Brody's Human Pharmacology: With STUDENT CONSULT

Chapter 49 Antimycobacterial Agents

MAJOR DRUG CLASSES

First-Line Drugs for Tuberculosis

Inhibitors of protein synthesis (Rifamycins)

Inhibitors of cell wall synthesis (Isoniazid, others)

Others

Second-Line Drugs for Tuberculosis

Fluoroquinolones

Aminoglycosides

Others

Drugs for Leprosy

Dapsone

Fluoroquinolones

Rifamycins

Tetracyclines

Drugs for Mycobacterium Avium

Macrolides

Therapeutic Overview

The genus Mycobacterium consists of relatively slow-growing, obligate aerobic bacilli with a unique lipid-rich cell wall that allows these organisms to take up basic dyes and resist decolorization with acid-alcohol (“acid-fast” organisms). The acid-fast cell wall of Mycobacterium contains a large amount of glycolipids. A waxy lipid called mycolic acid makes up approximately 60% of the cell wall and makes it relatively impermeable. The major human mycobacterial pathogens are the virulent M. tuberculosis and M. leprae, while most mycobacteria inhabit soil and water and only occasionally cause human disease. For example, M. avium complex (MAC) causes infections among highly immunocompromised patients with human immunodeficiency virus (HIV) infection (CD4+ T lymphocyte counts of <75/μL) and in persons with abnormal lung anatomy or physiology. More rapidly growing non-tuberculous mycobacteria can cause skin and soft-tissue infection after trauma or surgery (e.g., M. chelonae or M. fortuitum) or after exposure to salt water (M. marinum). This chapter focuses on agents used to treat M. tuberculosisM. leprae, and M. avium complex.

Tuberculosis (TB) is transmitted person to person by airborne droplet nuclei, which are small particles (1 to 5μ diameter). TB classically is a pulmonary disease, but disseminated and extrapulmonary disease, especially among immunocompromised persons, also occurs.

Tuberculosis has emerged as a global public health epidemic and is the second leading cause of death worldwide caused by an infectious disease. In 2005, the World Health Organization (WHO) estimated that more than 8 million persons developed active disease, and more than 1.5 million deaths occurred, mostly in resource-poor

Abbreviations

AIDS

Acquired immunodeficiency syndrome

CNS

Central nervous system

CSF

Cerebral spinal fluid

DNA

Deoxyribonucleic acid

DOT

Directly observed therapy

GI

Gastrointestinal

HIV

Human immunodeficiency virus

IM

Intramuscular

INH

Isoniazid (isonicotinic acid hydrazide)

IV

Intravenous

LTBI

Latent TB infection

MAC

Mycobacterium avium complex

MDR

Multi-drug resistance

PAS

p-Aminosalicylic acid

POA

Pyrazinoic acid

PZA

Pyrazinamide

PZase

Nicotinamidase/pyrazinamidase

RNA

Ribonucleic acid

TB

Tuberculosis

WHO

World Health Organization

XDR-TB

Extensive drug-resistant TB

countries. Overall, it is estimated that one third of the people in the world are currently infected with the TB bacillus. In the United States there was a resurgence of TB between 1985 and 1992, largely because of underfunding and decline of the public health infrastructure. With increased attention and funding, since 1992 there has been a decline in the number of TB cases in the United States to 14,097 TB cases in 2005 (4.8 per 100,000 population). The global epidemic of TB has impacted the United States, where most cases now occur among foreign-born persons. There are great racial/ethnic disparities among case rates. For individuals born in the United States, in 2005, the rate among African-Americans was almost eight times that of Caucasians.

Treatment of TB is much different than treatment of other diseases because of its public health implications. The provider has the responsibility for prescribing an appropriate regimen and ensuring that treatment is completed. Directly observed therapy (DOT) is recommended for all patients with active TB disease and can help ensure higher completion rates (Fig. 49-1), decrease risk for emergence of resistance, and enhance TB control. DOT is generally provided by public health agencies. Active TB should never be treated with a single drug because of the risk of emergence of resistance; therefore multidrug therapy is required. The minimum length of therapy is 6 to 9 months. Patients with drug resistance, especially multidrug resistance (MDR) (i.e., resistance to at least isoniazid and rifampin) require longer therapy. MDR-TB is associated with much higher morbidity and mortality. Drug resistance is an important factor in determining the appropriate therapeutic regimen. Patients who are infected with M. tuberculosis (latent TB infection, or LTBI) are at risk for progressing to active disease. This can be greatly reduced by treating persons with LTBI who are at high or increased risk for progression to active disease (e.g., HIV infection, other illnesses that increase risk of progression, recent infection, or recent immigration from high TB endemic area).

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FIGURE 49–1 Impact of directly observed therapy (DOT) on completion rates of antituberculosis therapy. Range and median treatment completion rates classified by treatment intervention for pulmonary tuberculosis.

Modified from Chaulk CP, Kazdanjian VA. J Am Med Assoc 1998; 279:943-948.

More recently, extensively drug-resistant TB (XDR-TB) has emerged, which is resistant to the two best first-line drugs, the fluoroquinolones, and to at least one of the three alternatives: amikacin, kanamycin, or capreomycin. Because of the resistance, patients with XDR-TB have more limited therapeutic choices and poorer outcomes.

Leprosy, also caused by a mycobacterium, is rare in the United States and Canada but is not uncommon in developing countries. Approximately 410,000 new cases were reported in 2004, compared with 804,000 in 1998. According to the WHO, 290,000 cases were being treated at the beginning of 2005. India, Brazil, and Nepal have the highest prevalence of the disease, while the largest number of cases exists in Southeast Asia. Transmission is thought to occur by the respiratory route, because the nasal discharge from patients with untreated multibacillary leprosy often contains large numbers of bacilli. Transmission may occasionally occur through direct skin contact. In the United States, leprosy is seen primarily among immigrants, although small pockets occur in Texas, Hawaii, and Louisiana. M. lepraeis the causative organism, which multiplies very slowly with a generation time of 12.5 days and an incubation period of years. Clinical manifestations depend on the infected person’s immune response toM. leprae. Skin and peripheral nerves in cooler areas of the body are most commonly affected. Prompt recognition is key to limiting morbidity caused by irreversible nerve damage. The disease is curable with multidrug therapy.

