Antimycobacterial agents: drugs for tuberculosis, leprosy, and mycobacterium avium complex infection

CHAPTER 90


Antimycobacterial agents: drugs for tuberculosis, leprosy, and mycobacterium avium complex infection


Our topic for this chapter is infections caused by three species of mycobacteria: Mycobacterium tuberculosis, Mycobacterium leprae, and Mycobacterium avium. The mycobacteria are slow-growing microbes, and the infections they cause require prolonged treatment. Because therapy is prolonged, drug toxicity and poor patient adherence are significant obstacles to success. In addition, prolonged treatment promotes the emergence of drug-resistant mycobacteria. Because mycobacteria resist decolorizing by the dilute acid used in some staining protocols, these microorganisms are often referred to as acid-fast bacteria.



Drugs for tuberculosis


Tuberculosis (TB) is a global epidemic. Worldwide, over 2 billion people harbor latent infection—nearly one-third of the Earth’s population. In 2009, TB killed 1.7 million people—more than any other infectious disease. Although new cases in the United States continue to decline (down from 20,673 in 1992 to 11,181 in 2010), in the rest of the world new cases are on the rise. The current estimate is 9 million new cases a year. Of these, the vast majority (95%) occur in developing countries. There are two reasons for this resurgence: HIV/AIDS and the emergence of multidrug-resistant mycobacteria.



Clinical considerations


Pathogenesis


Tuberculosis is caused by Mycobacterium tuberculosis, an organism also known as the tubercle bacillus. Infections may be limited to the lungs or may become disseminated. In most cases, the bacteria are quiescent, and the infected individual has no symptoms. However, when the disease is active, morbidity can be significant. In the United States, approximately 10 million people harbor tubercle bacilli. However, only a small fraction have symptomatic disease.



Primary infection

Infection with M. tuberculosis is transmitted from person to person by inhaling infected sputum that has been aerosolized, usually by coughing or sneezing. As a result, initial infection is in the lung. Once in the lung, tubercle bacilli are taken up by phagocytic cells (macrophages and neutrophils). At first, the bacilli are resistant to the destructive activity of phagocytes and multiply freely within them. Infection can spread from the lungs to other organs via the lymphatic and circulatory systems.


In most cases, immunity to M. tuberculosis develops within a few weeks, and the infection is brought under complete control. The immune system facilitates control by increasing the ability of phagocytes to suppress multiplication of tubercle bacilli. Because of this rapid response by the immune system, most individuals (90%) with primary infection never develop clinical or radiologic evidence of disease. However, even though symptoms are absent and the progression of infection is halted, the infected individual is likely to harbor tubercle bacilli lifelong, unless drugs are given to eliminate quiescent bacilli. Hence, in the absence of treatment, there is always some risk that latent infection may become active.


If the immune system fails to control the primary infection, clinical disease (tuberculosis) develops. The result is necrosis and cavitation of lung tissue. Lung tissue may also become caseous (cheese-like in appearance). In the absence of treatment, tissue destruction progresses, and death may result.




Diagnosis and treatment of active tuberculosis


Modern chemotherapeutic agents have dramatically altered the treatment of TB. In the past, most patients required lengthy hospitalization. Today, hospitalization is generally unnecessary. Prolonged bed rest is neither required nor recommended. To reduce emergence of resistance, treatment is always done with two or more drugs. In addition, direct observation of dosing is now considered standard care.


The goal of treatment is to eliminate symptoms and prevent relapse. To accomplish this, treatment must kill tubercle bacilli that are actively dividing as well as those that are “resting.” Success is indicated by an absence of observable mycobacteria in sputum and by the failure of sputum cultures to yield colonies of M. tuberculosis.



Diagnosis

Diagnostic testing is indicated for (1) individuals with clinical manifestations that suggest TB and (2) individuals with a positive skin test or blood test (see below under Diagnosis and Treatment of Latent Tuberculosis), who are at high risk of developing active disease. A definitive diagnosis is made with a chest radiograph and microbiologic evaluation of sputum. A chest radiograph should be ordered for all persons suspected of active infection.


