US Pharm. 2012;37(7):HS2-HS6.
The CDC estimates that one-third of the world’s population is affected by tuberculosis (TB).1 According to the World Health Organization, there were 8.8 million cases of active TB and 1.45 million deaths attributed to TB in 2010.2 In 2011, there were 10,521 reported cases of active TB in the United States, which represents a 6.4% decline compared to 2010.3 Guidelines for targeted tuberculin testing and treatment of latent tuberculosis infection (LTBI) are available from the American Thoracic Society (ATS) and the CDC.4 Guidelines for the treatment of active TB are available from the ATS, the CDC, and the Infectious Diseases Society of America (IDSA).5 This review is intended to educate pharmacists about the proper management of both LTBI and active TB according to published guidelines and selected new studies.
ETIOLOGY AND RISK FACTORS
The causative agent responsible for TB is an acid-fast bacillus known as Mycobacterium tuberculosis.6 Compared to other bacteria, this bacterium does not stain well with Gram stain, but is able to take in the carbol-fuchsin dye upon Ziehl-Neelsen staining and displays a red color resistant to acid-alcohol washes when seen under a microscope. The growth of this mycobacterium occurs at a very slow rate, doubling about every 20 hours compared to every 20 minutes for most nonmycobacteria.6 Primary infection occurs from inhaling airborne droplets containing the bacterium.6 The number of organisms inhaled, their virulence, and the host’s immune response determine whether the infection progresses to active TB or remains latent.6
There are a variety of risk factors for TB.7 Patients who were recently infected or those with close contact to individuals with TB, such as health care workers, are at increased risk of acquiring the disease.7 Others include those who were born in or have emigrated from countries with a high prevalence of TB and those who are homeless, incarcerated, or IV drug users, or who live in unsanitary conditions.7 Race and ethnicity are important risk factors. Hispanics, African Americans, and Asian Americans carry a greater risk of TB when compared to whites.3 The percentage of foreign-born persons with TB is higher than that of U.S.-born persons, and most cases of TB in the U.S. are found in the major points of entry: California, Florida, New York, and Texas.3,7 Finally, patients with weakened immune systems such as those with cancer, solid-organ transplants, and HIV have an increased risk for TB.7
TB spreads from one person to another by coughing or sneezing and occurs when droplets of M tuberculosis are suspended in the air and then inhaled into the lungs.8 Once in the alveoli, macrophages attempt to ingest the bacilli. If the bacilli continue to multiply, macrophages may rupture and release the bacilli, causing the spread of the bacteria to the lymph nodes and possibly into the blood.8 Cell-mediated immunity begins with the presentation of antigens to the T lymphocytes. Upon activation, T lymphocytes release interferon-gamma as well as other cytokines, which causes the macrophages to become bactericidal.8 Delayed-type hypersensitivity also occurs after activation and multiplication of T lymphocytes. A few weeks after exposure, macrophages typically form granulomas to hold the bacilli and prevent the spread of the infection.8 Bacilli contained within granulomas may become dormant, resulting in LTBI. This is shown in most patients by a positive tuberculin skin test (TST) due to tissue hypersensitivity.8 Patients with LTBI are not infectious and cannot spread the disease. In 10% of infected patients, LTBI may progress to active TB.8 Patients with active TB are infectious and can spread the disease.8
CLINICAL PRESENTATION AND DIAGNOSTIC CONSIDERATIONS
A comprehensive patient history, including travel history and clinical presentation, is important when evaluating a patient for TB. While LTBI is usually asymptomatic, patients with active pulmonary TB may present with persistent productive cough, hemoptysis, fever, dull or aching chest pain, night sweats, loss of appetite, weight loss, and/or fatigue.8,9 Moderate leukocytosis particularly lymphocytosis may also be observed on hematology reports.8 Presence of nodular infiltrates on a chest radiograph, especially in the upper lobe, as well as formation of cavities, is usually consistent with TB, and the presence of acid-fast bacilli in the sputum indicates a positive result.8,10