Therapeutic Overview

Tuberculosis

Tuberculosis is a huge global health problem; the second leading cause of death due to an infectious disease worldwide.

More than 8 million new cases and 1.5 million deaths occur annually.

M. tuberculosis is an aerobic organism.

M. tuberculosis can cause latent infection and active pulmonary or extrapulmonary disease.

Combinations of drugs are used for active disease; a single drug can be used for latent infection.

Long-term treatment is needed (at least 6-9 months).

Bacterial resistance is of growing importance.

Multidrug-resistant tuberculosis is associated with increased morbidity and mortality.

Directly observed therapy is an important component in treatment.

Leprosy (Hansen’s disease)

Leprosy is caused by M. leprae, an aerobic acid-fast bacillus organism.

M. leprae grows extremely slowly with a long incubation period (average 2-4 years).

It is a chronic disease; clinical manifestations depend upon immune responses.

Long-term treatment is needed, usually with multidrug therapy.

Leprosy “reactions” can result from immunologically mediated acute inflammatory responses.

Mycobacterium avium complex (MAC) disease

Disseminated MAC most commonly occurs in patients with advanced HIV/AIDS.

Pulmonary infections are also seen in HIV-seronegative individuals, particularly with underlying or chronic pulmonary disease.

Treatment requires a multidrug regimen for prolonged periods.

Prophylaxis is indicated in patients with advanced HIV infection.

The incidence of invasive (i.e., disseminated) MAC disease among HIV-infected persons in the United States has decreased markedly in recent years because of the use of highly active antiretroviral therapy and MAC prophylaxis. In immunocompetent individuals, MAC most commonly causes pulmonary disease among those with underlying or chronic lung disease.

A summary of the characteristics and issues associated with tuberculosis, leprosy, and MAC is presented in the Therapeutic Overview Box.

Mechanisms of Action

Anti-Tuberculosis Drugs

Anti-TB drugs can be categorized on the basis of whether they are first- or second-line agents (see Major Drug Classes Box). They are divided into three groups based on their mechanism of action.

Inhibition of Protein Synthesis

The rifamycins (rifampin, rifabutin, rifapentine) are bactericidal and inhibit deoxyribonucleic acid (DNA)-dependent ribonucleic acid (RNA) polymerase of mycobacteria (but not mammals). This enzyme is composed of four subunits; rifamycins bind to the β-subunit, which results in blocking the growing RNA chain (Fig. 49-2). Resistance is conferred by single mutations that tend to occur (>95%) in an 81-base pair region of the rpoB gene that codes for the β-subunit. The aminoglycosides streptomycin, kanamycin, and amikacin act by inhibiting protein synthesis and are described in Chapter 47. Capreomycin, a macrocyclic polypeptide antibiotic, has similar activity and toxicities as aminoglycosides.

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FIGURE 49–2 Mechanism of rifampin action. The drug binds to the β-subunit of DNA-dependent RNA polymerase and inhibits RNA synthesis. A, Drug is absent. B, Drug is bound to the polymerase and distorts the conformation of the enzyme so that it cannot initiate a new chain.

Inhibition of Cell Wall Synthesis: Isoniazid (INH)

INH is a bactericidal agent that is thought to inhibit mycolic acid synthesis. Mycolic acids are a major constituent of mycobacterial cell walls (along with arabinogalactan and peptidoglycan). The mode of action of INH is complex, and a current model is shown in Figure 49-3. INH is a prodrug that has to be activated by the M. tuberculosis catalase-peroxidase enzyme encoded by the katG gene. Deletions or mutations in this gene may account for 40% to 50% of clinical INH-resistant isolates. Other mechanisms of resistance may include mutations in three other genes. inhA and kasA code for mycolic acid biosynthetic enzymes, and mutations are found in some INH-resistant isolates. ahpC has also been associated with some INH resistance strains, but its role is unclear.

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FIGURE 49–3 Mechanism by which isoniazid kills tubercle bacilli. INH enters by passive diffusion and is activated by katG to a range of reactive species or radicals and isonicotinic acid. These attack multiple targets, including mycolic acid synthesis, lipid peroxidation, DNA, and NAD metabolism. Deficient efflux and insufficient antagonism of INH-derived radicals, such as defective antioxidative defense, may underlie the unique susceptibility of M. tuberculosis to INH.

Pyrazinamide (PZA) is active only against M. tuberculosis and M. africanum; it is inactive against M. bovis and nontuberculous mycobacteria. PZA is active at a low pH (e.g., pH 5), is bactericidal, and has excellent sterilizing activity against semidormant bacteria. PZA is thought to enter M. tuberculosis by passive diffusion and is then converted to the active metabolite pyrazinoic acid (POA) by nicotinamidase/pyrazinamidase (PZase). The target of POA may involve fatty acid synthase I and disruption of mycobacterial membranes by acid (Fig. 49-4). Selected mutations in the PZase gene (pncA) are associated with PZA resistance in M. tuberculosis.

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FIGURE 49–4 Proposed mechanism of action of pyrazinamide (PZA). PZA is converted to pyrazinoic acid (POA) by the enzyme encoded by pncA. Its ability to kill M. tuberculosis and not other Mycobacteria species may be due to a selective defect in POA efflux in M. tuberculosis. Proposed targets include the mycobacterial fatty acid synthase 1 and disruption of mycobacterial membranes by acidic action.

Modified from Chan ED, Chatterjee D, Iseman MD, et al. Pyrazinamide, ethambutol, ethionamide, and aminoglycosides. In Rom WN, Garay SM, editors: Tuberculosis, 2nd ed, Philadelphia, Lippincott, Williams & Wilkins, 2004.

The mechanism of action of ethambutol is not well understood. It is thought to interfere with mycobacterial cell wall synthesis by inhibiting synthesis of polysaccharides and transfer of mycolic acids to the cell wall. The target is thought to be encoded by a three-gene operon (embC, embA, embB) that produces arabinosyl transferases that mediate polymerization of arabinose into arabinogalactan, particularly embB. Resistance to ethambutol is most common among M. tuberculosis isolates that are also resistant to INH and rifampin (i.e., MDR strains), probably because of mutations in embB. Ethambutol is effective only on actively dividing mycobacteria.

