Antimicrobial Agents: Drugs Used in the Chemotherapy of Tuberculosis, Mycobacterium avium Complex Disease

Isoniazid

Isoniazid (isonicotinic acid hydrazide; NYDRAZID, others) is still considered to be the primary drug for the chemotherapy of tuberculosis, and all patients with disease caused by isoniazid-sensitive strains of the tubercle bacillus should receive the drug if they can tolerate it.

History

The discovery of isoniazid was somewhat fortuitous. In 1945, Chorine reported that nicotinamide possesses tuberculostatic action. Examination of the compounds related to nicotinamide revealed that many pyridine derivatives possess tuberculostatic activity; among these are congeners of isonicotinic acid. Because the thiosemicarbazones were known to inhibit M. tuberculosis, the thiosemicarbazone of isonicotinaldehyde was synthesized and studied. The starting material for this synthesis was the methyl ester of isonicotinic acid, and the first intermediate was isonicotinylhydrazide (isoniazid). The interesting history of these chemical studies has been reviewed by Fox (1953).

Chemistry

Isoniazid is the hydrazide of isonicotinic acid; the structural formula is as follows:

The isopropyl derivative of isoniazid, iproniazid (1-isonicotinyl-2-isopropylhydrazide), also inhibits the multiplication of the tubercle bacillus. This compound, which is a potent inhibitor of monoamine oxidase, is too toxic for use in human beings. However, its study led to the use of monoamine oxidase inhibitors for the treatment of depression (seeChapter 19: Drugs and the Treatment of Psychiatric Disorders: Depression and Anxiety Disorders).

Antibacterial Activity

Isoniazid is bacteriostatic for 'resting' bacilli but is bactericidal for rapidly dividing microorganisms. The minimal tuberculostatic concentration is 0.025 to 0.05 g/ml. The bacteria undergo one or two divisions before multiplication is arrested. The drug is remarkably selective for mycobacteria, and concentrations in excess of 500 g/ml are required to inhibit the growth of other microorganisms.

Isoniazid is highly effective for the treatment of experimentally induced tuberculosis in animals and is strikingly superior to streptomycin. Unlike streptomycin, isoniazid penetrates cells with ease and is just as effective against bacilli growing within cells as it is against those growing in culture media.

Among the various nontuberculous (atypical) mycobacteria, only M. kansasii is usually susceptible to isoniazid. However, sensitivity always must be tested in vitro, since the inhibitory concentration required may be rather high.

Bacterial Resistance

When tubercle bacilli are grown in vitro in increasing concentrations of isoniazid, mutants are readily selected that are resistant to the drug, even when the drug is present in enormous concentrations. However, cross-resistance between isoniazid and other agents used to treat tuberculosis (except ethionamide, which is structurally related to isoniazid) does not occur. The most common mechanism of isoniazid resistance is mutations in catalase-peroxidase that decrease its activity, preventing conversion of the prodrug isoniazid to its active metabolite (Blanchard, 1996). Another mechanism of resistance is related to a missense mutation within the mycobacterial inhA gene involved in mycolic acid biosynthesis (Banerjee et al., 1994).

As with the other agents described, treatment with isoniazid alone leads to the emergence in vivo of resistant strains. The shift from primarily sensitive to mainly insensitive microorganisms occasionally occurs within a few weeks after therapy is started; however, the time of appearance of this phenomenon varies considerably from one case to another. Approximately one in 10⁶ tubercle bacilli will be genetically resistant to isoniazid; since tuberculous cavities may contain as many as 10⁷ to 10⁹ microorganisms, it is not surprising that treatment with isoniazid alone results in the selection of these resistant bacteria. The incidence of primary resistance to isoniazid in the United States until recently had been fairly stable at 2% to 5% of isolates of M. tuberculosis. Resistance currently is estimated at 8% of isolates, but it may be much higher in certain populations, including Asian and Hispanic immigrants and in large urban areas and coastal or border communities (Centers for Disease Control and Prevention, 1999; Iseman, 1993).

Mechanism of Action

Takayama and associates (1975) were among the first to suggest that a primary action of isoniazid is to inhibit the biosynthesis of mycolic acids, important constituents of the mycobacterial cell wall. The mechanism of action of isoniazid is complex, with resistance mapping to mutations in at least five different genes (katG, inhA, ahpC, kasA, and ndh). The preponderance of evidence points to inhA as the primary drug target. The inhA gene encodes the enoyl-ACP reductase of fatty acid synthase II, which converts -unsaturated to saturated fatty acids on the pathway to mycolic acid biosynthesis (Vilcheze et al., 2000). Because mycolic acids are unique to mycobacteria, this action explains the high degree of selectivity of the antimicrobial activity of isoniazid. Exposure to isoniazid leads to a loss of acid-fastness and a decrease in the quantity of methanol-extractable lipid of the microorganisms.

Absorption, Distribution, and Excretion

Isoniazid is readily absorbed when administered either orally or parenterally. Aluminum-containing antacids may interfere with absorption. Peak plasma concentrations of 3 to 5 g/ml develop 1 to 2 hours after oral ingestion of usual doses.

Isoniazid diffuses readily into all body fluids and cells. The drug is detectable in significant quantities in pleural and ascitic fluids; concentrations in the cerebrospinal fluid (CSF) with inflamed meninges are similar to those in the plasma (Holdiness, 1985). Isoniazid penetrates well into caseous material. The concentration of the agent is initially higher in the plasma and muscle than in the infected tissue, but the latter retains the drug for a long time in quantities well above those required for bacteriostasis.

From 75% to 95% of a dose of isoniazid is excreted in the urine within 24 hours, mostly as metabolites. The main excretory products in human beings are the result of enzymatic acetylation (acetylisoniazid) and enzymatic hydrolysis (isonicotinic acid). Small quantities of an isonicotinic acid conjugate (probably isonicotinyl glycine), one or more isonicotinyl hydrazones, and traces of N-methylisoniazid also are detectable in the urine.