The Mantoux test, also known as the purified protein derivative (PPD) test or TST, has been the gold standard for TB testing for many years. Once an intradermal tuberculin injection is given, individuals with prior exposure to TB will produce a delayed-type hypersensitivity reaction characterized by an induration.4 The reaction peaks at 48 to 72 hours and should be read within that time frame.4 Based on the maximum induration, a positive test is confirmed according to patient-specific factors.4 A positive skin test requires further examination to determine whether a person has LTBI or active TB. Many factors affect the result of the tuberculin skin test, especially being infected with nontuberculous mycobacteria and being immunized with the bacille Calmette-Guérin (BCG) vaccine.4 This vaccine is used in many parts of the world, but is not routinely used in the U.S. New tests such as nucleic acid amplification and interferon-gamma release assay are generally considered more sensitive and specific in detecting M tuberculosis and may potentially replace the TST once more data become available.11,12
TABLES 1 and 2 highlight the first- and second-line anti-tuberculous agents. Typical doses used in the treatment of active TB as well as selected adverse events and monitoring parameters associated with these medications are also listed. One of the main adverse events associated with antituberculous agents is drug-induced hepatitis, which is defined by an elevation of the serum aspartate aminotransferase (AST) level three or more times the upper limit of normal (ULN) in the presence of symptoms, or an elevation of the serum AST level more than five times the ULN in the absence of symptoms.5 In this case, all hepatotoxic agents should be discontinued immediately, and two or more nonhepatotoxic agents may be used. When the AST level drops below two times the ULN, first-line agents may be sequentially reinitiated with close supervision.5
Latent Tuberculosis Infection
The ATS and the CDC released guidelines for the treatment of LTBI in 2000.4 Since then, several studies have been conducted to evaluate the efficacy and safety of various regimens in reducing the likelihood of progression to active TB. The most commonly used monotherapy is isoniazid 300 mg po daily for 6 to 9 months. This regimen is associated with rash, hepatotoxicity, and peripheral neuropathy. Alcohol consumption increases the risk of isoniazid-induced hepatitis and neuropathy. Pyridoxine 25 to 50 mg po daily decreases the risk of neuropathy and should be administered to high-risk patients such as those with diabetes, HIV, malnutrition, seizures, or uremia, and to pregnant women.4,13,14 Isoniazid 900 mg po twice weekly for 6 to 9 months is an alternative regimen but must be administered by directly observed therapy (DOT), in which patients are observed to ingest each dose of antituberculous agent to maximize the likelihood of treatment completion and minimize the risk of resistance.4,13,14 Another commonly used monotherapy is rifampin 600 mg po daily for 4 months. This regimen is associated with a low risk of hepatotoxicity and hematologic toxicity, but a high risk of drug interactions, as rifampin is a potent inducer of CYP450 3A4. Concerns regarding efficacy and lack of data limit the use of this regimen.4,13,14
A commonly used combination therapy is isoniazid 300 mg and rifampin 600 mg administered daily for 3 months. Although this regimen can be administered for a relatively short duration of therapy, it is not well studied in the HIV-negative population and is associated with rash, hepatotoxicity, peripheral neuropathy, hematologic toxicity, and a high risk for drug interactions.4,13-15 The newest combination therapy is isoniazid 900 mg and rifapentine 900 mg administered once weekly by DOT. Compared to isoniazid monotherapy, this regimen is associated with a higher rate of treatment completion and a lower rate of hepatotoxicity, but with a higher risk of hypersensitivity reactions and drug interactions, as rifapentine is a potent inducer of CYP3A4.16,17 The combination rifampin and pyrazinamide, whether administered daily for 2 months or twice weekly for 2 to 3 months by DOT, is no longer recommended because of an unacceptably high rate of severe hepatotoxicity.18
Drug-Susceptible Pulmonary Tuberculosis