Other Mechanisms

p-Aminosalicylic acid (PAS) acts as a competitive inhibitor of p-aminobenzoic acid in folate synthesis. Because PAS inhibits only this step in M. tuberculosis, and sulfonamides do not generally inhibit mycobacteria, the enzyme in tubercle bacilli is thought to be distinct.

Other agents used in treatment of mycobacterial diseases include the fluoroquinolones (e.g., levofloxacin, moxifloxacin), which have emerged as important second-line drugs used in the treatment of XDR-TB. They are discussed in Chapter 48.

Anti-Leprosy Drugs

Drugs for treatment of leprosy include rifampin, dapsone, clofazimine, ofloxacin, and minocycline. Rifampin is highly bactericidal against M. leprae and is discussed in the previous text. Its mechanism of action is presumed to be inhibition of M. leprae DNA-dependent RNA polymerase. Similar to sulfonamides, dapsone acts as an inhibitor of dihydropteroate synthetase in folate synthesis to produce a bacteriostatic effect. Clofazimine is active against M. leprae (weakly bactericidal), but its mechanism of action is unknown. Ofloxacin, a fluoroquinolone, is discussed in Chapter 48, and the tetracyclineminocycline is discussed in Chapter 47.

Anti-M. avium Complex (MAC) Drugs

Clarithromycin and azithromycin have excellent activity against MAC, and these macrolides are the cornerstone of therapy. They can be used in both prevention and treatment of disease (see Chapter 47). Ethambutol is usually combined with clarithromycin (or azithromycin) for treatment of MAC infections, especially among HIV-infected patients with disseminated MAC. Rifabutin can also be used to prevent MAC in HIV-infected patients who are unable to take macrolide drugs, and it can also be used in combination with other agents. Amikacin and the fluoroquinolones also have activity against MAC and are discussed in Chapters 47 and 48, respectively.

Pharmacokinetics

Key pharmacokinetic parameters are summarized in Table 49-1 and in Chapters 47 and 48.

TABLE 49–1 Selected Pharmacokinetic Properties

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Anti-Tuberculosis Drugs

First Line

INH is well absorbed orally and is widely distributed, with peak concentrations achieved in pleural, peritoneal, and synovial fluids. Cerebrospinal fluid (CSF) concentrations are approximately 20% of plasma levels but can increase to 100% with meningeal inflammation. INH is metabolized by a liver N-acetyltransferase, and the rate of acetylation determines its concentration in plasma and its half-life. As discussed in Chapter 2, slow acetylation is inherited as an autosomal recessive trait. The average plasma concentration of drug in rapid acetylators is half of that in slow acetylators. However, there is no evidence that these differences are therapeutically important if INH is administered once daily, because plasma levels are well above inhibitory concentrations.

Rifampin is well absorbed orally and widely distributed, achieving therapeutic concentrations in lung, liver, bile, bone, and urine and entering pleural, peritoneal, and synovial fluids and CSF, tears, and saliva. Its high lipid solubility enhances its entrance into phagocytic cells, where it kills intracellular bacteria. Rifampin is metabolized in the liver to a desacetyl derivative that is biologically active. Unmetabolized drug is excreted in bile and reabsorbed from the gastrointestinal (GI) tract into the enterohepatic circulation; the deacetylated metabolite is poorly reabsorbed with eventual elimination in urine and from the GI tract. Rifampin induces its own metabolism by inducing the expression of cytochrome P450s, resulting in increased biliary excretion with continued therapy. Induction of metabolism results in reduction of the plasma life by 20% to 40% after 7 to 10 days of therapy. Patients with severe liver disease may require dose reduction, but dose adjustment is not necessary in renal failure. Oral bioavailability of rifabutin is less than that of rifampin, and the plasma half-life is approximately 10 times greater. Rifabutin is more lipid soluble than rifampin and is extensively distributed. Rifabutin also induces its own metabolism but has less of an effect on cytochrome P450s. Rifapentine is used once weekly in the continuation phase of highly selected patients with TB. It is metabolized in a similar manner but does not significantly induce its own metabolism.

Rifamycins are among the most-potent known inducers of hepatic cytochrome P450 oxidative enzymes and the P-glycoprotein transport system and have a large number of drug interactions. This greatly impacts clinical care as discussed in the following text.

PZA is well absorbed orally and widely distributed, readily penetrating cells and the walls of cavities. It enters the CSF if meninges are inflamed. PZA is metabolized by the liver, and its metabolic products are excreted mainly by the kidneys. Dose modifications are necessary in renal failure.

Approximately 75% to 80% of ethambutol is orally absorbed and widely distributed. Ethambutol crosses the placenta, and under normal circumstances, little penetrates into the CSF. However, with meningeal inflammation, CSF concentrations can reach 10% to 50% of plasma values. Ethambutol is mainly excreted unchanged by the kidneys, and dose adjustments are necessary in renal failure. It can be removed from the body by peritoneal dialysis or hemodialysis.

Second Line

The fluoroquinolones are discussed in Chapter 48 and the aminoglycosides in Chapter 47.

Capreomycin is administered by intramuscular (IM) or intravenous (IV) routes and is eliminated by the kidneys. It enters the CSF poorly and accumulates during renal dysfunction.

Ethionamide is well absorbed orally and widely distributed, entering the CSF and reaching concentrations equal to those in plasma. It is metabolized in the liver, with metabolites renally excreted. Ethionamide interferes with INH acetylation.

Cycloserine is rapidly absorbed orally and widely distributed, with CSF concentrations equal to those in plasma. Approximately 35% is metabolized; the remainder is excreted by glomerular filtration. It accumulates in renal failure but can be removed by hemodialysis.

PAS is available in the United States as granules in 4-g packets, and a solution for IV administration is available in Europe. PAS is well absorbed orally and enters lung tissue and pleural fluid. It is metabolized in the liver by an acetylase different from that acting on isoniazid. Most of the absorbed dose is excreted in the urine as metabolites.

