding woman should be treated or given prophylaxis with the same antibiotic as her infant based on what is most safe and effective for the infant (see pediatric guidelines herein) to minimize risk to the infant.

The antibiotic treatment or postexposure prophylaxis for anthrax among those who are immunosuppressed has not been studied in human or animal models of anthrax infection. Therefore, the working group consensus recommendation is to administer antibiotics as for immunocompetent adults and children (Table 2 and Table 3).

There are no data to suggest patient-to-patient transmission of anthrax occurs.^{8, 46} Thus, standard barrier isolation precautions are recommended for hospitalized patients with all forms of anthrax infection, but the use of high-efficiency particulate air filter masks or other measures for airborne protection are not indicated.⁶⁶ There is no need to immunize or provide prophylaxis to patient contacts (e.g., household contacts, friends, coworkers) unless a determination is made that they, like the patient, were exposed to the aerosol at the time of the attack.

In addition to immediate notification of the hospital epidemiologist and state health department, the local hospital microbiology laboratories should be notified at the first indication of anthrax so that safe specimen processing under biosafety level 2 conditions can be undertaken.^{41, 67} A number of disinfectants used for standard hospital infection control, such as hypochlorite, are effective in cleaning environmental surfaces contaminated with infected bodily fluids.^{17, 66}

Proper burial or cremation of humans and animals who have died because of anthrax infection is important in preventing further transmission of the disease. Serious consideration should be given to cremation. Embalming of bodies could be associated with special risks.⁶⁶ If autopsies are performed, all related instruments and materials should be autoclaved or incinerated.⁶⁶ Animal transmission might occur if infected animal remains are not cremated or buried.^{16, 21}

Recommendations regarding decontamination in the event of an intentional aerosolization of anthrax spores are based on evidence concerning aerosolization, anthrax spore survival, and environmental exposures at Sverdlovsk and among goat hair mill workers. The greatest risk to human health following an intentional aerosolization of anthrax spores occurs during the period in which anthrax spores remain airborne, called primary aerosolization. The duration for which spores remain airborne and the distance spores travel before they become noninfectious or fall to the ground is dependent on meteorological conditions and aerobiological properties of the dispersed aerosol.^{8, 65} Under circumstances of maximum survival and persistence, the aerosol would be fully dispersed within hours to 1 day at most, well before the first symptomatic cases would be seen. Following the discovery that a bioweapon has been used, anthrax spores may be detected on environmental surfaces using rapid assay kits or culture, but they provide no indication as to the risk of reaerosolization.

The risk that anthrax spores might pose to public health after the period of primary aerosolization can be inferred from the Sverdlovsk experience, investigations in animal hair processing plants, and modeling analyses by the US Army. At Sverdlovsk, new cases of inhalational anthrax developed as late as 43 days after the presumed date of release, but none occurred during the months and years afterward.⁶⁸ Some have questioned whether any of those cases with onset of disease beyond 7 days might have represented illness following resuspension of spores from the ground or other surfaces, a process that has been called secondary aerosolization. While it is impossible to state with certainty that secondary aerosolizations did not occur, it appears unlikely. It should be noted that few efforts were made to decontaminate the environment after the accident and only 47,000 of the city’s 1 million inhabitants were vaccinated.⁸ The epidemic curve (Figure 4) is typical for a common-source epidemic, and it is possible to account for virtually all patients having been within the area of the plume on the day of the accident. Moreover, if secondary aerosolization had been important, new cases almost certainly would have continued for a period well beyond the observed 43 days.

Although persons working with animal hair or hides are known to be at increased risk of developing inhalational or cutaneous anthrax, surprisingly few of those exposed in the United States have developed disease. During the first half of this century, a significant number of goat hair mill workers were likely exposed to aerosolized spores. Mandatory vaccination became a requirement for working in goat hair mills only in the 1960s. Meanwhile, many unvaccinated person-years of high-risk exposure had occurred, but only 13 cases of inhalational anthrax were reported.^{19, 44}One study of environmental exposure was conducted at a Pennsylvania goat hair mill at which workers were shown to inhale up to 510 B. anthracis particles of at least 5 µm in diameter per person per 8-hour shift. These concentrations of spores were constantly present in the environment during the time of this study,⁴⁴ but no cases of inhalational anthrax occurred.

Modeling analyses have been carried out by US Army scientists seeking to determine the risk of secondary aerosolization. One study concluded that there was no significant threat to personnel in areas contaminated by 1 million spores per square meter either from traffic on asphalt-paved roads or from a runway used by helicopters or jet aircraft.⁶⁹ A separate study showed that in areas of ground contaminated with 20 million Bacillus subtilis spores per square meter, a soldier exercising actively for a 3-hour period would inhale between 1000 and 15,000 spores.⁷⁰

Much has been written about the technical difficulty of decontaminating an environment contaminated with anthrax spores. A classic case is the experience at Gruinard Island in the United Kingdom. During World War II, British military undertook explosives testing with anthrax spores on this island off the Scottish coast. Spores persisted and remained viable for 36 years following the conclusion of testing. Decontamination of the island occurred in stages, beginning in 1979 and ending in 1987, when the island was finally declared fully decontaminated. The total cost is unpublished, but materials required included 280 tons of formaldehyde and 2000 tons of seawater.^{17, 71}

If an environmental surface is proved to be heavily contaminated with anthrax spores in the immediate area of a spill or close proximity to the point of release of an anthrax aerosol, decontamination of that area may decrease the slight risk of acquiring anthrax by secondary aerosolization. However, decontamination of large urban areas or even a building following an exposure to an anthrax aerosol would be extremely difficult and is not indicated. Although the risk of disease caused by secondary aerosolization would be extremely low, it would be difficult to offer absolute assurance that there was no risk whatsoever. Postexposure vaccination, if vaccine were available, might be a possible intervention that could further lower the risk of anthrax infection in this setting.

In the setting of an announced alleged anthrax release, such as the series of anthrax hoaxes occurring in many areas of the United States in 1998,⁴⁸ any person coming in direct physical contact with a substance alleged to be anthrax should perform thorough washing of the exposed skin and articles of clothing with soap and water.72 Further decontamination of directly exposed individuals or of others is not indicated. In addition, any person in direct physical contact with the alleged substance should receive postexposure antibiotic prophylaxis until the substance is proved not to be anthrax. If the alleged substance is proved to be anthrax, immediate consultation with experts at the CDC and USAMRIID should be obtained.

To develop a maximally effective response to a bioterrorist incident involving anthrax, the medical community will require new knowledge of the organism, its genetics and pathogenesis, improved rapid diagnostic techniques, improved prophylactic and therapeutic regimens, and an improved second-generation vaccine.⁴⁷ A recently published Russian study indicates that genes transferred from the related B cereus can act to enable B. anthracis to evade the protective effect of the live attenuated Russian vaccine in a rodent model.⁷³ Research is needed to determine the role of these genes with respect to virulence and ability to evade vaccine-induced immunity. Furthermore, the relevance of this finding for the US vaccine needs to be established. An accelerated vaccine development effort is needed to allow the manufacture of an improved second-generation product that requires fewer doses. Finally, an expanded knowledge base is needed regarding possible maximum incubation times after inhalation of spore-containing aerosols and optimal postexposure antibiotic regimens.

Ex Officio Participants in the Working Group on Civilian Biodefense: George Curlin, MD, National Institutes of Health, Bethesda, Md; Margaret Hamburg, MD, and William Raub, PhD, Office of Assistant Secretary for Planning and Evaluation, DHHS, Washington, DC; Robert Knouss, MD, Office of Emergency Preparedness, DHHS, Rockville, Md; Marcelle Layton, MD, Office of Communicable Disease, New York City Health Department, New York, NY; and Brian Malkin and Stuart Nightingale, MD, FDA, Rockville.

Disclaimers: In many cases, the indication and dosages and other information are not consistent with current approved labeling by the US Food and Drug Administration (FDA). The recommendations on the use of drugs and vaccine for uses not approved by the FDA do not represent the official views of the FDA or of any of the federal agencies whose scientists participated in these discussions. Unlabeled uses of the products recommended are noted in the sections of this article in which these products are discussed. Where unlabeled uses are indicated, information used as the basis for the recommendation is discussed.

The working group wishes to thank Jeanne Guillermin, PhD, professor of sociology, Boston College, Boston, Mass, for her comments on the manuscript. Starting in 1992, Dr Guillermin directed the interview project to verify onset, hospital, and death data for the 1979 Sverdlovsk victims, which will be detailed in Anthrax, A Book of Names, from California Press. We also thank Matthew Meselson, Timothy Townsend, MD, Martin Hugh-Jones, MA, VetMB, MPH, PhD, and Philip Brachman, MD, for their review and commentary of the manuscript.

