October 2001                                        Bruce H. Woolley, Pharm.D., Editor                                        Vol. 8, No. 10
Kenneth J. Hunt, Associate Editor

Advisory to Clinicians on Biological Weapons

In the wake of recent threats of terrorist acts, including the use of biological weapons, it is essential that health professionals are able to recognize and treat early disease caused by hazardous organisms and to respond to requests from anxious patients in the setting of bioterrorism involving anthrax. For this reason, we would like to review the consensus recommendations for testing and treating persons suspected to have been infected with the organism.


Testing: It is not recommended that asymptomatic persons be tested, unless they have been in an area of known or suspected exposure. Swabbing the anterior nares and normal skin of unexposed persons for culture is a useful investigative measure, but results do not reliably predict risk of infection. Polymerase chain reaction (PCR) technology can be used for rapid testing with high sensitivity and specificity. Commercially available testing kits promoted for home use by consumers are not sufficiently sensitive or specific to justify their use.

Patients who are symptomatic early in the course of illness and in an area of documented or strongly suspected outbreak should be tested for anthrax. Testing is not recommended for worried but asymptomatic people or those with minor flu-like illness, gastroenteritis, or nonspecific rash not at reasonable risk of exposure. The gold standard for diagnosis is culture of the organism. Use proper procedures to ensure proper handling of materials and notify public health authorities.

Suspected inhalation anthrax presents as flu-like illness of fever, headache, and cough. To test, obtain blood cultures and sputum for Gram's stain and culture, notifying the lab of anthrax concern. Check a chest x-ray for widening mediastinum due to mediastinal node enlargement or mediastinitis. Cutaneous anthrax presents as a pruritic erythematous maculopapular lesion on area of exposed skin progressing within 12-48 hours to small ulceration with surrounding small vesicles, followed by painless enlarging ulcer with black eschar painful lymphadenopathy. Swab ulcer or carefully open vesicle and send for Gram's stain and culture. Obtain blood cultures if the patient is febrile. Gastrointestinal anthrax presents as oral or esophageal ulcer, nausea and vomiting, malaise, progressing to bloody diarrhea, acute abdomen. Diagnose by sending stool for Gram's stain and culture.

Treatment: Unless symptomatic, treating patients is only recommended for persons at high risk for exposure. There is no need to prescribe prophylactic antibiotics to those not at high risk or to treat family members in contact with exposed persons, since person-to-person transmission does not occur. Potentially exposed persons can be instructed to shower with soap and water and wash clothes in ordinary laundry detergent. If a patient is part of an exposed group, then begin oral fluoroquinolone therapy (ciprofloxacin 500 mg bid x 60 days or doxycycline 10 mg PO bid x 60 days). It is important to complete a full 60 days of prophylactic antibiotic therapy since the spores can take up to 60 days to germinate and cause infection.

For symptomatic patients with high probability of exposure, treat empirically but aggressively and early while awaiting culture results. Admit promptly to hospital and begin IV fluoroquinolone treatment (ciprofloxacin 400 mg IV q12h) or doxycycline (100 mg IV q12h). The CDC recommends the inclusion of an additional antibiotic, such as rifampin, imipenem, chloramphenicol, penicillen, ampicillin, clindamycin, or clarithromycin in order to counter risk of emerging antibiotic resistance. Clindamycin is used by many experts as one of the additional antibiotics because it may block new anthrax toxin production. Skin anthrax can be treated with a single drug, but treatment must be for 60 days since such exposed patients are still at risk for inhalation disease during that period.

Inglesby TV, Henderson DA, Ascher SM, et al. JAMA 1999;281:1735-1745.
Centers for Disease Control. Morbidity, Mortality Weekly Report: October 25, 2001


The other commonly feared weapon of bioterrorism is smallpox, an organism that vaccination essentially eradicated from the Western world and is, consequently no longer routinely vaccinated against. If such an attack is carried out in the United States, early recognition and treatment is imperative. A 12-14 day latency period is common prior to onset of symptoms, with rash and fever being first signs of disease. Onset consists typically of a centrifugal maculopapular rash, presenting most densely on the face and extremities. The rash progresses to vesicles within 1-2 days and then to pustules; crusts form by day 8 or day 9. Lesions appear deeply embedded in the skin and often include the palms and soles. Viral titers are greatest and the patient is the most infectious in the first week.