Anti-Leprosy Drugs

Rifampin is discussed earlier in the chapter. Ofloxacin, a fluoroquinolone, is discussed in Chapter 48; minocycline, a tetracycline, is discussed in Chapter 47.

Dapsone is well absorbed from the upper GI tract, is distributed to all body tissues, and achieves therapeutic concentrations in skin. It is approximately 70% bound to plasma proteins, excreted in bile, and reabsorbed via the enterohepatic circulation. It is acetylated in liver by the same enzyme that acetylates isoniazid, but the acetylation phenotype does not affect its half-life. Dapsone is excreted as glucuronide and sulfate conjugates in urine. It has a plasma half-life of 25 hours, which is reduced in patients receiving rifampin. Dosage should be reduced in renal failure.

The pharmacokinetics of clofazimine are complex. Clofazimine is variably absorbed from the GI tract and distributed in a complex pattern, with high concentrations reached in subcutaneous fat and the reticuloendothelial system. It is not metabolized but is excreted slowly by the biliary route. It is estimated to have a half-life of 70 days.

Anti-M. avium Complex Drugs

Most of the drugs used to treat MAC infections (e.g., macrolides, ethambutol, rifamycins, fluoroquinolones) are described earlier or in Chapter 47 or 48.

Relationship of Mechanisms of Action to Clinical Response

Anti-Tuberculosis Drugs

The goals of anti-TB therapy are to kill tubercle bacilli rapidly, to minimize or prevent development of drug resistance, and to eliminate persistent organisms from the host’s tissue to prevent relapse.Multidrug therapy is required for prolonged periods (at least 6 to 9 months for susceptible disease), and ensuring adherence to therapy (through use of DOT) is an important component of treatment. INHand rifampin are the two most important anti-TB drugs and the cornerstones of therapy. Resistance to both drugs (MDR-TB) is associated with much higher morbidity and mortality rates. PZA is an important first-line drug that is a necessary component for “short-course” therapy (6 to 9 months). Ethambutol is also a first-line drug included in the initial four-drug regimen.

It is believed that there are three separate subpopulations of M. tuberculosis in the host with TB disease. The first and largest consists of rapidly growing extracellular organisms that mainly reside in well-oxygenated cavities (abscesses) containing 107 to 108 organisms. The second subpopulation consists of poorly oxygenated, closed, solid caseous lesions (e.g., noncaseating granulomas) containing 104 to 105 organisms. These organisms are considered semidormant and undergo only intermittent bursts of metabolic activity. The third subpopulation consists of a small number of organisms (less than 104 to 105) believed to be semidormant within acidic environments—both intracellular (e.g. in macrophages) or extracellular within areas of active inflammation and recent necrosis. INH is most potent in killing rapidly multiplying M. tuberculosis (the first subpopulation) during the initial part of therapy (early bactericidal activity). Rifampin and ethambutol have less early bactericidal activity than INH but considerably more than PZA, which has weak early bactericidal activity during the first 2 weeks of treatment. Drugs with potent early bactericidal activity reduce the chance of resistance emerging. Multidrug therapy is required to prevent development of resistance as a consequence of the selection pressure from administration of a single agent.

The rapidly dividing population of bacilli (first subpopulation) is eliminated early in effective therapy, and by 2 months of treatment approximately 80% of patients are culture negative. The remaining (second and third) subpopulations account for treatment failures and relapses and are the reason prolonged therapy is required. The sterilizing activity of a drug is defined by its ability to kill bacilli mainly in the second and third subpopulations that persist beyond the early months of therapy, thus decreasing the risk of relapse. The use of drugs with good sterilizing activity is essential for short-course therapy (e.g., 6 months). Rifampin and PZA have the greatest sterilizing activity, followed by INH and streptomycin. The sterilizing activity of rifampin persists throughout the course of therapy, whereas that of PZA is mainly seen during the initial 2 months.

There are two phases of treatment of patients with TB disease: the initiation phase (bactericidal or intensive phase) and the continuation phase (subsequent sterilizing phase). Patients with TB, or a high clinical suspicion for TB, should be initiated on a four-drug regimen consisting of INH, rifampin, PZA, and ethambutol. It is important to obtain appropriate specimens for acid-fast bacilli smear and culture to try to establish a definitive diagnosis so that a positive culture for M. tuberculosis can be obtained. All initial isolates should undergo susceptibility testing, which is essential in providing appropriate drug therapy. For patients with drug-susceptible disease, PZA and ethambutol can be discontinued after 2 months of therapy, whereas INH and rifampin are continued in the continuation phase (4 more months). Patients at high risk for relapse include those with cavitary pulmonary disease who remain culture positive after 2 months of therapy. Such patients should have the continuation phase extended 3 more months (to complete 9 months of total therapy).

Several different regimens are available for treatment of drug-susceptible disease. In addition to the total duration of therapy, the number of completed doses should be counted and tracked to ensure the proper amount of therapy is given. Nonadherence is the most common cause of treatment failure, relapse, and emergence of resistance. DOT has been proven to improve completion rates and outcomes and is recommended for all patients with TB. Administration of anti-TB therapy on an intermittent basis is possible (especially in the continuation phase) for patients with drug susceptible disease and facilitates supervision of therapy. Intermittent therapy (e.g., twice or thrice weekly) should only be given by DOT to patients with drug-susceptible disease. Specific regimens for treatment of active TB disease have been developed (Fig. 49-5) but are beyond the scope of this text.