Human populations show genetic heterogeneity with regard to the rate of acetylation of isoniazid (Evans et al., 1960). The distribution of slow and rapid inactivators of the drug is bimodal owing to differences in the activity of an acetyltransferase (Figure 481). The rate of acetylation significantly alters the concentrations of the drug that are achieved in plasma and its half-life in the circulation. The half-life of the drug may be prolonged in the presence of hepatic insufficiency.

The frequency of each acetylation phenotype is dependent upon race but is not influenced by gender or age. Fast acetylation is found in Inuit and Japanese. Slow acetylation is the predominant phenotype in most Scandinavians, Jews, and North African Caucasians. The incidence of 'slow acetylators' among the various racial types in the United States is about 50%. Since high acetyltransferase activity (fast acetylation) is inherited as an autosomal dominant trait, 'fast acetylators' of isoniazid are either heterozygous or homozygous. The average concentration of active isoniazid in the circulation of fast acetylators is about 30% to 50% of that present in persons who acetylate the drug slowly. In the whole population, the half-life of isoniazid varies from less than 1 to more than 4 hours (Figure 481). The mean half-life in fast acetylators is approximately 70 minutes, whereas 2 to 5 hours is characteristic of slow acetylators. However, because isoniazid is relatively nontoxic, a sufficient amount of drug can be administered to fast acetylators to achieve a therapeutic effect equal to that seen in slow acetylators. A dosage reduction is recommended for slow acetylators with hepatic failure.

The clearance of isoniazid is dependent to only a small degree on the status of renal function, but patients who are slow inactivators of the drug may accumulate toxic concentrations if their renal function is impaired. Bowersox and colleagues (1973) have suggested that 300 mg per day of the drug can be administered safely to individuals in whom the plasma creatinine concentration is less than 12 mg/dl (1.1 mM).

Therapeutic Uses

Isoniazid is still the most important drug worldwide for the treatment of all types of tuberculosis. Toxic effects can be minimized by prophylactic therapy with pyridoxine and careful surveillance of the patient. The drug must be used concurrently with another agent for treatment, although it is used alone for prophylaxis.

Isoniazid is available for oral and parenteral administration. The commonly used total daily dose of isoniazid is 5 mg/kg, with a maximum of 300 mg; oral and intramuscular doses are identical. Isoniazid usually is given orally in a single daily dose but may be given in two divided doses. Although doses of 10 to 20 mg/kg, with a maximum of 600 mg, occasionally are used in severely ill patients, there is no evidence that this regimen is more effective. Children should receive 10 to 20 mg/kg per day (300 mg maximum). Isoniazid may be used as intermittent therapy for tuberculosis; after a minimum of 2 months of daily therapy of tuberculosis due to sensitive strains of M. tuberculosis with isoniazid, rifampin, and pyrazinamide, patients may be treated with twice-weekly doses of isoniazid (15 mg/kg orally) plus rifampin (10 mg/kg, up to 600 mg per dose) for 4 months.

Pyridoxine (15 to 50 mg per day) should be administered with isoniazid to minimize adverse reactions (see below) in malnourished patients and those predisposed to neuropathy (e.g., the elderly, pregnant women, HIV-infected individuals, diabetics, alcoholics, and uremics; Snider, 1980).

Untoward Effects

The incidence of adverse reactions to isoniazid was estimated to be 5.4% among more than 2000 patients treated with the drug; the most prominent of these reactions were rash (2%), fever (1.2%), jaundice (0.6%), and peripheral neuritis (0.2%). Hypersensitivity to isoniazid may result in fever, various skin eruptions, hepatitis, and morbilliform, maculopapular, purpuric, and urticarial rashes. Hematological reactions also may occur (agranulocytosis, eosinophilia, thrombocytopenia, anemia). Vasculitis associated with antinuclear antibodies may appear during treatment but disappears when the drug is stopped. Arthritic symptoms (back pain; bilateral proximal interphalangeal joint involvement; arthralgia of the knees, elbows, and wrists; and the 'shoulder-hand' syndrome) have been attributed to this agent.

If pyridoxine is not given concurrently, peripheral neuritis (most commonly paresthesia of feet and hands) is the most common reaction to isoniazid and occurs in about 2% of patients receiving 5 mg/kg of the drug daily. Higher doses may result in peripheral neuritis in 10% to 20% of patients. Neuropathy is more frequent in slow acetylators and in individuals with diabetes mellitus, poor nutrition, or anemia. The prophylactic administration of pyridoxine prevents the development not only of peripheral neuritis but also of most other nervous system disorders in practically all instances even when therapy lasts as long as 2 years.

Isoniazid may precipitate convulsions in patients with seizure disorders and, rarely, in patients with no history of seizures. Optic neuritis and atrophy also have occurred during therapy with the drug. Muscle twitching, dizziness, ataxia, paresthesias, stupor, and toxic encephalopathy that may be fatal are other manifestations of the neurotoxicity of isoniazid. A number of mental abnormalities may appear during the use of this drug; among these are euphoria, transient impairment of memory, separation of ideas and reality, loss of self-control, and florid psychoses.

Isoniazid is known to inhibit the parahydroxylation of phenytoin, and signs and symptoms of toxicity occur in approximately 27% of patients given both drugs, particularly in those who are slow acetylators (Miller et al., 1979). Concentrations of phenytoin in plasma should be monitored and adjusted if necessary. The dosage of isoniazid should not be changed.