Corresponding Author and Reprints: Thomas V. Inglesby, MD, Johns Hopkins Center for Civilian Biodefense Studies, Johns Hopkins University, Candler Bldg, Suite 850 , 11 1 Market Pl, Baltimore, MD 21202 (e-mail: tvijhmi.edu).

Author Affiliations: The Center for Civilian Biodefense Studies (Drs Inglesby, Henderson, Bartlett, O’Toole, Perl, and Russell), and the Schools of Medicine (Drs Inglesby, Bartlett, and Perl) and Public Health (Drs Henderson, O’Toole, and Russell), Johns Hopkins University, Baltimore, Md; Viral and Rickettsial Diseases, California Department of Health, Berkeley (Dr Ascher); US Army Medical Research Institute of Infectious Diseases, Frederick, Md (Drs Eitzen, Friedlander, and Parker); Office of Emergency Management, New York, NY (Mr Hauer); Centers for Disease Control and Prevention, Atlanta, Ga (Dr McDade); Acute Disease Epidemiology, Minnesota Department of Health, Minneapolis (Dr Osterholm); and the Office of Emergency Preparedness, Department of Health and Human Services, Rockville, Md (Dr Tonat).

v Update: Investigation of Bioterrorism-Related Anthrax and Interim Guidelines for Exposure Management and Antimicrobial Therapy, October 2001

Since October 3, 2001, CDC and state and local public health authorities have been investigating cases of bioterrorism-related anthrax. This report updates previous findings, provides new information on case investigations in two additional areas, presents the susceptibility patterns of Bacillus anthracis isolates, and provides interim recommendations for managing potential threats and exposures and for treating anthrax.

As of October 24, investigations in the District of Columbia (DC), Florida, New Jersey, New York City (NYC), Maryland, Pennsylvania, and Virginia have identified 15 (11 confirmed and four suspected) cases of anthrax according to the CDC surveillance case definition(1). Seven of the 15 cases were inhalational anthrax and eight were cutaneous. Of the seven inhalational cases, five occurred in postal workers in New Jersey and DC, and one in a person who sorted and distributed mail at a media company in Florida. Two letters mailed to two different recipients in NYC and one letter mailed to a recipient in DC are known to have contained B. anthracis spores. Six cases were identified in employees of media companies; one was a 7-month-old infant who visited a media company; and eight cases are consistent with exposures along the postal route of letters known to be contaminated with B. anthracis spores in New Jersey and DC. Using molecular typing, analysis of B. anthracis isolates from cases in Florida, NYC, and DC indicated that the isolates are indistinguishable(2). Epidemiologic investigations and surveillance in other locations are continuing; no additional cases have been identified.

As of October 24, investigations in Florida have identified two confirmed cases of inhalational anthrax in persons who worked at the same media company; no additional cases of disease have been identified since the last report ⁽¹⁾. A pleural biopsy for the second confirmed patient was positive for B. anthracis by immunohistochemical (IHC) staining. In addition, a >4-fold increase in levels of serum antibody (IgG) to the protective antigen (PA) component of the anthrax toxin using enzyme-linked immunosorbant assay (ELISA) was demonstrated.

Environmental sampling of the work site revealed B. anthracis contamination and implicated one or more mailed letters or packages as the likely source of exposure. Several environmental specimens from regional and local postal centers that provided mail services to the work site were culture-positive for B. anthracis. Thirty postal workers had no evidence of B. anthracis exposure by nasal swab testing. No cases of disease have been identified among postal workers. On the basis of the positive environmental swabs, focused clean-up procedures continue at regional and local postal centers. The Environmental Protection Agency (EPA), in consultation with health officials, is conducting decontamination of the work site.

Approximately 1,100 persons were started on antimicrobial prophylaxis for suspected B. anthracis exposure; 555 worked either full- or part-time in the affected building. The majority of other persons reported spending at least 1 hour in the affected building since August 1. Additional follow-up for compliance with prophylaxis recommendations and monitoring adverse events associated with long-term antimicrobial prophylaxis is ongoing.

Investigations in NYC have identified five (three confirmed and two suspected) cutaneous anthrax cases; three cases (one confirmed and two suspected) have been identified since the last report ⁽¹⁾ . These five cases were associated with four media companies (A-D). The two previously reported cases were related to work sites A and B, and the three additional cases were related to work sites C, D, and A, respectively. No cases among postal workers have been identified.

On October 1, a 27-year-old woman who regularly handled mail at work site C sought medical care at a local hospital for two lesions on the left cheek, which developed surrounding erythema and edema and local adenopathy. A biopsy obtained on October 16 was positive by IHC staining for the cell wall antigen of B. anthracis and serologic testing was weakly reactive. No suspicious letter was identified from her work site.

Two suspected cases of cutaneous anthrax also have been detected. The first suspected case, a 29-year-old woman with onset of illness on September 22, frequently handled mail at work site D. At her work site, an unopened letter postmarked September 18, which contained powder contaminated with B. anthracis was found on October 19. The second suspected case, a 23-year-old woman with onset of illness on September 28, handled a suspicious letter postmarked September 18 from work site A. All three patients were treated with ciprofloxacin and have shown clinical improvement. A total of three persons were confirmed by nasal swabs to have been exposed to B. anthracis, presumably acquired during handling and processing of specimens during the investigation of the first confirmed case ⁽¹⁾ .

In work site A, potentially exposed persons were identified and prescribed antimicrobial prophylaxis. An environmental investigation of work site A was conducted subsequently; environmental samples taken from work site A were culture-positive for B. anthracis. Of 1,360 persons who were tested by nasal swabs from work site A, all were confirmed negative. Nasal swabs were obtained from 1,202 persons from work sites B, C, and D; 1,183 tested negative and 19 are pending final results. Environmental samples taken from work site A were positive. Testing of environmental specimens from work sites B, C, and D is ongoing.

Prophylaxis was recommended for potentially exposed persons at work site A. Antimicrobial prophylaxis was initiated for nine persons who had recent contact with the sealed letter containing B. anthracis in work site D.

T o date, investigations in New Jersey and Pennsylvania have identified four (two confirmed and two suspected) anthrax cases. Cutaneous disease has been diagnosed in three patients and one has illness suspected to be inhalational anthrax, but laboratory tests to confirm the diagnosis are pending. All four of these patients worked at one of two postal facilities in New Jersey. Although no specific contaminated letter was identified, contaminated letters destined for both NYC and DC passed through at least one of these postal facilities in New Jersey.

On October 1, a 45-year-old female mail carrier sought medical care at a local hospital for a 4-day history of worsening skin lesions on her right forearm. A biopsy was obtained and arrived at CDC on October 17 and later that night was found positive by IHC. In addition, tissue was positive for B. anthracis by polymerase chain reaction (PCR), and serologic testing was reactive. The patient’s condition improved on antimicrobial therapy.

On October 16, a 35-year-old male mail processor, with a history of a chronic, bullous-like skin condition, was taken to a local hospital complaining of a 2-day history of a large pustular lesion on his neck. He returned 1 day later with increasing ulceration of the skin lesion associated with fatigue, chills, and a swollen throat; he was afebile but had vesicles and bullae around the pustular lesion. Biopsy was positive by IHC, and serologic testing was reactive to B. anthracis . The patient’s lesions responded to antimicrobial therapy.

Two suspected cases also have been detected. The first case occurred in a 39-year-old male machine mechanic who was taken to a local hospital on September 26 for two bullous, vesicular lesions with surrounding erythema, edema, and induration on the right forearm, which progressed to black eschars. The patient was treated for cellulitis with ceftriaxone followed by amoxicillin/clavulanate. The patient was reported to CDC on October 17 and serologic testing at CDC was reactive to B. anthracis. No biopsy was obtained. The patient’s condition improved.

O n October 14, the second suspected case occurred in a 56-year-old female postal worker who sought medical care for fever, diarrhea, and vomiting at a local hospital. On October 14, the second suspected case occurred in a 56-year-old female postal worker who sought medical care for fever, diarrhea, and vomiting at a local hospital. On October 19, the patient was admitted to the hospital with chills, dry cough, and pleuritic chest pain. A chest radiograph showed a small right infiltrate and bilateral effusions, but no evidence of a widened mediastinum. The next day, her respiratory status and pleural effusions worsened. A chest computerized tomography (CT) showed an enlarged mediastinal and cervical lymph nodes without parenchymal disease. The pleural fluid was positive for B. anthracis by PCR. Bilateral pleural effusions have complicated the patient’s hospital course and she continues to require supplemental oxygen.