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FIGURE 49–5 Treatment algorithm for tuberculosis. Patients in whom tuberculosis is proven or strongly suspected should have treatment with isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB) for an initial 2 months. A repeat smear and culture should be performed at that time. If cavities were seen on chest radiograph (CXR) or the acid-fast bacillus (AFB) smear is positive after 2 months, the continuation phase should consist of INH and RIF daily or twice-weekly for 4 months to complete a total of 6 months of treatment. If cavitation was present on the initial CXR and the culture at the time of completion of 2 months of therapy is positive, the continuation phase should be lengthened to 7 months (total 9 months). If no cavitation was seen on CXR and there are negative AFB smears at completion of 2 months of treatment, the continuation phase may consist of either once-weekly INH and rifapentine (RPT) or daily or twice-weekly INH and RIF, to complete a total of 6 months (bottom). Patients receiving INH and RPT, and whose 2-month cultures are positive, should have treatment extended by an additional 3 months. Modified from Blumberg H, Burman WJ, Chaisson RE, et al. Am J Respir Crit Care Med 2003; 167:603-662.) * EMB may be discontinued when results of drug susceptibility testing indicate no resistance. PZA may be discontinued after 2 months.  RPT should not be used in HIV-infected patients with TB or in patients with extrapulmonary TB. # Therapy should be extended to 9 months if 2-month culture is positive.

HIV serologic testing should be offered to all patients with TB. Treatment in patients with HIV is similar to that in other patients, with two major exceptions. The first is that HIV coinfected patients should not be treated with a once-weekly INH-rifapentine regimen in the continuation phase (which is reserved for highly selected HIV seronegative patients without cavitary disease), and HIV-infected patients with CD4+ lymphocyte counts of <100/μL should not receive twice-weekly intermittent regimens (e.g., INH-rifampin or INH-rifabutin) because of increased risk of relapse resulting in rifamycin resistance. As discussed in the following text, there are many drug interactions between rifamycins and other drugs, including antiretroviral agents. Paradoxical or immune reconstitution reactions are more common among HIV-infected patients with TB who are started on antiretroviral therapy early in the course of TB treatment. Therefore some have recommended a delay of initiation of antiretroviral therapy in HIV-infected patients, if possible, until after 1 to 2 months of TB disease therapy. However, data are lacking, and recommendations on the use of antiretroviral therapies in HIV-infected patients with TB continue to evolve. They are available from the Centers for Disease Control and Prevention at www.cdc.gov/nchstp/tb/.

Treatment of XDR-TB, especially MDR-TB, is quite challenging and should be done by, or in close consultation with, an expert. Treatment of INH monoresistance can be accomplished with a daily regimen of rifampin, PZA, and ethambutol for 6 months. Treatment of isolated rifampin-resistant disease requires a minimum of 12 months (e.g., INH, PZA, ethambutol, and a fluoroquinolone). Treatment of MDR-TB (resistance to both INH and rifampin) requires 18 to 24 months, depending on the resistance pattern, and is associated with higher morbidity and mortality rates. Specific treatment regimens are available elsewhere and must be individualized based on the drug-susceptibility pattern.

Therapy for LTBI can markedly reduce the risk of progression to active disease and is recommended in those infected with M. tuberculosis who are at increased risk. The tuberculin skin test is the most common diagnostic test, but there is hope that improved tests will become available. The risk of progression from infection to active disease can range from a 5% to 10% lifetime risk in immunocompetent persons to 10% per year in HIV-infected persons with LTBI. HIV/acquired immunodeficiency syndrome (AIDS) is clearly the greatest risk factor. Others include recent infection and LTBI among injection drug users and those with silicosis, diabetes mellitus, renal failure, certain malignancies, gastrectomy or jejunoileal bypass, solid organ transplantation, or use of immunosuppressive drugs. Others at increased risk include immigrants who have arrived in the United States within 5 years from areas with a high incidence of TB, racial/ethnic minorities, children 4 years of age or younger with LTBI, and children and adolescents exposed to high-risk adults. All persons with suspected LTBI should have a chest radiograph performed to exclude active disease. Those with LTBI and risk factors for progression should be encouraged to take LTBI therapy, which generally involves a 9-month course of INH. A course of 6 months of INH is an alternative in HIV-seronegative adults. Rifampin for 4 months is an alternative therapy for adults or those suspected of being infected with an INH-resistant strain of M. tuberculosis. A 2-month short course of rifampin plus PZA for treatment of LTBI is not recommended because of a high rate of hepatotoxicity (although these drugs remain important in multidrug regimens for active TB).

Anti-Leprosy Drugs

Recommended therapy for leprosy is based on the classification of disease and includes multidrug therapy. Rifampin, dapsone, and clofazimine are included in the recommended regimens. Rifampin is the most effective agent; it is bactericidal against M. leprae, and a single dose kills 99.99% of organisms, rendering patients with lepromatous leprosy noninfectious within days. Patients with paucibacillary disease receive rifampin (via supervised therapy) once monthly, plus dapsone on a daily basis (self-administered) for 6 months. Dapsone is a slow-acting bacteriostatic drug. It was formerly used as monotherapy, which led to emergence of resistance (up to 40%). Patients with single-lesion paucibacillary disease can be treated with single-dose multidrug therapy (rifampin, ofloxacin, and minocycline). Patients with multibacillary disease require a minimum of 12 months of triple-drug therapy (i.e., rifampin plus dapsone monthly by supervised therapy plus clofazimine either monthly or daily), although they are frequently treated for 24 months. Long-term follow-up (5 to 10 years) has been suggested, because relapses generally occur late. Treatment can be complicated by immune reactions that can be severe and cause significant morbidity because of nerve damage, described in the following text. Unfortunately, chemoprophylaxis with rifampin or dapsone for high-risk contacts of leprosy patients has proven unsuccessful.

Anti-M. avium Complex Drugs

In AIDS patients with disseminated MAC disease, a regimen combining clarithromycin (or azithromycin) (see Chapter 47) with ethambutol is recommended. Rifabutin may be added as a third drug, although data on whether this improves outcome are conflicting. The addition of clofazimine to a multidrug anti-MAC regimen is contraindicated, because it was found to be associated with a worse outcome and higher mortality in HIV-seropositive patients. In treatment of MAC infections in HIV-seronegative immunocompetent patients (e.g., pulmonary MAC), treatment regimens generally include clarithromycin, ethambutol, and rifabutin (or rifampin). Rifabutin is preferred by some because it decreases the serum levels of clarithromycin less than rifampin and may be more active in vitro against MAC. Treatment of MAC disease requires long-term therapy (at least 12 months). Adult and adolescent HIV-infected patients with disseminated MAC should receive lifelong therapy unless immune reconstitution occurs as a consequence of highly active antiretroviral therapy. Among immunocompetent patients with pulmonary MAC, treatment is often recommended for 12 months after sputum conversion.