Although jaundice has been known for some time to be an untoward effect of exposure to isoniazid, not until the early 1970s did it become apparent that severe hepatic injury leading to death may occur in some individuals receiving this drug (Garibaldi et al., 1972). Additional studies in adults and children have confirmed this observation; the characteristic pathological process is bridging and multilobular necrosis. Continuation of the drug after symptoms of hepatic dysfunction have appeared tends to increase the severity of damage. The mechanisms responsible for this toxicity are unknown, although acetylhydrazine, which is a metabolite of isoniazid, causes hepatic damage in adults. Hence, patients who are rapid acetylators of isoniazid might be expected to be more likely to develop hepatotoxicity than slow acetylators. Whether or not this is true, however, is unresolved. A contributory role of alcoholic hepatitis has been noted, but chronic carriers of the hepatitis B virus tolerate isoniazid (McGlynn et al., 1986). Age appears to be the most important factor in determining the risk of isoniazid-induced hepatotoxicity. Hepatic damage is rare in patients less than 20 years old; the complication is observed in 0.3% of those 20 to 34 years old, and the incidence increases to 1.2% and 2.3% in individuals 35 to 49 and older than 50 years of age, respectively (Bass et al., 1994; Comstock, 1983). Up to 12% of patients receiving isoniazid may have elevated plasma aspartate and alanine transaminase activities (Bailey et al., 1974). Patients receiving isoniazid should be carefully evaluated at monthly intervals for symptoms of hepatitis (anorexia, malaise, fatigue, nausea, and jaundice) and warned to discontinue the drug if such symptoms occur. Some clinicians also prefer to determine serum aspartate aminotransferase activities at monthly intervals (Byrd et al., 1979) and recommend that an elevation greater than five times normal is cause for discontinuation of the drug. Most hepatitis occurs 4 to 8 weeks after the start of therapy. Isoniazid should be administered with great care to those with preexisting hepatic disease.

Among miscellaneous reactions associated with isoniazid therapy are dryness of the mouth, epigastric distress, methemoglobinemia, tinnitus, and urinary retention. In persons predisposed to pyridoxine-deficiency anemia, the administration of isoniazid may result in its appearance in full-blown form. Treatment with large doses of the vitamin gradually returns the blood to normal in such cases (seeGoldman and Braman, 1972). A drug-induced syndrome resembling systemic lupus erythematosus has been reported. Overdose of isoniazid, as in attempted suicide, may result in nausea, vomiting, dizziness, slurred speech, and visual hallucinations followed by coma, seizures, metabolic acidosis, and hyperglycemia. Pyridoxine is an antidote in this setting; it should be given in a dose that approximates the amount of isoniazid ingested.

Rifampin

The rifamycins (rifampin, rifabutin, rifapentine) are a group of structurally similar, complex macrocyclic antibiotics produced by Streptomyces mediterranei (Farr, 2000); rifampin (RIFADIN RIMACTANE) is a semisynthetic derivative of one of theserifamycin B.

Chemistry

Rifampin is soluble in organic solvents and in water at acidic pH. It has the following structure:

Antibacterial Activity

Rifampin inhibits the growth of most gram-positive bacteria as well as many gram-negative microorganisms such as Escherichia coli, Pseudomonas, indole-positive and indole-negative Proteus, and Klebsiella. Rifampin is very active against Staphylococcus aureus and coagulase-negative staphylococci; bactericidal concentrations range from 3 to 12 ng/ml. The drug also is highly active against Neisseria meningitidis and Haemophilus influenzae; minimal inhibitory concentrations range from 0.1 to 0.8 g/ml. Rifampin is very inhibitory to Legionella species in cell culture and in animal models.

Rifampin in concentrations of 0.005 to 0.2 g/ml inhibits the growth of M. tuberculosisin vitro. Among nontuberculous mycobacteria, Mycobacterium kansasii is inhibited by 0.25 to 1 g/ml. The majority of strains of Mycobacterium scrofulaceum, Mycobacterium intracellulare, and M. avium are suppressed by concentrations of 4 g/ml, but certain strains may be resistant to 16 g/ml. Mycobacterium fortuitum is highly resistant to the drug. Rifampin increases the in vitro activity of streptomycin and isoniazid, but not that of ethambutol, against M. tuberculosis (Hobby and Lenert, 1972).

Bacterial Resistance

Microorganisms, including mycobacteria, may develop resistance to rifampin rapidly in vitro as a one-step process, and one of every 10⁷ to 10⁸ tubercle bacilli is resistant to the drug. Resistance in most cases is due to mutations between codons 507 and 533 of the polymerase rpoB gene (Blanchard, 1996). This also appears to be the case in vivo, and therefore the antibiotic must not be used alone in the chemotherapy of tuberculosis. When rifampin has been used for eradication of the meningococcal carrier state, failures have been due to the appearance of drug-resistant bacteria after treatment for as little as 2 days. Microbial resistance to rifampin is due to an alteration of the target of this drug, DNA-dependent RNA polymerase. Certain rifampin-resistant bacterial mutants have decreased virulence. Tuberculosis caused by rifampin-resistant mycobacteria has been described in patients who had not received prior chemotherapy, but this is very rare (usually less than 1%; Cauthen et al., 1988).

Mechanism of Action

Rifampin inhibits DNA-dependent RNA polymerase of mycobacteria and other microorganisms by forming a stable drugenzyme complex, leading to suppression of initiation of chain formation (but not chain elongation) in RNA synthesis. More specifically, the subunit of this complex enzyme is the site of action of the drug, although rifampin binds only to the holoenzyme. Nuclear RNA polymerase from a variety of eukaryotic cells does not bind rifampin, and RNA synthesis is correspondingly unaffected. While rifampin can inhibit RNA synthesis in mammalian mitochondria, considerably higher concentrations of the drug are required than for the inhibition of the bacterial enzyme. High concentrations of rifamycin antibiotics also inhibit viral DNA-dependent RNA polymerases and reverse transcriptases. Rifampin is bactericidal for both intracellular and extracellular microorganisms.