An estimated ten percent of patients present with atypical forms of the disease (e.g., hemorrhagic and malignant). Immunocompromised persons may be at heightened risk of presenting in this manner. In the hemorrhagic variety, a prodrome of severe prostration, high fever, headache, and abdominal pain is followed by dusky erythema, diffuse petechiae, and then frank hemorrhage into the skin and mucous membranes. The malignant form consists of abrupt onset of severe prodromal symptoms, followed by development of confluent maculopapular rash that does not become vesicular.

Collecting a sample for definitive diagnosis of an outbreak is essential if in a community has not yet been definitively confirmed. Once confirmed, additional sample collections are unnecessary. Persons who will collect specimens should already be vaccinated and should wear gloves and a mask, as lesions are highly infectious. Samples are best obtained from a recently formed vesicle. To take a sample, unroof an intact vesicle with a sharp instrument, collect the contents with a cotton swab, place the swab in a vacutainer tube, and seal it with tape. Place the sealed tube in a second watertight container, and contact public health authorities to retrieve the sample for laboratory testing at a specialized facility. Electron microscopy provides rapid initial identification, confirmed by growing the virus or using PCR assay techniques.

Vaccination is effective in preventing infection and death. Full immunity lasts about 10 years, thus anyone previously immunized is not presently considered immune because the last immunizations were in the 1970s. Although the risk for serious complications from smallpox vaccination is relatively small (1 in 300,000), the frequency of such risk gives public health authorities pause in ordering massive immunization of the population in the absence of an outbreak. Complications can be minimized with concurrent administration of vaccinia immune globulin (VIG). Supplies of vaccine and VIG are limited at present, stockpiled by the CDC, and available for rapid shipment to area(s) of outbreak.

Suspected cases should be isolated at home or in a non-hospital facility due to risk of spread in hospital. Contacts need not be isolated but should be monitored closely for 17 days (time from exposure to onset of first signs of clinical disease is 12-14 days). The best mode of monitoring is a daily evening temperature determination. If fever ensues, watch closely for rash and isolate if it develops (patients are not infectious until the rash is present). Although isolation may not be necessary for asymptomatic contacts, quarantine of an area of outbreak may be required and ordered by public health authorities.

Henderson DA, Inglesby TV, Bartlett JG, et al. JAMA 1999;281:2127-2137.

Blood Pressure and CVD Risk

High blood pressure has long been associated with elevated risk of cardiovascular disease. According to a recent report in the New England Journal of Medicine, a blood pressure that is currently classified as "high-normal" is associated with an increased risk of cardiovascular disease. The group conducting the Framingham Heart Study in Massachusetts has investigated the association between baseline blood pressure and cardiovascular disease incidence in 6859 subjects. About 25% of the subjects had high-normal blood pressure which is defined as a systolic pressure 130 to 139 mm Hg or diastolic pressure 85 to 89 mm Hg. A further third of the patients had normal blood pressure, defined as systolic pressure 120 to 129 mm Hg or diastolic pressure 80 to 84 mm Hg. Many of the remainder of the patients had optimal blood pressure.

According to the article, men under age 65 with high-normal blood pressure faced a 10-year cumulative cardiovascular disease incidence of 8%, a rate of 9.2 events per 1000 person-years. The rate in men over age 65 was especially high, 28.1 events per 1000 person-years, translating into a 10-year cumulative cardiovascular disease incidence of 25%. Results were similar among women. Younger women with high-normal blood pressure experienced 4.7 events per 1000 person-years. The older group of women experienced 19.5 events per 1000 person-years.

Compared with subjects having optimal blood pressure, those having high-normal blood pressure faced substantially higher hazard ratios for cardiovascular disease (2.5 for women and 1.6 for men), the researchers note. Normal blood pressure, too, elevated the risk of cardiovascular disease 1.5-fold for women and 1.3-fold for men compared with optimal pressure. According to the authors, there is a continuum of increased cardiovascular disease risk that begins at levels below what is currently regarded as hypertension. The finding that high-normal blood pressure is more akin to high blood pressure than it is to normal pressure is an advance in our understanding of the importance of hypertension as a risk for cardiovascular disease.