The ATS, CDC, and IDSA released guidelines for the treatment of TB in 2003.5 The goals of therapy are to cure the individual patient, eradicate M tuberculosis, limit the development of resistance, and prevent disease relapse. There are four recommended regimens for the treatment of drug-susceptible TB, and each regimen has an initial phase of 2 months followed by a continuation phase of 4 to 7 months. The initial phase usually consists of four drugs (isoniazid, rifampin, pyrazinamide, and ethambutol), and the continuation phase usually includes two agents (isoniazid and rifampin).5
The use of multiple antituberculous agents is needed to address resistance issues, and an adherence plan that emphasizes DOT should be implemented when possible.5 TABLE 3 summarizes the recommended regimens for the treatment of drug-susceptible pulmonary TB. If pyrazinamide cannot be included in the initial regimen because of severe liver disease, gout, or pregnancy, then regimen 4 should be prescribed and the duration of therapy extended.5 If susceptibility results indicate the isolate is sensitive to all first-line antituberculous agents, then ethambutol should be discontinued since it does not shorten the duration of therapy.5 Sputum smears, cultures, and sensitivity should be obtained not only at the time of initiation but also at the time of completion of the first phase of therapy to identify patients at increased risk of relapse and refer them to an expert.5
Drug-Resistant Pulmonary Tuberculosis
Patients exposed to individuals with known drug-resistant TB, individuals with active TB who have had treatment failure or relapse, individuals who continue to have positive sputum smears after 2 months of therapy, or individuals who travel in a region where drug-resistant TB is highly prevalent are at increased risk of infection with drug-resistant TB.5 The development of drug resistance is most commonly seen in patients with cavitary pulmonary TB due to the presence of a large inoculum, in patients who are receiving an inappropriate regimen, and in those who fail to adhere to the prescribed regimen.19 For patients who are only resistant to isoniazid, the CDC suggests treatment with rifampin, pyrazinamide, and ethambutol for a total duration of 6 months. A fluoroquinolone may be added in patients with extensive disease.5 For patients who are only resistant to rifampin (cross-resistance to rifabutin and rifapentine), the CDC suggests treatment with isoniazid, ethambutol, and a fluoroquinolone for a total duration of 12 to 18 months, with pyrazinamide for the first 2 months. An injectable agent may be added for the first 2 to 3 months in patients with extensive disease.5
Multidrug-resistant tuberculosis (MDR-TB) is defined by resistance to both isoniazid and rifampin.5 Patients with MDR-TB are at higher risk of treatment failure and additional drug resistance.5 While the cure rate for individuals without drug resistance is 95% to 97%, the cure rate for individuals with MDR-TB is 50% to 60%.20 Nonetheless, patients with MDR-TB can be treated effectively through the use of second-line agents, although these drugs are less effective than first-line agents and are often associated with more adverse events and higher costs.20
Extensively drug resistant TB (XDR-TB) is defined as MDR-TB that is also resistant to fluoroquinolones and at least one second-line injectable drug.20 XDR-TB raises concern because the available therapeutic options are becoming ineffective and patients are becoming virtually untreatable without surgical resection.20 Patients with MDR-TB and XDR-TB should be referred to a specialist, or a consultation should be obtained from specialized treatment centers.20
Patients With HIV: It is estimated that 8% of patients with TB in the U.S. are co-infected with HIV, resulting in increased morbidity and mortality.3 Treating TB in patients with HIV is complex and requires vigilant care. Recommendations are similar to those for adults without HIV, with a few exceptions. Occasionally, HIV-infected patients who develop TB may temporarily experience exacerbation of symptoms while on treatment due to immune reconstitution.21 Guidelines for prevention and treatment of opportunistic infections in HIV-infected individuals are available from the CDC, the National Institutes of Health, and the HIV Medicine Association of IDSA.21 Since antiretroviral agents have the potential to interact with antituberculous agents, it is important to follow the guidelines for managing drug interactions in the treatment of HIV-related TB.22 In general, rifampin can be substituted with dose-adjusted rifabutin since the latter is less likely to interact with antiretroviral agents, and rifapentine should not be used because of an increased risk of rifamycin resistance.22