Absorption, Distribution, and Excretion

The oral administration of rifampin produces peak concentrations in plasma in 2 to 4 hours; after ingestion of 600 mg, this value is about 7 g/ml, but there is considerable variability. Aminosalicylic acid may delay the absorption of rifampin, and adequate plasma concentrations may not be reached. If these agents are used concurrently, they should be given separately at an interval of 8 to 12 hours (seeRadner, 1973).

Following absorption from the gastrointestinal tract, rifampin is eliminated rapidly in the bile, and an enterohepatic circulation ensues. During this time, the drug is progressively deacetylated, to a degree that, after 6 hours, nearly all of the antibiotic in the bile is in the deacetylated form. This metabolite retains essentially full antibacterial activity. Intestinal reabsorption is reduced by deacetylation (as well as by food), and thus metabolism facilitates elimination of the drug. The half-life of rifampin varies from 1.5 to 5 hours and is increased in the presence of hepatic dysfunction; it may be decreased in patients receiving isoniazid concurrently who are slow inactivators of this drug. The half-life of rifampin is progressively shortened by about 40% during the first 14 days of treatment, owing to induction of hepatic microsomal enzymes with acceleration of deacetylation of the drug. Up to 30% of a dose of the drug is excreted in the urine and 60% to 65% in the feces; less than half of this may be unaltered antibiotic. Adjustment of dosage is not necessary in patients with impaired renal function.

Rifampin is distributed throughout the body and is present in effective concentrations in many organs and body fluids, including the CSF (Sippel et al., 1974). This is perhaps best exemplified by the fact that the drug may impart an orange-red color to the urine, feces, saliva, sputum, tears, and sweat; patients should be so warned. (For various aspects of rifampin metabolism, seeFuresz, 1970; Farr, 2000.)

Therapeutic Uses

Rifampin is available alone and as a fixed-dose combination with isoniazid (150 mg of isoniazid, 300 mg of rifampin; RIFAMATE) or with isoniazid and pyrazinamide (50 mg of isoniazid, 120 mg of rifampin, and 300 mg pyrazinamide; RIFATER). Rifampin and isoniazid are the most effective drugs available for the treatment of tuberculosis. The dose of rifampin for treatment of tuberculosis in adults is 600 mg, given once daily, either 1 hour before or 2 hours after a meal. Children should receive 10 mg/kg, with a daily maximum, given in the same way. Doses of 15 mg/kg or higher are associated with increased hepatotoxicity in children (Centers for Disease Control, 1980). Rifampin, like isoniazid, should never be used alone for this disease because of the rapidity with which resistance may develop. Despite the long list of untoward effects from rifampin, their incidence is low, and treatment seldom has to be interrupted.

The use of rifampin in the chemotherapy of tuberculosis is detailed below. Rifampin also is indicated for the prophylaxis of meningococcal disease and H. influenzae meningitis. To prevent meningococcal disease, adults may be treated with 600 mg twice daily for 2 days or 600 mg once daily for 4 days; children should receive 10 to 20 mg/kg, to a maximum of 600 mg.

Untoward Effects

Rifampin generally is well tolerated. When given in usual doses, fewer than 4% of patients with tuberculosis have significant adverse reactions; the most common are rash (0.8%), fever (0.5%), and nausea and vomiting (1.5%) (seeGrosset and Leventis, 1983). Rarely, hepatitis and deaths due to liver failure have been observed in patients who received other hepatoxic agents in addition to rifampin or who had preexisting liver disease. Hepatitis from rifampin rarely occurs in patients with normal hepatic function; likewise, the combination of isoniazid and rifampin appears generally safe in such patients (Gangadharam, 1986). However, chronic liver disease, alcoholism, and old age appear to increase the incidence of severe hepatic problems when rifampin is given alone or concurrently with isoniazid.

Administration of rifampin on an intermittent schedule (less than twice weekly) and/or daily doses of 1200 mg or greater is associated with frequent side effects, and the drug should not be used in this manner. A flulike syndrome with fever, chills, and myalgias develops in 20% of patients so treated. The syndrome also may include eosinophilia, interstitial nephritis, acute tubular necrosis, thrombocytopenia, hemolytic anemia, and shock (Girling and Hitze, 1979).

Because rifampin is a potent inducer of hepatic microsomal enzymes, its administration results in a decreased half-life for a number of compounds, including HIV protease and nonnucleoside reverse transcriptase inhibitors, digitoxin, digoxin, quinidine, disopyramide, mexiletine, tocainide, ketoconazole, propranolol, metoprolol, clofibrate, verapamil, methadone, cyclosporine, corticosteroids, oral anticoagulants, theophylline, barbiturates, oral contraceptives, halothane, fluconazole, and the sulfonylureas (Farr, 2000). Rifabutin has less of an effect on the metabolism of the HIV protease inhibitors indinavir and nelfinavir. The significant interaction between rifampin and oral anticoagulants of the coumarin type leads to a decrease in efficacy of these agents. This effect appears about 5 to 8 days after rifampin administration is started and persists for 5 to 7 days after it is stopped (O'Reilly, 1975). The ability of rifampin to enhance the catabolism of a variety of steroids leads to the decreased effectiveness of oral contraceptives (Skolnick et al., 1976). The increased metabolism of methadone has led to reports of precipitation of withdrawal syndromes. Rifampin may reduce biliary excretion of contrast media used for visualization of the gallbladder (seeBaciewicz et al., 1987).