On October 20, the postal facility was closed; the New Jersey Department of Health and Senior Services recommended that postal workers at both postal facilities initiate antimicrobial prophylaxis pending further epidemiologic and environmental investigation. Both facilities have been closed pending results of further environmental evaluation. Environmental sampling is being conducted at both postal facilities. In one facility, 13 of 23 samples from high-risk areas were preliminarily culture-positive for B. anthracis. Clean-up efforts are ongoing. Results of cultures from samples taken in the second facility and results from approximately 600 nasal swab cultures obtained from postal employees are pending.

To date, investigations in DC, Maryland, and Virginia have identified four confirmed anthrax cases. All patients had inhalational illness and all worked at a single postal facility in DC.

On October 15, a staff member in the office of a U.S. Senator noted a small burst of dust released while opening a tightly sealed letter. The U.S. Capitol Police and Federal Bureau of Investigation (FBI) were notified and the area was vacated and secured immediately; ventilation systems for the Senator’s offices were deactivated within 45 minutes of recognizing the threat. The letter and surrounding carpet were removed and sent for testing. On October 16, the letter tested positive for B. anthracis by PCR, and an epidemiologic investigation was initiated by the health officials from the Office of Attending Physician, U.S. Capitol; DC Department of Health (DCDOH); Infectious Disease Service, National Naval Medical Center; and CDC.

Based on the initial investigation, the area of exposure was determined to consist of two floors in the southeast quadrant of the building where the U.S. Senator’s office is located. Approximately 340 staff and visitors potentially were exposed. Beginning October 15, nasal swab testing was performed on these persons and approximately 5,000 additional persons who referred themselves for testing. Twenty-eight persons had evidence of exposure by nasal swab testing; 13 were in the immediate office space where the letter was opened, nine were in adjacent areas, and six were first responders. Antimicrobial prophy laxis was administered to persons from the area of exposure and first-responders to the incident. Environmental specimens were collected at the affected building and other buildings in the U.S. Capitol complex. To date, environmental specimens are positive from the area of exposure as well as two mail rooms in the U.S. Capitol complex; one of the mail rooms did not process the contaminated letter. None of the mail room personnel and none of the postal workers at the post office serving the mail rooms had positive nasal swabs. These mail handlers were all offered prophylactic antibiotics. Initially, a single positive environmental sample for the post office serving these mail rooms was positive. Subsequent samples from this post office and the mail distribution center serving this post office were positive.

On October 19, enhanced regional surveillance activities (a collaborative effort between DCDOH, Maryland Department of Health and Mental Hygiene, and the Virginia Department of Health) identified a case of pulmonary illness in a postal worker. The postal worker, a 56-year-old man, sought medical care at a Virginia hospital for fever, chills, chest heaviness, malaise, and minimally productive cough of 3 days’ duration. Initial evaluation in the emergency department (ED) revealed a widened mediastinum on a chest radiograph; a subsequent CT scan revealed mediastinal lymphadenopathy and small, bilateral pleural effusions. The patient was hospitalized for suspected inhalational anthrax and was treated with broad spectrum antimicrobial agents, including ciprofloxacin. Blood cultures grew gram-positive rods within 15 hours of collection, later confirmed to be B. anthracis at the Virginia State Health Laboratory and CDC on October 21. The patient is clinically stable and remains hospitalized.

On October 20, a second postal worker, also a 56-year-old man, who worked at the same distribution center, was admitted to the hospital with a 3-day history of progressively worsening headache and night sweats. He had no fever, stiff neck, or other symptoms or signs consistent with meningitis. He had a mild sore throat and occasional dry cough. Because the patient was linked epidemiologically to the index case of inhalational anthrax, a chest radiograph and chest CT scan were performed that revealed mediastinal lymphadenopathy and a right middle lobe infiltrate. Antimicrobial therapy was initiated. Blood cultures grew B. anthracis within 18 hours. The patient is clinically stable and remains hospitalized.

On October 21, a third postal worker, a 55-year-old man, who worked at the same distribution center was admitted to the hospital with suspected inhalational anthrax. The patient had initially sought medical care at a physician’s office on October 18 for 2 days of progressive fatigue, myalgias, and fever. The patient had a temperature of 102 F (38.9 C) and normal white blood cell count and was sent home. The patient returned to the ED on October 21 with persistent symptoms, including chills, vague chest tightness, and temperature of 102 F (38.9 C). Chest radiograph revealed right middle and lower lobe alveolar infiltrates and right hilar and peritracheal soft tissue fullness. Evaluation revealed hypoxia, leukocytosis, and hemoconcentration. Antimicrobial therapy was initiated, and the patient was mechanically ventilated. The patient’s condition deteriorated, and he died on October 21. Blood cultures obtained on admission to the hospital grew gram-positive bacilli, which were confirmed later as B. anthracis at CDC.

On October 22, a fourth postal worker, a 47-year-old man, who worked at the same distribution center was admitted to the hospital with suspected inhalational anthrax. The patient had initially presented to the ED on October 21 with complaints of 5 days of progressive fatigue, nausea, vomiting, and diarrhea, and syncope. The patient was afebrile and had orthostatic hypotension. A chest radiograph was obtained and reported to be normal. The patient received intravenous fluids and was discharged. He returned to the ED 26 hours later following another syncopal episode and persistent gastrointestinal complaints. The patient was afebrile, hypotensive, diaphoretic, and in respiratory distress. A second chest radiograph and a chest CT revealed mediastinal lymphadenopathy and bilateral pleural effusions. Subsequent review of the first chest radiograph revealed an ill-defined area of increased density in the right subhilar region. Laboratory evaluation revealed leukocytosis and hemoconcentration. Antimicrobial therapy was initiated, and the patient was mechanically ventilated. Peripheral blood smear demonstrated gram-positive bacilli; blood cultures grew gram-positive bacilli within 18 hours and were confirmed as B. anthracis at CDC. The patient died on October 22.

On October 20, CDC and DCDOH initiated an investigation of the postal facility where the four patients were employed. Although no specific exposure event was identified, the contaminated tightly sealed letter that was mailed to the Senator’s office was processed at this facility on October 12 before entering the Capitol mail distribution system. The postal facility was closed on October 21, and antimicrobial prophylaxis was recommended to employees working in proximity to the same mail sorting area of the first patient. In addition, visitors to nonpublic operations areas of this facility also were offered antimicrobial prophylaxis.

On October 22, because of concern about the potential for unrecognized aerosol exposures among postal workers, antimicrobial therapy was recommended for all workers and visitors to nonpublic areas in this postal facility. Subsequently, this recommendation has been extended to all postal workers in the DC area directly served by this postal facility pending results of ongoing epidemiologic and environmental investigation.

The first patient also worked at a second postal facility. On October 21, this facility also was closed. Antimicrobial prophylaxis also was recommended for workers at this facility pending further epidemiologic and environmental testing.

Antimicrobial susceptibility patterns were determined for 11 B. anthracis isolates associated with intentional exposures in Florida, NYC, and DC. Susceptibility breakpoints for interpreting minimum inhibitory concentration (MIC) results for B. anthracis have not been determined by the National Committee for Clinical Laboratory Standards (NCCLS); thus, breakpoints for staphylococci were used (3). All B. anthracis isolates were susceptible to ciprofloxacin (MIC<0.06 µg/mL), doxycycline (MIC<0.03 µg/mL), chloramphenicol (MIC=4 µg/mL), clindamycin (MIC< 0.5 µg/mL), tetracycline (MIC=0.06 µg/mL), rifampin (MIC<0.5 µg/mL), and vancomycin (MIC=1-2 µg/mL). Limited testing of imipenem suggests that these organisms are also susceptible to this agent (MIC<0.12 µg/mL) and are likely susceptible to meropenem. Susceptibility of the isolates was considered intermediate to erythromycin (MIC=1 µg/mL) and borderline susceptible to azithromycin (MIC=2 µg/mL); clarithromycin was considered susceptible (MIC=0.25 µg/mL).

B. anthracis isolates were susceptible to penicillin (MIC range: <0.06 ug/mL-0.12 µg/mL) and amoxicillin (MIC< 0.06 µg/mL); ceftriaxone (MIC=16) was considered intermediate. NCCLS has not defined either a B. anthracis or staphylococcal interpretive breakpoint for ceftriaxone results; thus, breakpoints for gram-negative organisms were used to interpret ceftriaxone results. These ceftriaxone MICs and additional laboratory data at CDC indicate the presence in B. anthracis isolates of a cephalosporinase, an enzyme that inhibits the antibacterial activity of cephalosporins such as ceftriaxone. Additional studies were performed with some of the B. anthracis isolates to identify other beta-lactamases, the general class of enzymes that inactivate penicillins, cephalosporins, and related drugs. These preliminary studies indicate the presence of a class B cephalosporinase and suggest that a penicillinase also may be present. These enzymes often are present in naturally occurring B. anthracis isolates.