In traditional tests, the presence of M. tuberculosis in sputum is evaluated in two ways: by (1) microscopic examination of sputum smears and (2) culturing of sputum samples followed by laboratory evaluation. Microscopic examination cannot provide a definitive diagnosis. Why? Because direct observation cannot distinguish between M. tuberculosis and other mycobacteria. Furthermore, microscopic examination is much less sensitive than evaluation of cultured samples. Accordingly, sputum cultures are performed to permit a definitive diagnosis. Unfortunately, culturing M. tuberculosis is a slow process, taking 2 to 6 weeks to yield results.


With newer technology, known as nucleic acid amplification (NAA) tests, we can identify M. tuberculosis in sputum rapidly, typically within 24 to 48 hours. Note that this is 1 to 5 weeks sooner than when samples are cultured. Unfortunately, NAA tests have not been used widely in the United States, but this may soon change. Why? Because in 2009, the Centers for Disease Control and Prevention (CDC) issued new guidelines recommending that NAA tests be performed for each patient with signs and symptoms of pulmonary TB, providing a definitive diagnosis has not yet been established.



Drug resistance

Drug resistance is a major impediment to successful therapy. Some infecting bacilli are inherently resistant; others develop resistance over the course of treatment. Some bacilli are resistant to just one drug; others are resistant to multiple drugs. Infection with a resistant organism may be acquired in two ways: (1) through contact with someone who harbors resistant bacteria, and (2) through repeated ineffectual courses of therapy (see below).


The emergence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) are recent and ominous developments. MDR-TB is defined as TB that is resistant to both isoniazid and rifampin, our two most effective antituberculosis (anti-TB) drugs. XDR-TB, a severe form of MDR-TB, is defined as TB that is resistant not only to isoniazid and rifampin, but also to all fluoroquinolones (eg, moxifloxacin), and at least one of the injectable second-line anti-TB drugs (amikacin, kanamycin, or capreomycin). Infection with multidrug-resistant organisms greatly increases the risk of death, especially among patients with AIDS. In addition, multidrug resistance is expensive: The cost of treating one case of resistant TB is about $180,000, compared with $12,000 per case of nonresistant TB. Fortunately, multidrug resistance is rare in the United States: In 2009, there were 94 reported cases of MDR-TB (down from 134 in 2006) and no reported cases of XDR-TB (down from 4 in 2006).


The principal cause underlying the emergence of resistance is inadequate drug therapy. Treatment may be too short; dosage may be too low; patient adherence may be erratic; and, perhaps most importantly, the regimen may contain too few drugs.



The prime directive: always treat tuberculosis with two or more drugs

Antituberculosis regimens must always contain two or more drugs to which the infecting organism is sensitive. To understand why this is so, we need to begin with five facts:



Now, let’s assume we initiate therapy with a single drug, and that all bacteria present are sensitive when we start. What will happen? Over time, at least one of the more than 108 bacteria in our patient will mutate to a resistant form. Hence, as we proceed with treatment, we will kill all sensitive bacteria, but the descendants of the newly resistant bacterium will continue to flourish, thereby causing treatment failure. In contrast, if we initiate therapy with two drugs, treatment will succeed. Why? Because failure would require that at least one bacterium undergo two resistance-conferring mutations, one for each drug. Since two such mutations occur in only 1 of every 1016 bacteria (1016 is the product of the probabilities for each mutation), and since the total bacterial load is much less than 1016, the chances of the two events occurring in one of the bacteria in our patient are nil.


Not only do drug combinations decrease the risk of resistance, they can reduce the incidence of relapse. Because some drugs (eg, isoniazid, rifampin) are especially effective against actively dividing bacilli, whereas other drugs (eg, pyrazinamide) are most active against intracellular (quiescent) bacilli, by using proper combinations of anti-TB agents, we can increase the chances of killing all tubercle bacilli present, whether they are actively multiplying or dormant. Hence, the risk of relapse is lowered.


In Chapter 83 (Basic Principles of Antimicrobial Therapy), we noted that treatment with multiple antibiotics broadens the spectrum of antimicrobial coverage, thereby increasing the risk of suprainfection. This is not the case with multidrug therapy of TB. The major drugs used against M. tuberculosis are selective for this organism. As a result, these drugs, even when used in combination, do not kill off other microorganisms, and therefore do not create the conditions that lead to suprainfection.