Gastrointestinal disturbances produced by rifampin (epigastric distress, nausea, vomiting, abdominal cramps, diarrhea) have occasionally required discontinuation of the drug. Various symptoms related to the nervous system also have been noted, including fatigue, drowsiness, headache, dizziness, ataxia, confusion, inability to concentrate, generalized numbness, pain in the extremities, and muscular weakness. Among hypersensitivity reactions are fever, pruritus, urticaria, various types of skin eruptions, eosinophilia, and soreness of the mouth and tongue. Hemolysis, hemoglobinuria, hematuria, renal insufficiency, and acute renal failure have been observed rarely; these also are thought to be hypersensitivity reactions. Thrombocytopenia, transient leukopenia, and anemia have occurred during therapy. Since the potential teratogenicity of rifampin is unknown and the drug is known to cross the placenta, it is best to avoid the use of this agent during pregnancy.

Graber and associates (1973) have noted immunoglobulin light-chain proteinuria (either kappa, lambda, or both) in about 85% of patients with tuberculosis treated with rifampin. None of the patients had symptoms or electrophoretic patterns compatible with myeloma. However, renal failure has been associated with light-chain proteinuria (Warrington et al., 1977).

Rifampin is a drug of choice for chemoprophylaxis of meningococcal disease and meningitis due to H. influenzae in household contacts of patients with such infections. Combined with a -lactam antibiotic or vancomycin, rifampin may be useful for therapy in selected cases of staphylococcal endocarditis (on both natural and prosthetic valves) or osteomyelitis, especially those caused by staphylococci 'tolerant' to penicillin. Rifampin may be indicated for therapy of infections in patients with inadequate leukocytic bactericidal activity and for eradication of the staphylococcal nasal carrier state in patients with chronic furunculosis (Wheat et al., 1983).

Ethambutol

Chemistry

Ethambutol is a water-soluble and heat-stable compound. The structural formula is as follows:

Antibacterial Activity

Nearly all strains of M. tuberculosis and M. kansasii as well as a number of strains of M. avium complex are sensitive to ethambutol (Pablos-Mndez et al., 1998). The sensitivities of other nontuberculous organisms are variable. Ethambutol has no effect on other bacteria. It suppresses the growth of most isoniazid- and streptomycin-resistant tubercle bacilli. Resistance to ethambutol develops very slowly in vitro.

Mycobacteria take up ethambutol rapidly when the drug is added to cultures that are in the exponential growth phase. However, growth is not significantly inhibited before about 24 hours; the drug is tuberculostatic. Ethambutol blocks arabinosyl transferases involved in cell wall biosynthesis (Takayama et al., 1979). Bacterial resistance to the drug develops in vivo via single amino acid changes in the embA gene when ethambutol is given in the absence of another effective agent (Belanger et al., 1996).

Absorption, Distribution, and Excretion

About 75% to 80% of an orally administered dose of ethambutol is absorbed from the gastrointestinal tract. Concentrations in plasma are maximal in human beings 2 to 4 hours after the drug is taken and are proportional to the dose. A single dose of 25 mg/kg produces a plasma concentration of 2 to 5 g/ml at 2 to 4 hours. The drug has a half-life of 3 to 4 hours.

Within 24 hours, three-fourths of an ingested dose of ethambutol is excreted unchanged in the urine; up to 15% is excreted in the form of two metabolites, an aldehyde and a dicarboxylic acid derivative. Renal clearance of ethambutol is approximately 7 mlmin¹ kg¹; thus it is evident that the drug is excreted by tubular secretion in addition to glomerular filtration.

Therapeutic Uses

Ethambutol (ethambutol hydrochloride; MYAMBUTOL) has been used with notable success in the therapy of tuberculosis of various forms when given concurrently with isoniazid. Because of a lower incidence of toxic effects and better acceptance by patients, ethambutol has essentially replaced aminosalicylic acid (seeBobrowitz, 1974).

Ethambutol is available for oral administration in tablets containing the d isomer. The usual adult dose of ethambutol is 15 mg/kg given once a day. Some physicians prefer to institute therapy with a dose of 25 mg/kg per day for the first 60 days and then to reduce the dose to 15 mg/kg per day, particularly for those who have received previous therapy. Ethambutol accumulates in patients with impaired renal function, and adjustment of dosage is necessary.

Ethambutol is not recommended for children under 5 years of age, in part because of concern about the ability to test their visual acuity (see below). Children from ages 6 to 12 years should receive 10 to 15 mg/kg per day.

The use of ethambutol in the chemotherapy of tuberculosis is described below.

Untoward Effects

The most important side effect is optic neuritis, resulting in decrease of visual acuity and loss of ability to differentiate red from green. The incidence of this reaction is proportional to the dose of ethambutol and is observed in 15% of patients receiving 50 mg/kg per day, in 5% of patients receiving 25 mg/kg per day, and in fewer than 1% of patients receiving daily doses of 15 mg/kg (the recommended dose for treatment of tuberculosis). The intensity of the visual difficulty is related to the duration of therapy after the decrease in visual acuity first becomes apparent, and it may be unilateral or bilateral. Tests of visual acuity and red-green discrimination prior to the start of therapy and periodically thereafter are thus recommended. Recovery usually occurs when ethambutol is withdrawn; the time required is a function of the degree of visual impairment.

Ethambutol produces very few reactions. Daily doses of 15 mg/kg are minimally toxic. Fewer than 2% of nearly 2000 patients who received 15 mg/kg of ethambutol had adverse reactions; 0.8% experienced diminished visual acuity, 0.5% had a rash, and 0.3% developed drug fever. Other side effects that have been observed are pruritus, joint pain, gastrointestinal upset, abdominal pain, malaise, headache, dizziness, mental confusion, disorientation, and possible hallucination. Numbness and tingling of the fingers owing to peripheral neuritis are infrequent. Anaphylaxis and leukopenia are rare.