N Engl J Med 2001;345:1291-1297,1337-1340.

The First Hormonal Vaginal Contraceptive Ring

The FDA recently announced its approval of NuvaRing (etonogestrel and ethinyl estradiol ring), a vaginal contraceptive ring containing a combination of estrogen and progestin hormones released from a flexible polymer ring. The product is available by prescription only. The vaginal contraceptive ring, which is a new form of birth control, consists of a flexible, transparent, colorless vaginal ring about 2 inches in diameter containing the hormones etonogestrel and ethinyl estradiol, which are similar to the active ingredients in some oral contraceptives. After the ring is inserted, it releases a continuous low dose of the hormones. A new ring is used each month for continuous contraception.

The ring must be used as directed for maximum contraceptive effectiveness. A woman inserts the ring herself, and it should remain in the vagina for three weeks. She then removes the ring for one week during which she will have her menstrual period. Like oral contraceptives, NuvaRing is a highly effective contraceptive when used according to the labeling. There is a one to two percent chance of pregnancy per patient year. The patient brochure provides information about proper use, insertion, and removal, as well as storage and disposal of NuvaRing.

Side effects of NuvaRing may include vaginal discharge, vaginitis, and irritation. Like oral contraceptives, NuvaRing may increase the risk of blood clots, heart attack, and stroke. The labeling for NuvaRing also carries the warning that cigarette smoking increases the risk of serious cardiovascular side effects from combined hormonal contraceptive use, and therefore cautions that women who use NuvaRing should be strongly advised not to smoke. Patients who have not adhered to the prescribed regimen and who have missed a menstrual period should have a pregnancy test to rule out pregnancy.

The new vaginal ring was developed by Organon, Inc. Two large multi-center trials with more than 2,300 women were conducted in the United States, Canada, Europe, and Israel. The trials evaluated the product for its acceptability, contraceptive effectiveness, and safety. Women who have cardiovascular disease, blood clots, or certain types of cancer should not use NuvaRing.

Information from FDA Talk Paper, www.fda.gov/cder/

Bone Loss and Thyroid Hormone

It is known that bone remodeling is enhanced by thyroid hormones. Although the activity of both building and bone resorbing cells increase with elevated concentrations of thyroid hormones, it is resorption activity with consequential bone mass loss that prevails. Thyrotoxicosis is associated with elevated serum concentrations of osteocalcin and alkaline phosphatase; increased levels of these proteins are frequently accompanied by bone resorption. Elevated concentrations of these biochemical markers also seem to correlate with serum concentrations of thyroid hormones. However, the effects on bone metabolism of long-term treatment with thyroid hormone given at suppressive doses is poorly understood.

A recent study published in Medscape Women's Health, an online medical journal, was designed to determine whether long-term thyroxine therapy in the premenopausal period is a risk factor for the development of secondary osteoporosis and whether women receiving this therapy have increased bone loss during the premenopausal period.

The study group consisted of premenopausal women of mean ages 39 +/- 8 years, all of whom suffered from differentiated thyroid gland carcinoma. All subjects had undergone total thyroidectomy and subsequently initiated thyroxine suppressive therapy. The women had also been on suppressive therapy for an average of 9.4 years. Laboratory results were performed to exclude other possible factors for secondary osteoporosis. Bone mineral density (BMD) was conducted over a 4-year period on all subjects using the method of dual photon x-ray absorptiometry of the spine and the femoral neck and also by the method of single-photon absorptiometry of the distal radius.

Overall, nearly 50% of the women had osteopenia at the beginning of the study. A review of the individual scores revealed osteopenia in 6 patients at the distal radius; bone loss also occurred at the spine and the femoral neck in several women, but not to the extent that would establish osteopenia. After 4 years had passed, BMD measurements indicated significant bone loss. The results of this study suggest that women who begin long-term thyroxine therapy in the premenopausal period may be at greater risk of developing osteopenia by the beginning of menopause. Further research into the physiologic effects of thyroxine and potential prevention of medication-induced osteopenia is warranted.

Medscape Women's Health 6(5), 2001, www.medscape.com

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