Pregnant Women: If the probability of TB is moderate to high in a pregnant woman, treatment should be initiated with isoniazid, rifampin, and ethambutol supplemented with pyridoxine for a minimum of 9 months.5 Although isoniazid, rifampin, and ethambutol cross the placenta, they have not been associated with teratogenic effects.5 There are insufficient data to use pyrazinamide in pregnant women; thus, it is not recommended for general use.5
Patients With Hepatic Impairment: Patients with hepatic impairment are at high risk for developing drug-induced hepatitis.5 Isoniazid, rifampin, and pyrazinamide are known to be hepatotoxic.5,13 There are several options available in the setting of hepatic impairment. One option is a treatment without isoniazid. It includes rifampin, pyrazinamide, and ethambutol for 6 months.5 Another option is a treatment without pyrazinamide. It includes isoniazid and rifampin for a total of 9 months, with ethambutol for the initial 2 months or until drug susceptibility results are obtained.5 In cases of advanced liver disease, rifampin should generally be used along with ethambutol for a total of 12 to 18 months and an additional agent such as fluoroquinolone, cycloserine, or an injectable agent for the first 2 months.5
Patients With Renal Impairment: Isoniazid and rifampin are metabolized by the liver; thus, they do not require dosing adjustment in patients with renal impairment.5,13 Pyrazinamide and ethambutol are partially eliminated by the kidneys; thus, a longer interval involving thrice weekly dosing is recommended.5,13 Levofloxacin, aminoglycosides, and cycloserine also require dosing adjustment based on the degree of renal impairment.5,13 Measurement of serum concentrations should be considered in certain cases to avoid toxicity.5 In patients undergoing hemodialysis, antituberculous agents should be administered after dialysis to facilitate DOT and avoid premature removal.5
THE PHARMACIST’S ROLE
Pharmacists play a pivotal role in the management of patients with TB by providing their expertise within an interdisciplinary team approach to patient care. They can assess the appropriateness, efficacy, and safety of antituberculous therapy by monitoring patients and ensuring medication adherence. They can educate patients and clinicians about the expected therapy outcomes and the side effects as well as drug interactions associated with antituberculous agents. Minor adverse events such as gastrointestinal disturbances are common in the first few weeks of therapy and usually do not necessitate discontinuation of first-line agents. Patients may choose to take their medications with food, although absorption may be delayed. Other adverse events such as drug-induced hepatitis, pyrazinamide-induced hyperuricemia, and ethambutol-induced optical neuritis are more serious, require further evaluation, and may necessitate discontinuation of therapy. Pharmacists may recommend pyridoxine to decrease the risk of isoniazid-induced neuropathy. They should screen patients with comorbid conditions such as HIV infection for potential drug interactions, particularly those patients receiving rifamycins and protease inhibitors. Pharmacists can also educate patients and clinicians about the importance of adherence and DOT to ensure efficacy and minimize resistance. They should remain vigilant to avoid the addition of a single agent to a failing regimen.
Studies have shown better outcomes and substantially improved rates of treatment completion when pharmacists are directly involved in the management of patients with TB, including health care workers. Institutions should explore the possibility of adding a pharmacist to their TB management team.23-25
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23. Clark PM, Karagoz T, Apikoglu-Rabus S, et al. Effect of pharmacist-led patient education on adherence to tuberculosis treatment. Am J Health Syst Pharm. 2007;64:497-505.
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25. Last JP, Kozakiewicz JM. Development of a pharmacist-managed latent tuberculosis clinic. Am J Health Syst Pharm. 2009;66:1522-1523.
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