This information is current as of October 24, 2001, 9 p.m. eastern daylight time. Intensive surveillance activities and environmental and case investigations are in progress to identify and treat all U.S. Postal Service workers and others at potential risk for anthrax. Surveillance also is being conducted to monitor adverse events associated with antimicrobial prophylaxis for anthrax. CDC and FBI are collaborating to accelerate all aspects of the investigation surrounding these events.

Reported by: J Malecki, MD, Palm Beach County Health Dept, Palm Beach; S Wiersma, MD, State Epidemiologist, Florida Dept of Health. K Cahill, MD; M Grossman, MD, Columbia Presbyterian Medical Center, New York City; H Hochman, MD, Lenox Hill Hospital, New York City; A Gurtman, MD, Mount Sinai School of Medicine, New York City; Communicable Disease Program, New York City Dept of Health. E Bresnitz, MD, State Epidemiologist, G DiFerdinando, MD, New Jersey Dept of Health and Senior Svcs. P Lurie, MD, K Nalluswami, MD, Pennsylvania Dept of Health. L Siegel, MD, S Adams, I Walks, MD, J Davies-Coles, PhD, District of Columbia Dept of Health. R Brechner, State Epidemiologist, Maryland Dept of Health and Mental Hygiene. E Peterson, MD, Virginia Dept of Health. D Frank, MD, Greater SE Hospital, District of Columbia. S Bresoff-Matcha, MD, Mid-Atlantic Permanente Medical Group and Inova Fairfax Hospital, Falls Church, Virginia. C Chiriboga, MD, Southern MD Hosp, Clinton, Maryland. J Eisold, MD, G Martin, MD, Office of the Attending Physician, US Capitol. EIS officers, CDC.

Editorial Note: Bioterrorism attacks using B. anthracis spores sent through the mail have resulted in 15 anthrax cases and three deaths. The initial anthrax cases occurred among persons with known or suspected contact with opened letters contaminated with B. anthracis spores. Later, investigations identified four confirmed cases and one suspected case among postal workers who had no known contact with contaminated opened letters. This suggests that sealed envelopes contaminated with B. anthracis passing through the postal system may be the source of exposure. The number of contaminated envelopes passing through the postal system is not known. In addition, automated sorting could damage envelopes and release spores into postal environments; other circumstances that could contribute to the contamination of postal facility environments may be identified.

Because these cases are the result of intentional exposures, FBI and other law enforcement authorities are investigating these events as criminal acts and are working to identify and eliminate the source of these exposures. Until that occurs, the possibility of further exposure to B. anthracis and subsequent clinical illness exists. Clinicians and laboratorians should be vigilant for symptoms or laboratory findings that indicate B. anthracis infection, particularly among mail handlers. Information to guide health-care providers and laboratorians is available at <http://www.bt.cdc.gov>.

Letters containing B. anthracis spores have been sent to persons in NYC and DC. Prompt identification of a threat and institution of appropriate measures may prevent inhalational anthrax. To prevent exposure to B. anthracis and subsequent infection, suspicious letters or packages should be recognized and appropriate protective steps taken.

Characteristics of suspicious packages and letters include inappropriate or unusual labeling, strange return address or no return address, postmarks from a city or state different from the return address, excessive packaging material, and others. If a package appears suspicious, it should not be opened. The package should be handled as little as possible. The room should be vacated and secured promptly and appropriate security or law enforcement agencies promptly notified (Box 1).

Box 1. Handling of Suspicious Packages or Envelopes

Do not shake or empty the contents of a suspicious package or envelope.

Do not carry the package or envelope, show it to others, or allow others to examine it.

Put the package or envelope on a stable surface; do not sniff, touch, taste, or look closely at it or any contents that may have spilled.

Alert others in the area about the suspicious package or envelope. Leave the area, close any doors, and take actions to prevent others from entering the area. If possible, shut off the ventilation system.

Wash hands with soap and water to prevent spreading potentially infectious material to face or skin. Seek additional instructions for exposed or potentially exposed persons.

If at work, notify a supervisor, a security officer, or a law enforcement official. If at home, contact the local law enforcement agency.

If possible, create a list of persons who were in the room or area when this suspicious letter or package was recognized and a list of persons who also may have handled this package or letter. Give the list to both the local public health authorities and law enforcement officials.

Identification of a patient with anthrax or a confirmed exposure to B. anthracis should prompt an epidemiologic investigation. The highest priority is to identify at-risk persons and initiate appropriate interventions to protect them. The exposure circumstances are the most important factors that direct decisions about prophylaxis. Persons with an exposure or contact with an item or environment known, or suspected to be contaminated with B. anthracis--regardless of laboratory tests results–should be offered antimicrobial prophylaxis. Exposure or contact, not laboratory test results, is the basis for initiating such treatment. Culture of nasal swabs is used to detect anthrax spores. Nasal swabs can occasionally document exposure, but cannot rule out exposure to B. anthracis . As an adjunct to epidemiologic evaluations, nasal swabs may provide clues to help assess the exposure circumstances. In addition, rapid evaluation of contaminated powder, including particle size and characteristics, may prove useful in assessing the risk for inhalational anthrax.

CDC is working with U.S. Postal Service employees and managers on several strategies to address the risk for anthrax among workers involved in mail handling. These strategies include personal protective equipment for workers handling mail and engineering controls in mail facilities. Clinicians and laboratorians should be vigilant for symptoms or laboratory findings that indicate possible anthrax infection, particularly among workers involved in mail sorting and distribution. Information to guide health-care providers and laboratories is available at <http://www.bt.cdc.gov> ⁽¹⁾.

A high index of clinical suspicion and rapid administration of effective antimicrobial therapy is essential for prompt diagnosis and effective treatment of anthrax. Limited clinical experience is available and no controlled trials in humans have been performed to validate current treatment recommendations for inhalational anthrax. Based on studies in nonhuman primates and other animal and in vitro data, ciprofloxacin or doxycycline should be used for initial intravenous therapy until antimicrobial susceptibility results are known (Table 1). Because of the mortality associated with inhalational anthrax, two or more antimicrobial agents predicted to be effective are recommended; however, controlled studies to support a multiple drug approach are not available. Other agents with in vitro activity suggested for use in conjunction with ciprofloxacin or doxycycline include rifampin, vancomycin, imipenem, chloramphenicol, penicillin and ampicillin, clindamycin, and clarithromycin; but other than for penicillin, limited or no data exist regarding the use of these agents in the treatment of inhalational B. anthracis infection. Cephalosorins and trimethoprim-sulfamethoxazole should not be used for therapy. Regimens being used to treat patients described in this report include ciprofloxacin, rifampin, and vancomycin; and ciprofloxacin, rifampin, and clindamycin.

Penicillin is labelled for use to treat inhalational anthrax. However, preliminary data indicate the presence of constitutive and inducible beta-lactamases in the B. anthracis isolates from Florida, NYC, and DC. Thus, treatment of systemic B. anthracis infection using a penicillin alone (i.e., penicillin G and ampicillin) is not recommended. The B. anthracis genome sequence shows that this organism encodes two beta-lactamases: a penicillinase and a cephalosporinase. Data in the literature also show that some beta-lactamase negative B. anthracis strains for which the penicillin MICs are 0.06 µg/mL increase to 64 µg/mL and become beta-lactamase positive when exposed to semisynthetic penicillins ⁽⁴⁾. The frequency of this induction event is unknown. Although amoxicillin/clavulanic acid is more active than amoxicillin alone against beta-lactamase, producing strains in vitro, the combination may not be clinically effective for inhalational anthrax where large numbers of organisms are likely to be present.

Toxin-mediated morbidity is a major complication of systemic anthrax. Corticosteroids have been suggested as adjunct therapy for inhalational anthrax associated with extensive edema, respiratory compromise, and meningitis ⁽⁵⁾.

For cutaneous anthrax, ciprofloxacin and doxycycline also are first-line therapy (Table 2). As for inhalational disease, intravenous therapy with a multidrug regimen is recommended for cutaneous anthrax with signs of systemic involvement, for extensive edema, or for lesions on the head and neck (Table 2). In cutaneous anthrax, antimicrobial treatment may render lesions culture negative in 24 hours, although progression to eschar formation still occurs⁽⁵⁾. Some experts recommend that corticosteroids be considered for extensive edema or swelling of the head and neck region associated with cutaneous anthrax. Cutaneous anthrax is typically treated for 7-10 days; however, in this bioterrorism attack, the risk for simultaneous aerosol exposure appears to be high. Although infection may produce an effective immune response, a potential for reactivation of latent infection may exist. Therefore, persons with cutaneous anthrax associated with this attack should be treated for 60 days.