Therapy with ethambutol results in an increased concentration of urate in the blood in about 50% of patients, owing to decreased renal excretion of uric acid. The effect may be detectable as early as 24 hours after a single dose or as late as 90 days after treatment is started. This untoward effect is possibly enhanced by isoniazid and pyridoxine (Postlethwaite et al., 1972).

Streptomycin

A discussion of the pharmacology of streptomycin, including its adverse effects and its uses in infections other than tuberculosis, is presented in Chapter 46: Antimicrobial Agents: The Aminoglycosides. Only features of the drug related to its antibacterial activity and therapeutic effects in the management of diseases caused by mycobacteria are considered here.

History

Streptomycin was the first clinically effective drug to become available for the treatment of tuberculosis. At first, it was given in large doses, but problems related to toxicity and the development of resistant microorganisms seriously limited its usefulness. The antibiotic was then administered in smaller quantities, but streptomycin administered alone still proved to be far from the ideal agent for the management of all forms of the disease. However, the discovery of other compounds that, given concurrently with the antibiotic, reduced the rate at which microorganisms became drug-resistant enabled physicians to treat tuberculosis effectively with streptomycin. It is now the least used of the 'first-line' agents in the therapy of tuberculosis.

Antibacterial Activity

Streptomycin is bactericidal for the tubercle bacillus in vitro. Concentrations as low as 0.4 g/ml may inhibit growth. The vast majority of strains of M. tuberculosis are sensitive to 10 g/ml. M. kansasii is frequently sensitive, but other nontuberculous mycobacteria are only occasionally susceptible.

The activity of streptomycin in vivo is essentially suppressive. When the antibiotic is administered to experimental animals prior to inoculation with the tubercle bacillus, the development of disease is not prevented. Infection progresses until the animals' immunological mechanisms respond. The presence of viable microorganisms in abscesses and in the regional lymph nodes adds support to the concept that the activity of streptomycin in vivo is to suppress, not to eradicate, the tubercle bacillus. This property of streptomycin may be related to the observation that the drug does not readily enter living cells and thus cannot kill intracellular microbes.

Bacterial Resistance

Large populations of all strains of tubercle bacilli include a number of cells that are markedly resistant to streptomycin because of mutation. However, primary resistance to the antibiotic is found in only 2% to 3% of isolates of M. tuberculosis.

Selection for resistant tubercle bacilli occurs in vivo as it does in vitro. In general, the longer therapy is continued, the greater is the incidence of resistance to streptomycin. When streptomycin was used alone, as many as 80% of patients harbored insensitive tubercle bacilli after 4 months of treatment; many of these microorganisms were not inhibited by concentrations of drug as high as 1000 g/ml.

Therapeutic Uses

Since other effective agents have become available, the use of streptomycin for the treatment of pulmonary tuberculosis has been sharply reduced. Many clinicians prefer to give four drugs, of which streptomycin may be one, for the most serious forms of tuberculosis, such as disseminated disease or meningitis.

For tuberculosis, adults should be given 15 mg/kg per day in divided doses given every 12 hours, not to exceed 1 g per day. Children should receive 20 to 40 mg/kg per day in divided doses every 12 to 24 hours, not to exceed 1 g per day. Therapy usually is discontinued after 2 to 3 months, or sooner if cultures become negative. Dosage schedules for various forms of tuberculosis are discussed further below.

Untoward Effects

Untoward effects of streptomycin are considered in detail in Chapter 46: Antimicrobial Agents: The Aminoglycosides. Of 515 patients with tuberculosis who were treated with this aminoglycoside, 8.2% had adverse reactions; half of these involved the auditory and vestibular functions of the eighth cranial nerve. Other relatively frequent problems included rash (in 2%) and fever (in 1.4%).

Pyrazinamide

Chemistry

Pyrazinamide is the synthetic pyrazine analog of nicotinamide. It has the following structural formula:

Antibacterial Activity

Pyrazinamide exhibits bactericidal activity in vitro only at a slightly acidic pH. Activity at acid pH is ideal, since M. tuberculosis resides in an acidic phagosome within the macrophage (Jacobs, 2000). Tubercle bacilli within monocytes in vitro are inhibited or killed by the drug at a concentration of 12.5 g/ml. Resistance develops rapidly if pyrazinamide is used alone. The target of pyrazinamide appears to be the mycobacterial fatty acid synthase I gene involved in mycolic acid biosynthesis (Zimhony et al., 2000).

Absorption, Distribution, and Excretion

Pyrazinamide is well absorbed from the gastrointestinal tract, and it is widely distributed throughout the body. The oral administration of 500 mg produces plasma concentrations of about 9 to 12 g/ml at 2 hours and 7 g/ml at 8 hours. The plasma half-life is 9 to 10 hours in patients with normal renal function. The drug is excreted primarily by renal glomerular filtration. Pyrazinamide is distributed widelyincluding the CNS, lungs, and liverafter oral administration. Penetration of the drug into the CSF is excellent. Pyrazinamide is hydrolyzed to pyrazinoic acid and subsequently hydroxylated to 5-hydroxypyrazinoic acid, the major excretory product.

Therapeutic Uses

Pyrazinamide has become an important component of short-term (6-month) multiple-drug therapy of tuberculosis (British Thoracic Association, 1983; Bass et al., 1994).

Pyrazinamide is available in tablets for oral administration. The daily dose for adults is 15 to 30 mg/kg orally, given as a single dose. The maximum quantity to be given is 2 g per day, regardless of weight. Children should receive 15 to 30 mg/kg per day; daily doses should not exceed 2 g. Pyrazinamide also has been safe and effective when administered twice or thrice weekly (at increased dosages).