HIV-infected individuals should receive prophylaxis against disseminated MAC disease if they have a CD4+ T lymphocyte count of < 50 cells/μL. Clarithromycin or azithromycin are preferred. If they cannot be tolerated, rifabutin is an alternative, although its drug interactions can make its use difficult. MAC prophylaxis is indefinite unless immune reconstitution occurs. Patients with an increase in CD4+T lymphocyte counts to >100 cells/μL for more than 3 months can safely discontinue prophylaxis.

Pharmacovigilance: Side Effects, Clinical Problems, and Toxicity

The main adverse effects of the drugs used to treat Mycobacterium infections are outlined in the Clinical Problems Box.

Anti-Tuberculosis Drugs

First Line

Although adverse reactions to INH are not common, a few are serious. Hepatotoxicity is the most potentially serious side effect, although recent data suggest the incidence is lower than previously thought (0.1% to 0.15%). The risk of hepatotoxicity is age related and is rare in persons less than 20 years old; however, the incidence is approximately 2% in people aged 50 to 64 years old. The risk of hepatitis is higher when INH is administered with other potentially hepatotoxic drugs such as PZA or rifampin. The risk may also increase with underlying liver disease, a history of heavy alcohol consumption, or in the postpartum period (especially among Hispanics). Asymptomatic elevation of aminotransferases, which are generally transient, can occur in 10% to 20% of those taking INH for LTBI. Although the incidence of clinical hepatitis is low (approximately 1% of recipients), it can be fatal when it occurs. The drug should be discontinued when aminotransferases are increased by more than fivefold normal in asymptomatic patients or more than threefold in symptomatic patients. Patients should be advised to discontinue INH at the onset of symptoms consistent with hepatitis such as nausea, loss of appetite, and dull mid-abdominal pain. Routine laboratory monitoring is recommended for persons at increased risk of toxicity. Liver function tests should be obtained on any patient who develops symptoms that could suggest hepatitis.

Other side effects of INH include peripheral neuropathy, which occurs more commonly in slow acetylators, those with a nutritional deficiency, diabetes, HIV infection, renal failure, and alcoholism, and in pregnant and breast-feeding women. The neuropathy is due to a relative pyridoxine deficiency, because INH increases the excretion of pyridoxine. Thus pyridoxine is recommended for all patients with these risk factors to help prevent neuropathy and may be administered to reverse the neuropathy, should it occur. INH-induced central nervous system (CNS) toxicity is less common than peripheral neuropathy and includes dysarthria, irritability, psychosis, seizures, dysphoria, and inability to concentrate, but the prevalence is not well quantified. Other side effects include rare hypersensitivity reactions such as fever, rash, hemolytic anemia, and vasculitis. CNS toxicity can also be treated with pyridoxine. A lupus-like syndrome is rare (<1%), although approximately 20% of patients develop anti-nuclear antibodies.

Rifampin is generally well tolerated. Patients should be advised that it will result in an orange discoloration of sputum, urine, sweat, and tears, and soft contact lenses may become stained. Rifampin causes nausea and vomiting in 1% to 2% of patients, but they are rarely severe enough to warrant discontinuation. The major toxicity of rifampin is hepatitis. Transient, asymptomatic hyperbilirubinemia may occur in up to 0.6% of patients. More severe hepatitis that has a cholestatic pattern may also occur. It is more common when the drug is given in combination with INH (2.7%) than when given alone or in combination with other drugs (1.1%). Severe hepatic toxicity has been reported when rifampin is used in combination with PZA for short-course (2-month) therapy for treatment of LTBI, and the risk of death has been estimated to be as high as 0.09%. This combination is no longer recommended for LTBI, but both drugs remain important components of multidrug regimens described previously.

Hypersensitivity reactions are uncommon but include thrombocytopenia, hemolysis, transient leukopenia, and renal failure caused by interstitial nephritis. A flu-like syndrome with fever, chills, muscle aches, headache, and dizziness may occur when patients take the drug on a biweekly regimen, but it does not occur with a daily regimen.

Rifampin interacts with many other drugs, usually resulting in increased metabolism and enhanced clearance. It is a potent inducer of cytochrome P450 enzymes, resulting in a number of clinically significant drug-drug interactions (Box 49-1). The concomitant use of anti-TB drugs, including rifampin, and antiretroviral drugs is complex. Rifampin cannot be used with protease inhibitors, although it can be used with nucleoside and some non-nucleoside reverse transcriptase inhibitors. Rifabutin has less of an effect on cytochrome P450s than rifampin and can be used with several protease inhibitors. It is substituted for rifampin when treating HIV-infected patients taking protease inhibitors. The Centers for Disease Control and Prevention has established a website that provides updated information on TB/HIV drug interactions at http://www.cdc.gov/nchstp/tb/tb_hiv_drugs/toc.htm.

Box 49–1 Examples of Drugs with Reduced Half-Lives Caused by Concomitant Administration of Rifampin

Barbiturates

Chloramphenicol

Cimetidine

Clarithromycin

Clofibrate

Contraceptives (oral)

Cyclosporin

Dapsone

Digitoxin

Digoxin

Efavirenz

Estrogens

Fluconazole

Itraconazole

Ketoconazole

Metoprolol

Methadone

Phenytoin

Prednisone

Propranolol

Quinidine

Protease inhibitors

Ritonavir

Sulfonylureas

Tacrolimus

Theophylline

Thyroxine

Verapamil

Warfarin

Women of child-bearing age should be advised to use alternative contraceptive methods while on rifampin, because oral contraceptives will not be effective.

Adverse effects of rifabutin are similar to those of rifampin. In addition, neutropenia has been described, especially among persons with advanced HIV/AIDS. Rifabutin can also cause uveitis, and the risk is increased with higher doses or when used in combination with macrolide antibiotics that reduce its clearance. It may also occur with other drugs that reduce clearance, such as protease inhibitors and azole antifungal drugs. Although drug interactions are less problematic with rifabutin than with rifampin, they still occur, and close monitoring is required.