Prophylaxis for inhalational anthrax exposure has been addressed in a previous report ⁽¹⁾ and indicates the use of either ciprofloxacin or doxycycline as first line agents. High-dose penicillin (e.g., amoxicillin or penicillin VK) may be an option for antimicrobial prophylaxis when ciprofloxacin or doxycycline are contraindicated. The likelihood of beta-lactamase induction events that would increase the penicillin MIC is lower when only small numbers of vegetative cells are present, such as during antimicrobial prophylaxis.

All medications may have undesirable side effects and allergic reactions may result from any medication. Clinicians prescribing these medications should be aware of their side effects and consult an infectious disease specialist as needed. Patients should be urged to inform their health-care provider of any adverse event.

This is the first bioterrorism-related anthrax attack in the United States, and the public health ramifications of this attack continue to evolve. Additional updates and recommendations will be published in MMWR.

Table 1. Inhalational anthrax treatment protocol for cases associated with

this bioterrorism attack

Category

Adults

Initial therapy (intravenous) Duration

Ciprofloxacin 400 mg every 12 hrs* IV treatment initially **. Switch to oral

or antimicrobial therapy when clinically

appropriate:

Doxycycline 100 mg every 12 hrs^††Ciprofloxacin 500 mg po BID

and or

One or two additional antimicrobials¶ Doxycycline 100 mg pg BID

Continue for 60 days (IV and po

combined)

Children

Ciprofloxacin 10-15 mg/kg every 12h¶¶*** IV tratment initially**. Switch to oral

or antimicrobial therapy when clinically

Doxycycline:†††,¶¶ appropriate:

>8 yrs and >45 kg: 100 mg every 12 hrs Ciprofloxacin 10-15 mg/kg po

>8 yrs and £ 2.2 mg/kg every 12 hrs every 12 hours***

£ 8 yrs: 2.2 mg/kg every 12 hrs or

and Doxycycline:†††

One or two additional antimicrobials¶ >8 yrs and >45 kg: 100 mg BID

>8 yrs and £ 2.2 mg/kg po BID

£ 8 yrs: 2.2 mg/kg po BID

Continue for 60 days {IV and po

combined}

Pregnant

women

Immunocompro-

mised person

Same for nonpregnant adults (the high IV treatment initially. Switch to

deatgh rate from the infection outweights or antimicrobial therapy when

the risk posed by the antimicrobial agent) clinically appropriate.† Oral therapy

regimens same for nonpregnant adults.

Same for nonimmunocompromised Same for nonimmunocompromised

persons and children persons and children

*For gastrointestinal and oropharyngeal anthrax’ use regimens recommended for inhalational anthrax.

† Ciprofloxacin or doxycycline should be considered an essential part of first-line therapy for Inhalational anthrax.

§Steroids may be considered as an adjunct therapy for patients with severe edema and for meningitis based on experience with bacterial meningitis of other etiologies.

¶Other agents with in vitro activity include rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin. Because of concerns of constitutive and inducible beta-lactamases in Bacillus anthracis, penicillin and ampicillin should not be used alone. Consultation with an infectious disease specialist is advised.

** Initial therapy may be altered based on clinical course of the patient; one or two antimicrobial agents (e.g., ciprofloxacin or doxycycline) may be adequate as the patient improves.

††If meningitis is suited doxycycline may be less optimal because of poor central nervous system penetration.

§§Because of the potential persistence of spores after an aerosol exposure, antimicrobial therapy should be continued for 60 days.

¶¶ If intravenous ciprofloxacin is not available, oral ciprofloxacin may be acceptable because it is rapidly and well absorbed from the gastrointestinal tract with no substantial loss by first-pass metabolism. Maximum serum concentrations are affairs 1-2 hours after oral dosing but may achieved if vomiting or ileus are present.

††† The American Academy of Pediatrics recommends treatment of young children with tetracycline for serious infections (e.g., Rocky Mountain spotted fever).

¶¶ If intravenous ciprofloxacin is not available, oral ciprofloxacin may be acceptable because it is rapidly and well absorbed from the gastrointestinal tract with no substantial loss by first-pass metabolism.Maximum serum concentrations are affairs 1-2 hours after oral dosing but may achieved if vomiting or ileus are present.

††† The American Academy of Pediatrics recommends treatment of young children with tetracycline for serious infections (e.g., Rocky Mountain spotted fever).

§§§Although tetracyclines are not recommended during pregnancy, their use may be indicated for life-threatening illness. Adverse effects on developing teeth and bones are dose related therefore doxycycline might be used for a short time 47-14 days) before 6 months of gestation.

Anthrax is an acute infectious disease caused by the bacterium Bacillus anthracis. Children, like adults, may be affected by three clinical forms: cutaneous, inhalational, or gastrointestinal.

The symptoms and signs of anthrax infection in children older than 2 months of age are similar to those in adults. The clinical presentation of anthrax in young infants is not well defined. When children become ill and present for treatment, making a diagnosis may be more difficult than in adults because young children have difficulty reporting what has happened to them or telling a doctor exactly how they feel. Because respiratory illnesses are much more common in children than adults, the examining clinician should have an understanding of disease manifestations in children.

The following are clinical descriptions (based on experience with adults) of the three forms of anthrax (MMWR 2001;50(41):889-893).

Neither CDC nor the American Academy of Pediatrics (AAP) recommend dispensing antibiotics for parents to have on hand in case of a possible exposure to Bacillus anthracis. CDC and its partner organizations will dispense antibiotics through the National Pharmaceutical Stockpile (NPS) program if exposure occurs. The NPS was designed to ensure the availability of lifesaving pharmaceuticals; antimicrobials; chemical interventions; and medical, surgical, and patient-support supplies, as well as equipment for prompt delivery to disaster sites. Disasters include a possible biological or chemical terrorist event anywhere in the United States. For more detailed information about the NPS, see CDC’s Web site at www.bt.cdc.gov.

At this time, anthrax vaccine is not recommended for people younger than 18 years of age. Military personnel and civilians at high risk for repeated exposure (e.g., laboratory workers handling powders containing Bacillus anthracis may benefit from the vaccine.

Post-exposure prophylaxis is indicated to prevent inhalational anthrax after a confirmed or suspected aerosol exposure to Bacillus anthracis. Consultation with public health authorities is strongly encouraged to identify people who should receive prophylaxis. When no information is available about the antimicrobial susceptibility of the implicated strain of Bacillus anthracis, CDC recommends initial therapy with either ciprofloxacin or doxycycline for children, as follows:

Reference: CDC. Update: Investigation of anthrax associated with intentional exposure and interim public health guidelines, October, 2001. MMWR 2001;50 (41):889-893.

The National Pharmaceutical Stockpile (NSP) contains oral and liquid types of both drugs for use by children who are too small to tolerate pills. Both tetracyclines and fluoroquinolones can cause adverse health effects in children. These risks must be weighed carefully against the risk of developing a life-threatening disease due to Bacillus anthracis. As soon as the penicillin susceptibility of the organism has been confirmed, prophylactic therapy for children should be changed to oral amoxicillin 80 mg/kg of body mass per day divided every 8 hours (not to exceed 500 mg three times daily). The NSP also includes amoxicillin suspension for children. Bacillus anthracis is not susceptible to cephalosporins or to trimethoprim/sulfamethoxazole, and these agents should not be used for prophylaxis.

Some antibiotics and other treatments that have proven effective against anthrax in adults have not been studied as extensively in children. Therefore, CDC provides the following recommendations for treating anthrax in children:

Initial Therapy (intravenous)

Duration

Ciprofloxacin* 10-15 mg/kg/dose

every 12 hrs.

Doxycycline:¶

> 8 years and 45 kg: 100 mg every 12 hrs.

> 8 years and 45 kg or less: 2.2 mg/kg/dose

every 12 hours

8 years or younger: 2.2 mg/kg/dose

every 12 hrs

and

One or two additional antimicrobial§

IV treatment initially. Switch to oral antimicro-

bial therapy when clinically appropriate:

Ciprofloxacin 10-15 mg/kg/dose po every 12 hrs

every 12 hours

Doxycycline:¶

8 years and > 45 kg: 100 mg po BID

> 8 years and 45 kg or less:

2.2 mg/kg/dose po BID

8 years or younger: 2.2 mg/kg/dose po BID

and

Continue for 60 days (IV and po combined)

Antimicrobial therapy should be continued for 60 days because of the potential persistence of spores after an aerosol exposure. Initial therapy may be altered on the basis of the clinical course of the patient; one or two antimicrobial agents (e.g., ciprofloxacin or doxycycline) may be adequate as the patient improves.

*If intravenous ciprofloxacin is not available, oral ciprofloxacin may be acceptable because it is rapidly and well absorbed from the gastrointestinal tract with no substantial loss by first-pass metabolism. Maximum serum concentrations are attained 1 to 2 hours after oral dosing but may not be achieved if vomiting or ileus is present. In children, ciprofloxacin dosage should not exceed 1 g/day.