Untoward Effects

Injury to the liver is the most serious side effect of pyrazinamide. When a dose of 40 to 50 mg/kg is administered orally, signs and symptoms of hepatic disease appear in about 15% of patients, with jaundice in 2% to 3% and death due to hepatic necrosis in rare instances. Elevations of the plasma alanine and aspartate aminotransferases are the earliest abnormalities produced by the drug. Regimens employed currently (15 to 30 mg/kg per day) are much safer (Girling, 1978). All patients who are being treated with pyrazinamide should undergo studies of hepatic function before the drug is administered; these studies should be repeated at frequent intervals during the entire period of treatment. If evidence of significant hepatic damage becomes apparent, therapy must be stopped. Pyrazinamide should not be given to individuals with any degree of hepatic dysfunction unless this is absolutely unavoidable.

The drug inhibits excretion of urate, resulting in hyperuricemia in nearly all patients; acute episodes of gout have occurred. Other untoward effects that have been observed with pyrazinamide are arthralgias, anorexia, nausea and vomiting, dysuria, malaise, and fever. While some international organizations recommend the use of pyrazinamide in pregnancy, this is not the case in the United States because of inadequate data on teratogenicity (Bass et al., 1994).

Ethionamide

Chemistry

Synthesis and study of a variety of congeners of thioisonicotinamide revealed that an alpha-ethyl derivativeethionamide (TRECATOR-SC)is considerably more effective than the parent compound. It has the following structural formula:

Antibacterial Activity

The multiplication of M. tuberculosis is suppressed by concentrations of ethionamide ranging from 0.6 to 2.5 g/ml. Resistance can develop rapidly in vitro. A concentration of 10 g/ml or less will inhibit approximately 75% of photochromogenic mycobacteria; the scotochromogens are more resistant. Ethionamide is very effective in the treatment of experimental tuberculosis in animals, although its activity varies greatly with the animal model studied.

Absorption, Distribution, and Excretion

The oral administration of 1 g of ethionamide yields peak concentrations in plasma of about 20 g/ml in 3 hours; the concentration at 9 hours is 3 g/ml. The half-life of the drug is about 2 hours. Approximately 50% of patients are unable to tolerate a single dose larger than 500 mg because of gastrointestinal disturbance. Ethionamide is rapidly and widely distributed; the concentrations in the blood and various organs are approximately equal. Significant concentrations are present in CSF. Ethionamide, like aminosalicylic acid, inhibits the acetylation of isoniazid in vitro. Less than 1% of ethionamide is excreted in active form in the urine; there are several metabolites.

Therapeutic Uses

Ethionamide is a secondary agent, to be used concurrently with other drugs only when therapy with primary agents is ineffective or contraindicated.

Ethionamide is administered only orally. The initial dosage of ethionamide for adults is 250 mg twice daily; it is increased by 125 mg per day every 5 days until a dose of 15 to 20 mg/kg per day is achieved. The maximal dose is 1 g daily. The drug is best taken with meals in divided doses in order to minimize gastric irritation. Children should receive 15 to 20 mg/kg per day in two divided doses, not to exceed 1 g per day.

Untoward Effects

The most common reactions to ethionamide are anorexia, nausea, and vomiting. A metallic taste also may be noted. Severe postural hypotension, mental depression, drowsiness, and asthenia are common. Convulsions and peripheral neuropathy are rare. Other reactions referable to the nervous system include olfactory disturbances, blurred vision, diplopia, dizziness, paresthesias, headache, restlessness, and tremors. Severe allergic skin rashes, purpura, stomatitis, gynecomastia, impotence, menorrhagia, acne, and alopecia also have been observed. Hepatitis has been associated with the use of the drug in about 5% of cases (Simon et al., 1969). The signs and symptoms of hepatotoxicity clear when treatment is stopped. Hepatic function should be assessed at regular intervals in patients receiving ethionamide. The concomitant use of pyridoxine is recommended for patients being treated with ethionamide.

Aminosalicylic Acid

Chemistry

The structural formula of aminosalicylic acid (p-aminosalicylic acid, PAS) is as follows:

Antibacterial Activity

Aminosalicylic acid is bacteriostatic. In vitro, most strains of M. tuberculosis are sensitive to a concentration of 1 g/ml. The antimicrobial activity of aminosalicylic acid is highly specific, and microorganisms other than M. tuberculosis are unaffected. Most nontuberculous mycobacteria are not inhibited by the drug.

Studies of the treatment of experimental M. tuberculosis infections indicate that aminosalicylic acid exerts a beneficial effect on the disease. However, the doses required are relatively large, and the compound must be present continuously. Aminosalicylic acid alone is of little value in the treatment of tuberculosis in human beings.

Bacterial Resistance

Strains of tubercle bacilli insensitive to several hundred times the usual bacteriostatic concentration of aminosalicylic acid can be produced in vitro. Resistant strains of tubercle bacilli also emerge in patients treated with aminosalicylic acid, but much more slowly than with streptomycin.

Mechanism of Action

Aminosalicylic acid is a structural analog of paraaminobenzoic acid, and its mechanism of action appears to be very similar to that of the sulfonamides (seeChapter 44: Antimicrobial Agents: Sulfonamides, Trimethoprim-Sulfamethoxazole, Quinolones, and Agents for Urinary Tract Infections). Since the sulfonamides are ineffective against M. tuberculosis, and aminosalicylic acid is inactive against sulfonamide-susceptible bacteria, it is probable that the enzymes responsible for folate biosynthesis in various microorganisms may be quite exacting in their capacity to distinguish various analogs from the true metabolite.

Absorption, Distribution, and Excretion

Aminosalicylic acid is readily absorbed from the gastrointestinal tract. A single oral dose of 4 g of the free acid produces maximal concentrations in plasma of about 75 g/ml within 1.5 to 2 hours. The sodium salt is absorbed even more rapidly. The drug appears to be distributed throughout the total body water and reaches high concentrations in pleural fluid and caseous tissue. However, values in CSF are low, perhaps because of active outward transport.