Adverse effects of rifapentine are similar to those of rifampin. Monitoring is also similar.

Hepatotoxicity is the most serious adverse effect of PZA, and elevation of liver aminotransferase concentration is the first sign. The effect is less frequent in patients who receive the more current lower doses as compared with the higher doses used in earlier trials. Mild anorexia and nausea are common, but severe nausea and vomiting are rare. PZA causes hyperuricemia by inhibiting renal excretion of urate. Clinical gout caused by PZA is rare, although non-gouty polyarthralgia can occur in up to 40% of patients. As mentioned earlier, severe hepatotoxicity has been reported among patients taking rifampin and PZA for short-course therapy for LTBI, and liver function should be carefully monitored.

The most important toxicity of ethambutol is a dose-related retrobulbar (optic) neuritis. This is manifest as decreased visual acuity or decreased red-green color discrimination. Patients should have baseline visual acuity and color discrimination monitored and be questioned about possible visual disturbances. Monthly testing is recommended for patients taking doses greater than 15 mg/kg/day, receiving the drug for longer than 2 months, or with renal insufficiency.

Second Line

Most second-line drugs are less active against M. tuberculosis and have significantly greater toxicity. They are generally used in treatment of drug-resistant TB (including MDR-TB) and should be used only in consultation with an expert.

Adverse effects of the aminoglycosides and fluoroquinolones are discussed in Chapters 47 and 48. Adverse effects of capreomycin are similar to those of aminoglycosides and include nephrotoxicity and ototoxicity. Close monitoring of renal function is required.

CNS effects are most important for cycloserine and are not uncommon. They range from mild reactions, such as headache or restlessness, to severe reactions including depression, psychosis, and seizures. Cycloserine may exacerbate underlying seizure disorders or mental illness. Pyridoxine may help prevent and treat these side effects. Rarely cycloserine can cause peripheral neuropathy.

Ethionamide frequently causes significant GI reactions, and many patients cannot tolerate elevated doses. Nausea, vomiting, abdominal pain, diarrhea, a metallic taste in the mouth, and many CNS complaints including depression, headache, and feelings of restlessness are typical. Endocrine disturbances including gynecomastia, alopecia, hypothyroidism, and impotence have been described. Diabetes may be more difficult to manage. Ethionamide is similar in structure to INH and may cause similar side effects, including hepatitis (approximately 2%). Liver function tests should be monitored if there is underlying liver disease and if symptoms develop. Thyroid hormone levels should also be monitored.

The most common side effects of PAS include nausea, vomiting, abdominal pain, and diarrhea. The incidence of GI side effects is lower with the granular formulation, which is the only formulation available in the United States. A malabsorption syndrome has been described, and hypothyroidism is not uncommon, especially among those taking PAS and ethionamide. Hepatitis is uncommon. With prolonged therapy, thyroid function should be monitored.

Anti-Leprosy Drugs

Adverse effects of rifampin are discussed earlier in the chapter, and fluoroquinolones are discussed in Chapter 48.

Hemolytic anemia and methemoglobinemia are the common adverse effects of dapsone. Hemolysis is greatly enhanced in patients with glucose-6-phosphate dehydrogenase deficiency. Methemoglobinemia is caused by a dapsone N-oxidation product, is usually asymptomatic, but may become important if the patient develops hypoxemia from lung disease. Although bone marrow suppression is rare, agranulocytosis and aplastic anemia may occur. GI intolerance including anorexia, nausea, and vomiting can occur, as well as hematuria, fever, pruritus, and rash.

The most common adverse effects of clofazimine are GI intolerance, including anorexia, diarrhea, and abdominal pain. Skin pigmentation resulting from drug accumulation and producing red-brown to black discoloration is common, especially in dark-skinned persons.

Chemotherapy-Associated Reactions in Leprosy

Patients with leprosy can experience episodic immunologically mediated acute inflammatory responses termed “reactions,” which can cause nerve damage (see Clinical Problems Box). These reactions can be characterized by swelling and edema in preexisting skin lesions, or peripheral neuropathy/neuritis, which can cause pain, tenderness, and loss of function. They occur in up to one third of patients with leprosy and, if not recognized and treated aggressively, can lead to irreversible nerve damage and limb deformity. There are two common types: type I, or reversal, reactions characterized by cellular hypersensitivity; and type 2, or erythema nodosum leprosum, characterized by a systemic inflammatory response to immune complex deposition. In-depth characterization and treatment of these two types of reactions are beyond the scope of this chapter. However, the reversal reactions typically occur after initiation of treatment (especially with dapsone and rifampin) but can occur spontaneously before therapy or after multidrug therapy. A decline in type 2 reactions has been observed since introduction of multidrug therapy and is thought to be due in part to the antiinflammatory effects of daily clofazimine treatment. Recurrences of both types of reactions are common and can result in prolonged use of steroids for suppression.

Anti-M. avium Complex Drugs

The main problems posed by most anti-MAC drugs (macrolides, ethambutol) are noted earlier in this chapter and Chapter 47Rifabutin is generally well tolerated at the lower doses used for prophylaxis against MAC infections, although serious side effects such as uveitis have been reported.

CLINICAL PROBLEMS

Anti-tuberculosis Drugs

Isoniazid

Hepatotoxicity, peripheral neuropathy, CNS effects

Rifampin

Orange discoloration of secretions, GI upset, hepatotoxicity, hypersensitivity reactions, many drug interactions, rash

Pyrazinamide

GI upset, hepatitis, hyperuricemia, arthralgias

Ethambutol

Optic neuritis

Capreomycin

Ototoxicity, renal toxicity

Ethionamide

GI upset, hepatotoxicity

Cycloserine

Psychosis, seizures, headache, depression, other CNS effects

PAS

GI upset, hypersensitivity, hepatotoxicity, drug interactions

Anti-leprosy Drugs

Dapsone

Hemolytic anemia, methemoglobinemia

Clofazimine

GI upset, changes in skin pigmentation

Immune Reactions in Leprosy

Type I

Skin lesions, inflammation of nerve trunk

Type II

Skin lesions, fever, arthralgia, neuritis, vasculitis, adenopathy, iridocyclitis, orchitis, and dactylitis

New Horizons

Worldwide TB control will probably require development of an effective vaccine. The WHO-recommended DOT short-course program has made important contributions to control, and the number of countries implementing it has increased markedly over the past several years. However, most people with TB do not receive such treatment. Furthermore the impact of HIV on the TB epidemic will necessitate new strategies and technologies for the dream of TB elimination to be realized.

