The prophylaxis of tuberculosis is cost-effective in that it prevents hospitalizations and eliminates the need for multidrug treatment of active disease. Isoniazid is recommended for the prophylaxis of tuberculosis in patients with human immunodeficiency virus infection who have a positive tuberculin skin test, who have a history of a positive skin test, who have been in close contact with a person who has active tuberculosis or who are at high risk for tuberculosis because of certain behaviors or situations. Other patients with an altered immune status may also benefit from preventive therapy for tuberculosis. Of the atypical mycobacterial infections, only Mycobacterium avium-intracellulare complex disease (MAC) in AIDS patients has been effectively prevented. Rifabutin is now recommended for adult patients with CD4 counts below 100 per[mm.sup.3]. To prevent the selection of resistant organisms, active tuberculosis must be excluded before prophylactic therapy for tuberculosis or MAC is initiated.
Approximately 1.7 billion people (one third of the world's population) are infected with Mycobacterium tuberculosis. Each year, there are 8 million new cases of tuberculosis and nearly 3 million deaths from this disease.
For decades, immunosuppression has been recognized as a risk factor for tuberculosis. The estimated risk for active tuberculosis in some patient populations is shown in Table 1. Prevention of tuberculosis has become a crucial concern because of the resurgence of this disease worldwide and the increasing number of people infected with the human immunodeficiency virus (HIV).
Patients with carcinoma of the head and neck and patients who have undergone gastrectomy or jejunoileal bypass surgery may also be at increased risk for reactivation of dormant tuberculosis, most likely because of weight loss and malnutrition.[2,3,l6,l7] Preventive isoniazid therapy is generally recommended for these patients, as well as for patients with diabetes, transplant recipients and patients with chronic renal failure, although the value of such therapy requires further study.[18,19]
In the past, studies suggested that skin tests could be falsely negative secondary to suppressed cellular immunity during pregnancy. More well-designed studies have subsequently shown that the response to the tuberculin skin test is not affected measurably by pregnancy and that suppressed cellular immunity during pregnancy is not a predisposing condition for the development or progression of tuberculosis. Consequently, preventive isoniazid therapy in healthy pregnant women is usually delayed until after delivery.
Preventive Therapy for Multidrug-Resistant Mycobacterium tuberculosis
The U.S. Food and Drug Administration (FDA) has not approved any alternative regimens for prophylaxis if the infecting strain of M. tuberculosis is multidrug resistant (i.e., resistant to both isoniazid and rifampin). While many of the cases of multidrug-resistant tuberculosis have been reported in New York City, these strains can occur anywhere.
The most favored potential alternative regimens in HIV-positive patients are pyrazinamide, 25 to 30 mg per kg per day, plus ethambutol (Myambutol), 15 to 20 mg per kg per day, with both drugs given for 12 months. Alternatively, pyrazinamide plus a fluoroquinolone with reported in vitro activity against M. tuberculosis, such as ofloxacin (Floxin), 400 mg twice daily, or ciprofloxacin (Cipro), 750 mg twice daily, can be given for 12 months in HIV-infected patients. An aminoglycoside, such as streptomycin, kanamycin (Kantrex) or amikacin (Amikin), or the polypeptide antibiotic capreomycin (Capastat) may also be considered for inclusion in an alternative preventive therapy regimen. Side effects of these agents are listed in Table 3. Para-aminosalicylic acid, cycloserine (Seromycin) and ethionamide (Trecator-SC) are not recommended for preventive therapy because of their high frequency of side effects and their lower efficacy against M. tuberculosis.
Derived from Olin BR, ed. Drug facts and comparisons. St. Louis: Facts and Comparisons, 1996, and Brogden RN, Fitton A. Rifabutin: a review of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1994;47:983-1009.
Because of their structural similarities, rifabutin and rifampin may have some of the same side effects. Patients should be made aware of potential color changes in body fluids, and patients who are taking oral contraceptives should consider changing to nonhormonal methods of birth control. Patients also need to be advised to report symptoms suggestive of uveitis or systemic disease related to M. tuberculosis or MAC. Although the pharmacokinetics of rifabutin are influenced by renal dysfunction, dosage adjustments may be necessary only in patients who have a creatinine clearance of 10 mL per minute or less.
Rifabutin may not be an appropriate medication for all patients with AIDS. Its use may be limited by intolerance, drug interactions, cost, compliance and the potential for the selection of resistant strains of M. tuberculosis in endemic areas or in populations with a high risk of tuberculosis.
The most promising alternative agent for the prophylaxis of MAC is clarithromycin, a macrolide antibiotic that has demonstrated antimycobacterial activity both in vitro and in animal studies. One randomized trial of clarithromycin for prophylaxis against disseminated MAC infection in patients with advanced AIDS revealed that 500 mg administered orally twice daily was well tolerated and reduced the incidence of MAC bacteremia from 16 percent to 6 percent over a 10-month period. In addition, the risk of death was reduced from 41 percent to 32 percent. In the clarithromycin group, isolates from 11 of the 19 patients with MAC infection were resistant to clarithromycin. Overall, however, the data appear encouraging, and the FDA has recently approved clarithromycin for prophylaxis of MAC infection in patients with advanced AIDS.