In summary, because treatment is prolonged, there is a high risk that drug-resistant bacilli will emerge if only one anti-TB agent is employed. Because the chances of a bacterium developing resistance to two drugs are very low, treatment with two or more drugs minimizes the risk of drug resistance. Therefore, when treating TB, we must always use two or more drugs to which the organism is sensitive.



Determining drug sensitivity

Because resistance to one or more anti-TB drugs is common, and because many patterns of resistance are possible, it is essential that we determine drug sensitivity in isolates from each patient at treatment onset. How do we test drug sensitivity? The traditional method is to culture sputum samples in the presence of antimycobacterial drugs. Unfortunately, the process is slow, usually taking 6 to 16 weeks to complete. Until test results are available, drug selection must be empiric, based on (1) patterns of drug resistance in the community and (2) the immunocompetence of the patient. However, once test results are available, the regimen should be adjusted accordingly. In the event of treatment failure, sensitivity tests should be repeated.


A new, automated tuberculosis assay, known as Xpert MTB/RIF, can identify sensitivity to one key drug—rifampin—in less than 2 hours, while simultaneously confirming the presence of M. tuberculosis. This assay uses the NAA technology noted above. Unfortunately, the Xpert MTB/RIF device is expensive, and not yet approved for general use.



Treatment regimens

Several regimens may be employed for active TB. Drug selection is based largely on the susceptibility of the infecting organism and the immunocompetence of the host. Therapy is usually initiated with a four-drug regimen; isoniazid and rifampin are almost always included. In the event of suspected or proved resistance, more drugs are added; the total may be as high as seven. Representative regimens are shown in Table 90–1 and discussed below.



Treatment can be divided into two phases. The goal of the initial phase (induction phase) is to eliminate actively dividing extracellular tubercle bacilli, and thereby render the sputum noninfectious. The goal of the second phase (continuation phase) is to eliminate intracellular “persisters.”



Drug-sensitive tuberculosis.

If the infecting organisms are not resistant to isoniazid or rifampin, treatment is relatively simple. As indicated in Table 90–1, the induction phase, which lasts 2 months, consists of four drugs: isoniazid, rifampin, pyrazinamide, and ethambutol. Dosing may be done daily, twice weekly, or thrice weekly. The continuation phase, which lasts 4 months, consists of two drugs—isoniazid and rifampin—administered daily, twice weekly, or thrice weekly. Note that the entire course of treatment is prolonged, making adherence a significant problem.




Multidrug-resistant TB and extensively drug-resistant TB.

MDR-TB and XDR-TB are much harder to manage than drug-sensitive TB. Treatment is prolonged (at least 24 months) and must use second- and third-line drugs, which are less effective than the first-line drugs (eg, isoniazid and rifampin) and are generally more toxic. Initial therapy may consist of five, six, or even seven drugs. Hence, an initial regimen might include (1) isoniazid; (2) rifampin; (3) pyrazinamide; (4) ethambutol; (5) kanamycin, amikacin, or capreomycin; (6) ciprofloxacin or ofloxacin; and (7) cycloserine, ethionamide, or para-aminosalicylic acid. As a last resort, infected tissue may be removed by surgery. Even with all of these measures, the prognosis is often poor: Among patients with XDR-TB, between 40% and 60% die. Factors that determine outcome include the extent of drug resistance, infection severity, and the immunocompetence of the host.



Patients with TB plus HIV infection.

Between 2% and 20% of patients with HIV infection develop active TB. Because of their reduced ability to fight infection, these patients require therapy that is more aggressive than in immunocompetent patients, and should last several months longer.


Drug interactions are a big problem, especially for patients taking rifampin. Why? Because rifampin, a cornerstone of TB therapy, can accelerate the metabolism of antiretroviral drugs (ie, drugs used to fight HIV), and can thereby decrease their effects. Specifically, rifampin can decrease the effects of most protease inhibitors and most non-nucleoside reverse transcriptase inhibitors (NNRTIs). Accordingly, it is best to avoid combining rifampin with these agents. Unfortunately, this means that patients will be denied optimal treatment for one of their infections. That is, if they take rifampin to treat TB, they will be unable to take most protease inhibitors or NNRTIs for HIV. Conversely, if they take protease inhibitors and NNRTIs to treat HIV, they will be unable to take rifampin for TB. This dilemma does not have an easy solution.