Even if an effective vaccine is developed, there is still a critical need for new anti-TB drugs because of the large number of people currently developing active disease and the very large numbers of persons with LTBI at risk for progressing to active disease. New drugs are needed in order to:

• Shorten the length of therapy for drug-susceptible disease

• Improve treatment options and outcomes for patients with MDR-TB

• Provide more effective and shorter regimens for treatment of LTBI.

MDR-TB is emerging as a serious global problem, especially in republics of the former Soviet Union.

No novel compounds likely to have a significant impact on TB treatment are currently available. After decades of neglect, there is some hope for new anti-TB drug development, given the formation of the Global Alliance for TB

TRADE NAMES

(In addition to generic and fixed-combination preparations, the following trade-named materials are some of the important compounds available in the United States.)

First-line Drugs for Tuberculosis

Isoniazid (INH, Laniazid)

Rifampin (Rimactane)

Rifabutin (Mycobutin)

Rifapentine (Priftin)

Pyrazinamide

Ethambutol (Myambutol)

Second-line Drugs for Tuberculosis

Fluoroquinolones

Streptomycin

Kanamycin (Kantrex)

Amikacin (Amikin)

Capreomycin (Capastat)

Ethionamide (Trecator-SC)

p-Aminosalicylic acid (Paser)

Cycloserine (Seromycin)

Other Drugs

Dapsone

Clofazimine (Lamprene)

Minocycline (Dynacin, Minocin)

Azithromycin (Zithromax)

Clarithromycin (Biaxin)

Drug Development. This includes public-private partnerships whose objective is development of new, affordable, faster-acting anti-TB drugs.

Global eradication of leprosy is proposed by the World Health Organization. The total number of cases of leprosy has decreased and research has declined, but case detection is largely passive, even in countries of hyperendemicity. Public health programs have historically focused on education and then relied on patients to present themselves once they become symptomatic. Multidrug therapy has reduced the prevalence of leprosy, but the incidence rate has remained relatively stable because such therapy has little effect on transmission within households. Effective chemoprophylaxis would be welcome for high-risk contacts, but use of rifampin and dapsone have unfortunately been unsuccessful. The only prophylactic measure with any degree of success has been vaccination with bacille Camille Guerin, with one dose conferring approximately 50% protection. An effective vaccine would be highly desirable, and development of such a vaccine may benefit from the high priority of developing an effective vaccine for TB.

Further understanding of the immunology of leprosy is needed. It is hoped the sequencing of the M. leprae genome will help identify protective genomic DNA sequences and that there will be a continuing commitment to research. Because leprosy will persist in many countries, the unprecedented mobility of people around the globe suggests that cases of imported leprosy are likely to continue to occur in the United States. Clinicians must therefore be aware of the signs and symptoms so patients may be appropriately managed and treated.

FURTHER READING

Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med. 2003;167:603-662. (Also published as: Centers for Disease Control and Prevention. Treatment of Tuberculosis, American Thoracic Society, CDC, and Infectious Diseases Society of America. MMWR 2003; 52(No. RR-11):1-77)

Benson CA, Williams PL, Currier JS, et al. AIDS Clinical Trials Group 223 Protocol Team. A prospective, randomized trial examining the efficacy and safety of clarithromycin in combination with ethambutol, rifabutin, or both for the treatment of disseminated Mycobacterium avium complex disease in persons with acquired immunodeficiency syndrome. Clin Infect Dis. 2003;37:1234-1243.

Boggild AK, Keystone JS, Kain KC. Leprosy: A primer for Canadian physicians. CMAJ. 2004;170:71-78.

National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention: Division of Tuberculosis Elimination. TB Guidelineshttp://www.cdc.gov/tb/pubs/mmwr/maj_guide.htm. 4/18/2007 (Accessed on September 2, 2007).

Neurmberger E, Grassert J. Pharmacokinetics and pharmacodynamic issues in the treatment of mycobacterial infections. Eur J Clin Microbiol Infect Dis. 2004;23:243-255.

SELF-ASSESSMENT QUESTIONS

1. A 24-year-old patient receiving combination therapy for the treatment of tuberculosis becomes pregnant, although she has been using oral contraceptives. Which of the following drugs is responsible for interfering with the action of the oral contraceptives, resulting in medication failure?

A. Ethambutol

B. Isoniazid

C. Pyrazinamide

D. Rifampin

E. Streptomycin

2. A patient is newly diagnosed with active tuberculosis. Which of the following drug combinations should be initiated in this patient?

A. Amikacin, isoniazid, pyrazinamide, streptomycin

B. Ciprofloxacin, cycloserine, isoniazid, ethionamide

C. Ethambutol, isoniazid, rifabutin, moxifloxacin

D. Ethambutol, pyrazinamide, rifampin, streptomycin

E. Isoniazid, rifampin, pyrazinamide, ethambutol

3. Multidrug therapy is recommended for most mycobacterial infections. However, which of the following may be treated with a single drug?

A. Disseminated M. avium complex infections

B. Latent tuberculosis infection

C. Leprosy

D. Systemic tuberculosis

4. A 58-year-old woman from Greece is being treated for leprosy. She becomes severely anemic during treatment, and her drug regimen is changed. Which of the following drugs was she initially taking that led to her anemia?

A. Ciprofloxacin

B. Clofazamine

C. Dapsone

D. Ethionamide

E. Rifampin

5. Mycolic acids are major components of mycobacterial cell walls. Which of the following drugs inhibits the synthesis of this component?

A. Clofazamine

B. Ethambutol

C. Ethionamide

D. Isoniazid

E. Rifampin