Azithromycin (Zithromax), another macrolide antibiotic, has also been evaluated for the primary prophylaxis of MAC infection, as have regimens of rifabutin in combination with azithromycin. A recent randomized trial reported that azithromycin, 1,200 mg administered orally once a week, was effective in helping prevent disseminated MAC infection. Although the use of rifabutin or the macrolides for prophylaxis has raised concerns about the development of resistance in other bacteria, some investigators believe that primary prophylaxis against MAC infection should be considered the standard of care.
Data on other medications, such as clofazimine (Lamprene) and the combined use of dapsone and pyrimethamine (Daraprim), are insufficient to judge the efficacy of these agents at this time.
The authors thank Vickie White for assisting with the preparation of this manuscript.
Figure 1 adapted from Management of persons exposed to multidrug-resistant tuberculosis. MMWR Morb Mortal Wkly Rep 1992;41(RR-11):61-71.
RELATED ARTICLE: Positive Skin tests for Tuberculosis
What is tuberculosis?
Tuberculosis is an infectious disease caused by a bacterial germ called Mycobacterium tuberculosis. It is a very common infection.
Tuberculosis often affects the lungs, but it can also affect any part of the body. It is a serious but treatable disease. Tuberculosis is spread when a person who has tuberculosis of the lungs coughs up bacteria that are then breathed in by other people. Healthy people, as well as people with weak immune systems, can develop tuberculosis after they breathe in the bacteria.
What kind of test will show if a person is infected with tuberculosis?
A skin test is used to see if a person is infected with the tuberculosis germ. The skin test is called a PPD test or a tuberculin test. A nurse or other health care provider can easily give the skin test.
This test is done by pricking the skin on your arm with a small amount of tuberculin protein. If hardness develops two to three days later on your arm where the test was done, the test is called positive. A positive test means that the person probably has the tuberculosis germs.
A person infected with tuberculosis may feel well and not know they have the disease. This is why it is important to have a PPD test if you are at risk of tuberculosis.
Who should get a PPD skin test for tuberculosis?
A PPD test should be performed in people who may have been around someone with active tuberculosis and in people who have symptoms of the disease. Symptoms include a cough that won't go away, loss of weight, sweating at night, fever and trouble breathing. A skin test should also be done in persons with human immunodeficiency virus (HIV) infection. A PPD test should also be done if you have a condition that weakens your immune system or makes you more likely to get sick. Ask your doctor if you should have this test.
What will happen if my PPD skin test is postive?
The most important first step is fur your doctor to find out if you have active tuberculosis. You usually will need to have a physical examination, a chest x-ray and possibly some other tests (such as collecting samples of material that is coughed up).
If you have active tuberculosis, you have to follow a special treatment plan. You will most likely need to take at least three or four medicines for many months.
If you have a positive PPD test but don't have active tuberculosis, you may still have tuberculosis but just not the active form of the infection. This condition is sometimes called inactive tuberculosis. People with inactive tuberculosis may not have any symptoms. Inactive tuberculosis means that you are infected with the tuberculosis germ but your infection is mild.
What happens if I have a positive PPD skin test but not active tuberculosis?
If you have a positive skin test but do not have active tuberculosis, you may need to start taking a medicine called isoniazid. This medicine helps prevent the tuberculosis germ from growing and developing into active tuberculosis. The risk of developing active tuberculosis is increased in people who have weakened immune systems or chronic illness, such as diabetes, kidney failure or cancer.
The following people should take isoniazid if their PPD skin test is positive, but they do not have active tuberculosis:
* People with HIV infection
* People who had a negative PPD skin test in the past two years but now have a positive PPD skin test
* People who are in close contact (for example, living in the same house) with a person being treated for active tuberculosis
Isoniazid is usually taken for six months. The dose for adults is 300 mg per day taken by mouth. HIV-infected persons should take this medicine for one year.
If you take isoniazid, your doctor will want you to have a checkup regularly to make sure you're doing well while you're taking the medicine. It is important for you to take the medicine for six months or more to kill the tuberculosis germs that are causing the infection.
This information provides a general overview on preventing tuberculosis and related infections and may not apply to everyone. Talk to your family doctor to find out if this information applies to you and to get more information on this subject.
[Figure 1 ILLUSTRATION OMITTED]
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MARY BETH KRANCE, M.D. is currently an infectious diseases specialist in Marquette, Wis. Dr. Krance received her medical degree from the University of North Dakota School of Medicine, Grand Forks, and completed an internship and a residency in internal medicine at the Marshfield Clinic/St. Joseph's Hospital in Marshfield, Wis. She also completed a fellowship in infectious diseases at the West Virginia University Robert C. Byrd Health Sciences Center, Morgantown.
MELANIE ANN FISHER, M.D. is associate professor of medicine in the Department of Medicine, Infectious Diseases Section, at the West Virginia University Robert C. Byrd Health Sciences Center. A graduate of the Pennsylvania State College of Medicine, Hershey, Dr. Fisher completed an internship and a residency in internal medicine at West Virginia University Medical Center and a clinical and research fellowship in infectious diseases at the University of Pennsylvania School of Medicine, Philadelphia.
Address correspondence to Melanie A. Fisher, M.D. Department of Medicine, Infectious Diseases Section, West Virginia University Robert C. Byrd Health Sciences Center, One Medical Center Dr., Room 2178, Morgantown, WV 26506-9163.
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