Like rifampin, rifabutin can accelerate metabolism of antiretroviral drugs. However, the degree of acceleration is much less. As a result, many of the antiretroviral drugs that must be avoided in patients taking rifampin can still be used in patients taking rifabutin.




Promoting adherence: directly observed therapy combined with intermittent dosing

Patient nonadherence is the most common cause of treatment failure, relapse, and increased drug resistance. Recall that patients with TB must take multiple drugs for 6 months or more, making adherence a very real problem. Directly observed therapy (DOT), combined with intermittent dosing, helps ensure adherence and thereby increases the chances of success.


In DOT, administration of each dose is done in the presence of an observer, usually a representative of the health department. DOT is now considered the standard of care for TB. In addition to promoting bacterial kill, DOT permits ongoing evaluation of the clinical response and adverse drug effects.


Intermittent dosing is defined as dosing 2 or 3 times a week, rather than every day. Of course, each dose is larger than with daily dosing. Studies have shown that intermittent dosing is just as effective as daily dosing, and no more toxic. The great advantage of intermittent dosing is that it makes DOT more convenient, and hence improves adherence.



Evaluating treatment

Three modes are employed to evaluate therapy: bacteriologic evaluation of sputum, clinical evaluation, and chest radiographs.


In patients with positive pretreatment sputum tests, sputum should be evaluated every 2 to 4 weeks initially, and then monthly after sputum cultures become negative. With proper drug selection and good adherence, sputum cultures become negative in over 90% of patients after 3 months of treatment.


Treatment failures should be evaluated for drug resistance and patient adherence. In the absence of demonstrated drug resistance, treatment with the same regimen should continue, using DOT to ensure that medication is being taken as prescribed. In patients with drug-resistant TB, two effective drugs should be added to the regimen.


In patients with negative pretreatment sputum tests, treatment is monitored by chest radiographs and clinical evaluation. In most patients, clinical manifestations (eg, fever, malaise, anorexia, cough) should decrease markedly within 2 weeks. The radiograph should show improvement within 3 months.


After completing therapy, patients should be examined every 3 to 6 months for signs and symptoms of relapse.



Diagnosis and treatment of latent tuberculosis


In the United States, an estimated 9 to 14 million people have latent TB. In the absence of treatment, 5% to 10% of these people will develop active TB. Because latent TB can become active, the condition poses a threat to the infected individual and to the community as well. Accordingly, testing and treatment are clearly desirable—but not for everyone: Because treatment of latent TB is often prolonged and carries a risk of drug toxicity, testing and treatment should be limited to people who really need it. In 2000, the American Thoracic Society and the CDC issued revised clinical guidelines—Targeted Tuberculin Testing and Treatment of Latent Tuberculosis Infection—that specify who should be tested, who should be treated, and what drugs should be used. Recommendations specific to drug therapy were revised again in 2003. The discussion below reflects the 2003 recommendations.



Who should be tested for latent tuberculosis?

Testing should be limited to people who are at high risk of either (1) having acquired the infection recently or (2) progressing from latent TB to active TB. Included in this group are people with HIV infection, people receiving immunosuppressive drugs, recent contacts of TB patients, and people with high-risk medical conditions, such as diabetes, silicosis, or chronic renal failure. A complete list of candidates for testing is given in Table 90–2. Routine testing of low-risk individuals is not recommended.




How do we test for latent tuberculosis?

There are two types of tests for latent TB: (1) the tuberculin skin test (TST), which has been used for over 100 years; and (2) interferon gamma release assays (IGRAs), first approved for American use in 2001.



Tuberculin skin test.

The TST is performed by giving an intradermal injection of a preparation known as purified protein derivative (PPD), an antigen derived from M. tuberculosis. If the individual has an intact immune system and has been exposed to M. tuberculosis in the past, the PPD will elicit a local immune response. The test is read 48 to 72 hours after the injection. A positive reaction is indicated by a region of induration (hardness) around the injection site.


The decision to treat latent TB is based on two factors: (1) the risk category of the individual and (2) the size of the region of induration produced by the TST (Table 90–3). For individuals at high risk, treatment is recommended if the region of induration is relatively small (5 mm). For individuals at moderate risk, treatment is indicated when the region of induration is larger (10 mm). And for individuals at low risk (who should not be routinely tested), the region must be larger still (15 mm) to justify treatment.