¶ The AAP recommends treatment of young children with tetracyclines for serious infections (e.g., Rocky Mountain spotted fever). If meningitis is suspected, doxycycline may be less optimal because of poor central nervous system penetration.

§Other agents with in vitro activity include rifampin, vancomycin, penicillin, ampicillin, chloramphenicol, imipenem, clindamycin, and clarithromycin. Because of concerns of constitutive and inducible beta-lactamases in Bacillus anthracis isolates involved in the current bioterrorist attack, penicillin and ampicillin should not be used alone. Consultation with an infectious disease specialist is advised.

Cutaneous anthrax with signs of systemic involvement, extensive edema, or lesions on the head or neck requires intravenous therapy, and a multidrug approach is recommended. Ciprofloxacin or doxycycline should be considered first-line therapy. Amoxicillin 80 mg/kg/day divided every 8 hours is an option for completion of therapy after clinical improvement, if the organism is susceptible.

Previous guidelines have suggested treating cutaneous anthrax for 7 to 10 days, but 60 days is recommended in the setting of this attack, given the likelihood of exposure to aerosolized Bacillus anthracis.

For gastrointestinal and oropharyngeal anthrax, use regimens recommended for inhalational anthrax.

Children are more likely than adults to suffer side affects from some antibiotics used to prevent or treat the disease. If a child does develop side effects, testing should be done to determine whether the bacteria to which the child was exposed are susceptible to other drugs with fewer side effects, such as amoxicillin.

The American Academy of Pediatrics offers more extensive information about children and anthrax at its Web site, http://www.aap.org/advocacy/releases/smlpoxanthrax.htm. For information related to preparedness and bioterrorism, see CDC’s Web site at http://www.bt.cdc.gov.

Clinical features Human anthrax has three major clinical forms depending on the route of infection: cutaneous, inhalation, and gastrointestinal. Cutaneous anthrax begins as a pruritic papule or vesicle that enlarges and erodes (1-2 days) leaving a necrotic ulcer with subsequent formation of a central black eschar; inhalation anthrax may begin as a prodrome of fever, chills, nonproductive cough, chest pain, headache, myalgias, and malaise, with more distinctive clinical hallmarks of hemorrhagic mediastinal lymphadenitis, hemorrhagic pleural effusions, bacteremia and toxemia resulting in severe dyspnea, hypoxia and septic shock; gastrointestinal anthrax may result in pharyngeal lesions with sore throat, dypshagia marked neck swelling and regional lymphadenopathy, or intestinal infection characterized by fever, severe abdominal pain, massive ascites, hematemesis, and bloody diarrhea. As with any form of anthrax, hemorrhagic meningitis can result from hematogenous spread of the organism from the primary site.

Etiologic agent Bacillus anthracis is an encapsulated gram-positive, nonmotile, aerobic, spore-forming bacterial rod with a spore size of approximately 1 m x 2 m. The three virulence factors of B. anthracis are edema toxin, lethal toxin, and an antiphagocytic capsular antigen. The toxins are responsible for the primary clinical manifestations of hemorrhage, edema, and necrosis.

Incidence In the United States, incidence of naturally acquired anthrax is extremely rare (~ 1-2 cases of cutaneous disease per year). Gastrointestinal anthrax is rare, but may occur as explosive outbreaks associated with ingestion of infected animals. Worldwide, the incidence is unknown, though B. anthracis is present in most of the world. Unreliable reporting makes it difficult to estimate the true incidence of human anthrax worldwide. However, in fall 2001, 22 cases of anthrax (11 inhalation, 11 cutaneous) were identified in the United States following intentional contamination of the mail.

Sequelae If untreated, anthrax in all forms can lead to septicemia, hemorrhagic meningitis, and death. The case fatality ratio for patients with appropriately treated cutaneous anthrax is usually <1%, but for inhalation or gastrointestinal disease it can exceed 50%. Case-fatality rates for inhalation anthrax are high, even with appropriate antibiotics and supportive care. Among the eighteen cases of inhalation anthrax in the United States during the twentieth century, the overall case fatality was >75%. Following the bioterrorist attack in fall 2001, the case-fatality rate among patients with inhalation disease was 45% (5/11). The case-fatality rate of gastrointestinal anthrax is unknown but is estimated to be 25%-60%.

Transmission For humans, the source of infection in naturally acquired disease is through contact with infected livestock, wild animals, or contaminated animal products (including carcasses, hides, hair, wool, meat, and bone meal). Person-to-person transmission is extremely unlikely and only reported with cutaneous anthrax where discharges from cutaneous lesions are potentially infectious.

Risk groups Cutaneous anthrax is the most common manifestation of naturally acquired infection with B. anthracis. Inhalation (pulmonary) anthrax occurs in persons working in certain occupations where spores may be aerosolized from contaminated animal products, such as animal hair processing or through intentional release. Occupational risk groups include those coming into contact with livestock or products from livestock, e.g., veterinarians, animal handlers, abattoir workers, and laboratorians.

Surveillance For both livestock and humans, anthrax is a notifiable disease in the United States.

Trends In the United States, the annual incidence of naturally occurring human anthrax declined from estimated 130 cases annually in the early 1900’s to 2 cases each in 2000, 2001, and 2002. The recent cases of anthrax that occurred after B. anthracis spores were distributed through the U.S. mail have further underscored the potential dangers of this organism as a bioterrorism threat. In addition to aerosolization, there is a theoretical health risk associated with B. anthracis spores being introduced into food products or water supplies.

This drug belongs to a class of drugs called quinolone antibiotics. You have been given this drug for protection against possible exposure to an infection-causing bacteria. This drug prevents:

You have been provided a limited supply of medicine. Local emergency health workers or your healthcare provider will inform you if you need more medicine after you finish this supply. If so, upon your follow-up visit, you will be told how to get more medicine. You will be told if no more medicine is needed. You may also be switched from this medicine to a different medicine based on laboratory tests.

Keep taking your medicine, even if you feel okay, unless your doctor tells you to stop. If you stop taking this medicine too soon, you may become ill.

You should take this medicine with a full glass of water. Drink several glasses of water each day while you are taking this medicine. It is best to take this medicine 2 hours after a meal. If it upsets your stomach, you may take it with food, but do not take it with milk, yogurt, or cheese.

If you miss a dose, take the missed dose as soon as possible. If it is almost time for your next regular dose, wait until then to take your medicine, and skip the missed dose. Do not take two doses at the same time.

Drugs and foods to avoid : Do not take the following drugs within 2 hours of taking Ciprofloxocin: antacids such as Maalox or Mylanta, vitamins, iron supplements, zinc supplements, or sucralfate (Carafate). You may take them 2 hours after or 6 hours before Ciprofloxocin. Also, make sure your doctor knows if you are taking asthma medicine like theophylline, gout medicine like probenecid (Benemid), or a blood thinner such as Coumadin.

Avoid drinking more than one or two caffeinated beverages (coffee, tea, soft drinks) per day. Avoid taking this medicine with foods containing large amounts of calcium, like milk, yogurt, or cheese.

Warnings: If you have epilepsy or kidney disease, or if you are pregnant, become pregnant, or are breastfeeding, notify emergency healthcare workers before you start taking this medicine.

Do not take this medicine if you have had an allergic reaction to ciprofloxacin or other quinolone medicines such as norfloxacin (Noroxin), ofloxacin (Floxin) or nalidixic acid (NegGram).

This medicine may make you dizzy or lightheaded. Avoid driving or using machinery until you know how it will affect you.

This medicine increases the chance of sunburn; make sure to use sunscreen to protect your skin.

Side effects : Call your doctor or seek medical advice right away if you are having any of these side effects: rash or hives; swelling of face, throat, or lips; shortness of breath or trouble breathing; seizures; or severe diarrhea. Less serious side effects include nausea, mild diarrhea, stomach pain, dizziness, and headache. Talk with your doctor if you have problems with these side effects.

This drug belongs to a class of drugs called tetracycline antibiotics. You have been given this drug for protection against possible exposure to an infection-causing bacteria. This drug prevents:

You will be provided special dosing instructions for treatment of children under 8 years of age.

Keep taking your medicine, even if you feel okay, unless your healthcare provider tells you to stop. If you stop taking this medicine too soon, you may become ill.

You may take your medicine with or without food or milk, but food or milk may help you avoid stomach upset.

Drugs and foods to avoid : Do not take the following medicines within 2 hours of taking

Doxycycline : antacids such as Maalox or Mylanta, calcium or iron supplements, cholestyramine (Questran) or colestipol (Colestid).

While you are taking this medicine, birth control pills may not work as well; make sure to use another form of birth control.