Interferon gamma release assays.

The IGRAs are blood tests for TB, rather than skin tests. These new tests are based on the observation that immune white blood cells (WBCs), following exposure to M. tuberculosis, will release interferon gamma when exposed to M. tuberculosis again. In the IGRAs, a patient’s blood (or WBCs isolated from that blood) is exposed to antigens that represent M. tuberculosis. If the antigens trigger sufficient release of interferon gamma, the test is considered positive for TB.


In the United States, three IGRAs are now in use:



These IGRAs are as sensitive as the TST, and more specific. Moreover, results with the IGRAs are available faster than with the TST (24 hours vs. 48 to 72 hours), and only one office visit is required. Current CDC guidelines, issued in 2010, permit using IGRAs for all situations in which the TST has been used.



How do we treat latent tuberculosis?

In the United States, there are two preferred treatments for latent TB: (1) isoniazid alone taken daily for 9 months and (2) isoniazid plus rifapentine taken weekly for 3 months. Both treatments are equally effective. Isoniazid alone has been used for decades; isoniazid plus rifapentine is a new option. Because dosing with isoniazid plus rifapentine is so simple—just 12 doses instead of 270—completing the full course is more likely than with isoniazid alone.


Before starting treatment for latent TB, active TB must be ruled out. Why? Because latent TB is treated with just one or two drugs, and hence, if active TB were present, treatment would promote emergence of resistant bacilli. To exclude active disease, the patient should receive a physical examination and chest radiograph; if indicated, bacteriologic studies may also be ordered.



Isoniazid.

For over 30 years, isoniazid has been the standard treatment for latent TB. The drug is effective, relatively safe, and inexpensive. However, isoniazid does have two drawbacks. First, to be effective, isoniazid must be taken for a long time—at least 6 months and preferably 9 months. Second, isoniazid poses a risk of liver damage.


How long should treatment last? Ideally, treatmemt should continue for 9 months. Treatment for 6 months is an option, but is not as reliable.


How often is isoniazid given? Dosing may be done once daily or twice a week. When twice-weekly dosing is used, each dose should be administered by DOT to ensure adherence.


What’s the preferred isoniazid regimen? Of all the options, the preferred regimen is dosing once daily for 9 months. For adults, the daily dose is 5 mg/kg (max 300 mg). For children, the daily dose is 10–20 mg/kg (max 300 mg). When dosing is done twice weekly, higher doses are used.



Isoniazid plus rifapentine.

The combination of isoniazid plus rifapentine—taken just once a week for only 3 months—is just as effective as isoniazid alone taken once a day for 9 months, as shown in the PREVENT TB trial. Accordingly, in 2011, the CDC recommended isoniazid plus rifapentine as an equal alternative to 9 months of daily isoniazid. Because dosing is done just once a week, isoniazid plus rifapentine must be administered by DOT. In contrast, daily isoniazid is self-administered, without oversight by a healthcare provider.


Who can use the new regimen? Isoniazid plus rifapentine is recommended for people age 12 years and older, including those with HIV infection who are not taking antiretroviral drugs. As a rule, children age 2 to 11 years should use 9 months of daily isoniazid, and not isoniazid plus rifapentine. Because of its simplicity, the new regimen may be especially useful in correctional institutions, clinics for recent immigrants, and homeless shelters.


Who should not use the new regimen? The regimen should not be used by (1) children under 2 years old, because the safety and kinetics of rifapentine are unknown in this group, (2) HIV-infected patients taking antiretroviral drugs, because drug interactions have not been studied, (3) women who are pregnant or expecting to become pregnant during treatment, because safety in pregnancy is unknown, and (4) patients with latent TB with presumed resistance to isoniazid or rifapentine.


What’s the dosage for isoniazid and rifapentine? For adults and children, the dosage for isoniazid is 15 mg/kg (900 mg max). The dosage for rifapentine is based on body weight as follows:


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Jul 24, 2016 | Posted by in NURSING | Comments Off on Antimycobacterial agents: drugs for tuberculosis, leprosy, and mycobacterium avium complex infection

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