Warnings : If you have liver disease, or if you are or might be pregnant, or if you are breastfeeding, tell emergency healthcare workers before you start taking this medicine.

This medicine increases the chance of sunburn; make sure to use sunscreen to protect your skin.

Do not take this medicine if you have had an allergic reaction to any tetracycline antibiotics.

Side effects : Call your doctor or seek medical attention right away if you are having any of these side effects: skin rash, hives, or itching; wheezing or trouble breathing; swelling of the face, lips, or throat. Less serious side effects include diarrhea, upset stomach, nausea, sore mouth or throat, sensitivity to sunlight, or itching of the mouth or vagina lasting more than 2 days. Talk with your doctor if you have problems with these side effects.

This drug treats infections. It belongs to a class of drugs called penicillin antibiotics. You have been given this drug for protection against possible exposure to infection-causing bacteria. This drug treats:

Keep taking your medicine, even if you feel okay, unless your healthcare provider tells you to stop. If you stop taking this medicine too soon, you may become ill.

You may take your medicine with or without food or milk, but food or milk may help you avoid stomach upset.

Drugs and foods to avoid: Make sure your healthcare provider knows if you are taking the medication Probenecid. Probenecid causes penicillin to build up in the blood, which may increase your chance of having side effects.

While you are taking this medicine, birth control pills may not work as well; make sure to use another form of birth control.

Warnings : Make sure your healthcare provider knows if you are pregnant or breast-feeding. Penicillins as a class are generally considered safe for use in pregnancy. Research suggests that it is unlikely that penicillin causes birth defects when taken by pregnant women. Penicillin passes into breast milk, though only in small amounts, and may cause allergic reactions, diarrhea, fungus infections, and skin rash in nursing babies.

Do not take this medicine if you have had an allergic reaction to penicillin or cephalosporin antibiotics such as Keflex or Ceclor.

Side effects: Call your doctor or seek medical attention right away if you are having any of these side effects: wheezing or trouble breathing; skin rash, hives or itching; swelling of the face, lips, or throat; or severe diarrhea. Less serious side effects include mild diarrhea, nausea, upset stomach, sore throat or mouth, itching of the mouth or vagina lasting more than 2 days. Talk with your doctor if you have problems with these side effects.

Patient Information: Amoxicillin 250 MG – Oral Capsules Or Amoxicillin 250 MG/5 ML– Oral Suspension

Drugs and foods to avoid : Make sure your healthcare provider knows if you are taking the medication Probenecid. Probenecid causes amoxicillin to build up in the blood, which may increase your chance of having side effects.

While you are taking this medicine, birth control pills may not work as well; make sure to use another form of birth control.

Warnings : Make sure your healthcare provider knows if you are pregnant or breast-feeding. An expert review of published data on experiences with amoxicillin use during pregnancy concluded that therapeutic doses during pregnancy are unlikely to pose a substantial risk for birth defects. However, there are no data available to assess the effects of long-term therapy in pregnant women, such as that proposed for treatment of anthrax exposure. Amoxicillin passes into breast milk but is considered "usually compatible with breastfeeding" by the American Academy of Pediatrics.

Do not take this medicine if you have had an allergic reaction to amoxicillin or penicillin or cephalosporin antibiotics such as Keflex or Ceclor.

Side effects : Call your doctor or seek medical attention right away if you are having any of these side effects: wheezing or trouble breathing; skin rash, hives or itching; swelling of the face, lips, or throat; or severe diarrhea. Less serious side effects include mild diarrhea, nausea, upset stomach, sore throat or mouth, itching of the mouth or vagina lasting more than 2 days. Talk with your doctor if you have problems with these side effects.

On November 18, 2001, a meeting was held at the Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, to discuss the prophylaxis, diagnosis, and treatment of anthrax. Participants included clinicians and health department personnel from areas where anthrax cases were identified, infectious disease experts, representatives of professional societies, and experts from federal agencies. A patient recovering from inhalational anthrax also described her illness. The following is a summary of the presentations and discussion.

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 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.

Of the 11 patients with inhalational anthrax, 9 (and possibly all 11) are believed to have been exposed to mail containing or contaminated with B. anthracis spores. Median age was 56 years (range 43-94 years). Average incubation from known exposure to symptoms was 4 days (range 4-6 days). Fever, chills, drenching sweats, profound fatigue, minimally productive cough, nausea or vomiting, and chest discomfort were symptoms reported by most patients. Rhinorrhea and productive cough were uncommon. Chest X-ray at initial examination showed mediastinal widening, paratracheal fullness, hilar fullness, and pleural effusions or infiltrates or both, but in some patients these initial findings were subtle. Pleural effusions were a complication in all 11 patients; among all 8 patients who had not received antibiotics, B. anthracis grew in blood cultures drawn at initial examination. Six (55%) of 11 patients have survived with aggressive supportive care and multidrug antibiotic regimens including a fluoroquinolone⁽¹¹⁾ .

The differential diagnosis of inhalational anthrax versus influenza-like illness is challenging. Respiratory viruses, including influenza, are common causes of influenza-like illness and tend to circulate in winter. These viruses are readily communicable, in contrast to anthrax, which is not spread from person to person. A history of influenza vaccination is not helpful in evaluating the likelihood of anthrax. Influenza-like illnesses have many causes besides influenza viruses, and influenza vaccine is not 100% effective. Unlike patients with inhalational anthrax, adults with influenza or other viral respiratory illnesses do not usually have shortness of breath and vomiting but often have sore throat or rhinorrhea. Rapid identification tests for influenza are available but vary widely in sensitivity.

In the current climate, emergency department and primary-care physicians should maintain a high index of suspicion for inhalational anthrax. Complicating diagnosis is the fact that patients initially may not appear very ill ⁽¹¹⁾. A careful history with assessment of epidemiologic risk factors for anthrax (e.g., working for the postal service) should be obtained. Communication between clinicians and health authorities is critical for obtaining up-to-date assistance with diagnosis and management.

The classic chest X-ray findings—widened mediastinum or pleural effusions—may be subtle or absent on initial medical evaluation. In addition, these radiographic findings are not unique to anthrax: histoplasmosis, sarcoidosis, tuberculosis, and lymphoma, for example, are included in the differential diagnosis. A chest computed tomography scan is helpful in detecting hemorrhagic mediastinal lymph nodes and edema, peribronchial thickening, and pleural effusions, findings seen in patients with inhalational anthrax.

Hyperdense mediastinal and hilar adenopathy plus mediastinal edema suggest anthrax. The hemorrhagic pleural effusions of inhalational anthrax typically increase during hospitalization.

Blood cultures and B. anthracis-specific polymerase chain reaction (PCR) of sterile fluids (e.g., blood and pleural fluid) are important in the diagnosis of inhalational anthrax. Serologic testing has also been valuable. An enzyme-linked immunosorbent assay (ELISA) to detect immunoglobulin (Ig) G response to B. anthracis protective antigen (PA) is highly sensitive (detects 98.6% of true positives) but is only approximately 80% specific. To improve specificity, a PA-competitive inhibition ELISA is used as a second, confirmatory step. Preliminary studies indicate that specific IgG anti-PA antibody can be detected as early as 10 days, but peak IgG may not be seen until 40 days after onset of symptoms.

Immunohistochemical examination of pleural fluid or transbronchial biopsy specimens, using antibodies to B. anthracis cell wall and capsule, also has an important role in the diagnosis of inhalational anthrax, especially in patients who have received prior antibiotics. Immunohistochemical examination can detect intact bacilli or B. anthracis antigens. PCR, serologic tests, and immunohistochemical tests are currently available at CDC or at certain laboratories in the Laboratory Response Network (LRN).

Seven confirmed and four suspected cases of cutaneous anthrax were identified during the 2001 outbreak. Skin trauma was not associated with these cases of cutaneous anthrax. Exposure to contaminated mail was the apparent source of infection in all patients. The incubation periods after exposure ranged from 1 to 10 days. The initial symptom was often a pruritic papule resembling an insect bite. The papules vesiculated, with some becoming hemorrhagic. The vesicles ruptured to form depressed ulcers, often with local edema, ultimately forming dry eschars. These stages occur regardless of antibiotic therapy. The differential diagnosis of cutaneous anthrax includes brown recluse spider bite, ecthyma, ulceroglandular tularemia, accidental vaccinia, and necrotic herpes simplex. Cutaneous anthrax is painless, does not include rash, and results in a black eschar. Patients with cutaneous anthrax may have fever, extensive edema, and other systemic signs.

Gram stain and culture of the lesion are recommended; however, prior antibiotic treatment rapidly renders the infected site culture-negative for B. anthracis . Serologic testing and punch biopsy at the edge of the lesion, examined by silver staining and immunohistochemical testing, are useful in diagnosing cutaneous anthrax in patients who have received antibiotic therapy.

Clinical recognition and diagnosis issues needing further consideration and research include rapid, reliable, and readily available detection methods (e.g., PCR and antigen detection); education and ready access to information for clinicians regarding anthrax clinical features and risk stratification; recognition of anthrax in children; and the role of serologic testing in the diagnosis and management of both inhalational and cutaneous anthrax.

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 also 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.

v Additional Options for Preventive Treatment For Those Exposed to Inhalational Anthrax

Many of those who were exposed to inhalational anthrax in the recent mail attacks are presently concluding their 60-day course of preventive antibiotic treatment. Some of these persons, especially those who may have been exposed to very high levels of anthrax spores, may wish to take additional precautions. The Department of Health and Human Services (HHS) is providing two additional options beyond the 60-day antibiotic course, for those who may wish to pursue them: an extended course of antibiotics, and investigational post-exposure treatment with anthrax vaccine.

HHS will make anthrax vaccine available to those who were exposed to inhalational anthrax, who have concluded their antibiotic treatment and who wish to receive the vaccine as an investigational product. The vaccine is being made available in this investigational mode, under an investigational new drug application (IND) at the option of the individual, in recognition of the limited nature of the data now available concerning inhalation anthrax treatment and the factors underlying development of the disease, as well as uncertainty concerning the extent of exposure to spores that some persons may have received in the recent anthrax incidents. The decision to use this vaccine is at the discretion of the individual, in consultation with his or her physician.

Existing data, based especially on animal models, indicate that inhalational anthrax is unlikely to occur after 60 days following exposure. This is the basis of the recommendation for 60 days treatment with an effective antibiotic. So far, no known cases have developed in individuals who were recently exposed to inhalation anthrax and who were prescribed the 60-day antibiotic course. HHS health agencies continue to recommend that those who were prescribed the 60-day antibiotic course and who conclude this course of treatment, or who stopped taking the medicine prior to 60 days, should remain watchful of their health and be in close communication with a physician who is aware of their exposure status. A number of individuals have already concluded the 60-day course, or have stopped taking the antibiotics prior to the 60-day conclusion, and no cases have been reported among them.

At the same time, other animal data indicate that live spores may continue to reside in the lungs beyond the 60-day period, even though these animals did not develop disease. Traces of live spores have been detected in the lungs up to 100 days following exposure. This raises the theoretical possibility that the spores remaining in the lung area might still, after 60 days, result in anthrax.

If such a late infection were to occur, HHS scientists believe that the infection could be successfully treated, as were cases of inhalation anthrax that were identified early during the anthrax mail attacks. At the same time, HHS recognizes that some individuals may wish to take extra precautions, especially those whose exposure may have been especially high.

All those who are concluding a 60-day course of antibiotic treatment should monitor their health and be in close contact with their physician. Those who may wish to continue taking antibiotics for an additional 40 days should consult their physician about this course. Those who may wish to take part in the investigational post-exposure use of the anthrax vaccine should consult their physician or a physician at the site where vaccine is being administered.

Table 1. Diagnosis of Inhalational Infection
Epidemiology	Sudden appearance of multiple cases of severe flu like illness with fulminant course and high mortality
Diagnostic studies Microbiology	Chest radiograph: widened mediastinum Peripheral blood smear: gram-positive bacilli on unspun smear
Diagnostic studies Microbiology	Blood culture growth of large gram-positive bacilli with preliminary identification of Bacillus species
Pathology	Hemorrhagic mediastinitis, hemorrhagic thoracic lymphadenitis, hemorrhagic meningitis

Cause	Bacillus anthracis
	Encapsulated, aerobic, gram-positive, spore-forming, rod-shaped (bacillus) bacterium
Systems affected	Skin or cutaneous (most common) Respiratory tract or inhalational (rare) Gastrointestinal (GI) tract (rare) Oropharyngeal form (least common)
Transmission	Skin: direct skin contact with spores; in nature, contact with infected animals or animal products (usually related to occupational exposure) Respiratory tract: inhalation of aerosolized spores GI: consumption of undercooked or raw meat products or dairy products from infected animals No person-to-person transmission of inhalational or GI anthrax
Reporting	Report suspected or confirmed anthrax cases immediately to your local or state department of health.
Cutaneous Anthrax
Incubation period	Usually an immediate response up to 1 day
Typical signs/symptoms	Local skin involvement after direct contact with spores or bacilli Localized itching followed by 1) papular lesion that turns vesicular and 2) subsequent development of black eschar within 7–10 days of initial lesion
Treatment (See Cutaneous Anthrax Treatment Protocol for specific therapy)	Obtain specimens for culture Before initiating antimicrobial therapy. Do Not use extended-spectrum cephalosporins or trimethoprim/sulfamethoxazole because anthrax may be resistant to these drugs.
Precautions	Standard contact precautions. Avoid direct contact with wound or wound drainage.
Inhalational Anthrax
Incubation period	Usually <1 week; may be prolonged for weeks (up to 2 months)
Typical signs/ symptoms often biphasic, but symptoms may progress	Initial phase Subsequent phase • Non-specific symptoms such • 1–5 days after onset of as low-grade fever, nonproductive initial symptoms cough, malaise, rapidly fatigue, • May be preceded by 1-3 days myalgias, profound sweat, chest of improvement discomfort (upper respiratory • Abrupt onset of high fever and tract symptoms are rare) severe respiratory distress • Maybe rhonchi on exam, (dyspnea, stridor, cyanosis) otherwise normal • Shock, death within 24-36 • Chest X-ray: hours � mediastinal widening � pleural effusion (often) � infiltrates (rare)
Laboratory	• Coordinate all aspects of testing, Clues to diagnosis packaging, and transporting with • Gram-positive bacilli on unspun public health laboratory/Labora- peripheral blood smear or CSF tory Response Network (LRN). • Aerobic blood culture • Obtain specimens appropriate growth of large, gram-positive to system affected: bacilli provides preliminary � blood (essential) identification of Bacillus � pleural fluid species. � cerebral spinal fluid (CSF) skin lesion
Treatment (See (Inhalational Anthrax Treat- ment Protocol for specific therapy)	• Obtain specimens for culture Before initiating antimicrobial therapy. • Initiate antimicrobial therapy immediately upon suspicion. • Do Not use extended-spectrum-cephalosporins or trimethoprim/ sulfamethoxazole because anthrax may be resistant to these drugs. • Supportive care including controlling pleural effusions
Precautions	Standard contact precautions
Gastrointestinal Anthrax
Incubation period	Usually 1–7 days
Typical signs/symptoms	Initial phase Subsequent phase • Nausea, anorexia, vomiting, • 2–4 days after onset of and fever progressing to severe symptoms, ascites develops abdominal hematemesis, as abdominal pain decreases and diarrhea that is almost • Shock death within 2–5 always bloody days of onset • Acute abdomen picture with rebound tenderness may develop. • Mesenteric adenopathy on computed tomography (CT) scan likely. Mediastinal widening on chest X-ray has been reported
Laboratory	• Coordinate all aspects of testing, Clues to diagnosis packaging, and transporting with • Gram-positive bacilli on public health laboratory/LRN. unspun peripheral blood • Obtain specimens appropriate to smear or ascitic fluid system affected: • Pharyngeal swab for � blood (essential) pharyngeal form � ascitic fluid • Aerobic blood culture growth of large, gram- positive bacilli provides preliminary identification of Bacillus species.
Treatment (See Inhalational Anthrax Treatment Protocol for specific therapy)	• Obtain specimens for culture before initiating antimicrobial therapy. • Early (during initial phase) antimicrobial therapy is critical. • Do NOT use extended-spectrum cephalosporins or trimethoprim/sulfamethoxazole because anthrax may be resistant to these drugs.
Precautions	• Standard precautions
Oropharyngeal Anthrax
Incubation period	• Usually 1–7 days
Typical signs/ symptoms	Initial phase Subsequent phase • Fever and marked unilateral and hyperemic or bilateral neck swelling • Ulcers may progress to caused by regional lymphade- necrosis nopathy • Swelling can be severe • Severe throat pain and enough to compromise dysphagia the airway • Ulcers at the base of the tongue, initially edematous
Laboratory	• Coordinate all aspects of • Aerobic blood culture testing, packing, and trans- growth of large, gram- porting with public health positive bacilli provides laboratory/LRN. preliminary identification • Obtain specimens appropriate of Bacillus species to system affected: � blood (essential) � throat
Treatment (See Anthrax Treatment Protocol for specific therapy)	• Obtain specimens for culture before initiating antimicrobial therapy. • Do not use extended-spectrum cephalosporins or trimethoprim/sulfame-thoxazole because anthrax may be resistant to these drugs. • Supportive care including controlling ascites
Precautions	Standard contact precautions

7.

Anthrax