The drug has a half-life of about 1 hour, and concentrations in plasma are negligible within 4 to 5 hours after a single conventional dose. Over 80% of the drug is excreted in the urine; more than 50% is in the form of the acetylated compound. The largest portion of the remainder is made up of the free acid. Excretion of aminosalicylic acid is greatly retarded in the presence of renal dysfunction, and the use of the drug is not recommended in such patients. Probenecid decreases the renal excretion of this agent.

Therapeutic Uses

Aminosalicylic acid is a 'second-line' agent. Its importance in the management of pulmonary and other forms of tuberculosis has markedly decreased since more active and better-tolerated drugs, such as rifampin and ethambutol, have been developed (seeChemotherapy of Tuberculosis, below).

Aminosalicylic acid is administered orally in a daily dose of 10 to 12 g. Because it is a gastric irritant, the drug is best administered after meals, the daily dose being divided into two to four equal portions. Children should receive 150 to 300 mg/kg per day in three to four divided doses.

Untoward Effects

The incidence of untoward effects associated with the use of aminosalicylic acid is approximately 10% to 30%. Gastrointestinal problemsincluding anorexia, nausea, epigastric pain, abdominal distress, and diarrheaare predominant, and patients with peptic ulcer tolerate the drug poorly. Compliance is often poor because of gastrointestinal distress. Hypersensitivity reactions to aminosalicylic acid are seen in 5% to 10% of patients. High fever may develop abruptly, with intermittent spiking, or it may appear gradually and be low-grade. Generalized malaise, joint pains, or sore throat may be present at the same time. Skin eruptions of various types appear as isolated reactions or accompany the fever. Among the hematological abnormalities that have been observed are leukopenia, agranulocytosis, eosinophilia, lymphocytosis, an atypical mononucleosis syndrome, and thrombocytopenia. Acute hemolytic anemia may appear in some instances.

Cycloserine

Cycloserine SEROMYCIN) is a broad-spectrum antibiotic produced by Streptococcus orchidaceus. It was first isolated from a fermentation brew in 1955 and was later synthesized. Currently, cycloserine is used in conjunction with other tuberculostatic drugs in the treatment of pulmonary or extrapulmonary tuberculosis when primary agents (isoniazid, rifampin, ethambutol, pyrazinamide, streptomycin) have failed.

Chemistry

Cycloserine is D-4-amino-3-isoxazolidone; the structural formula is as follows:

The drug is stable in alkaline solution but is rapidly destroyed when exposed to neutral or acidic pH.

Antibacterial Activity and Mechanism of Action

Cycloserine is inhibitory for M. tuberculosis in concentrations of 5 to 20 g/ml in vitro. There is no cross-resistance between cycloserine and other tuberculostatic agents. While the antibiotic is effective in experimental infections caused by other microorganisms, studies in vitro reveal no suppression of growth in cultures made in conventional media, which contain D-alanine; this amino acid blocks the antibacterial activity of cycloserine. The two compounds are structural analogs, and cycloserine inhibits reactions in which D-alanine is involved in bacterial cell-wall synthesis (seeChapter 45: Antimicrobial Agents: Penicillins, Cephalosporins, and Other -Lactam Antibiotics). The use of media free of D-alanine reveals that the antibiotic inhibits the growth in vitro of enterococci, Escherichia coli, Staphylococcus aureus, Nocardia species, and Chlamydia.

Absorption, Distribution, and Excretion

When given orally, 70% to 90% of cycloserine is rapidly absorbed. Peak concentrations in plasma are reached 3 to 4 hours after a single dose and are in the range of 20 to 35 g/ml in children who receive 20 mg/kg; only small quantities are present after 12 hours. Cycloserine is distributed throughout body fluids and tissues. There is no appreciable bloodbrain barrier to the drug, and CSF concentrations in all patients are approximately the same as those in plasma. About 50% of a parenteral dose of cycloserine is excreted unchanged in the urine in the first 12 hours; a total of 65% is recoverable in the active form over a period of 72 hours. Very little of the antibiotic is metabolized. The drug may accumulate to toxic concentrations in patients with renal insufficiency; it may be removed from the circulation by dialysis.

Therapeutic Uses

Cycloserine should be used only when retreatment is necessary or when microorganisms are resistant to other drugs. When cycloserine is employed to treat tuberculosis, it must be given together with other effective agents. Cycloserine is available for oral administration. The usual dose for adults is 250 to 500 mg twice daily.

Untoward Effects

Reactions to cycloserine most commonly involve the central nervous system. They tend to appear within the first 2 weeks of therapy and usually disappear when the drug is withdrawn. Among the central manifestations are somnolence, headache, tremor, dysarthria, vertigo, confusion, nervousness, irritability, psychotic states with suicidal tendencies, paranoid reactions, catatonic and depressed reactions, twitching, ankle clonus, hyperreflexia, visual disturbances, paresis, and tonic-clonic or absence seizures. Large doses of cycloserine or the ingestion of ethyl alcohol increases the risk of seizures. Cycloserine is contraindicated in individuals with a history of epilepsy.

Other Drugs

The agents grouped in this section are similar in several aspects. They are all 'second-line' drugs that are used only for treatment of disease caused by resistant microorganisms or by nontuberculous mycobacteria. They all must be given parenterally, and they have similar pharmacokinetics and toxicity. Since these agents are potentially ototoxic and nephrotoxic, no two drugs from this group should be employed simultaneously, and these drugs should not be used in combination with streptomycin.

Kanamycin, an aminoglycoside that is discussed in Chapter 46: Antimicrobial Agents: The Aminoglycosides, inhibits the growth of M. tuberculosisin vitro in a concentration of 10 g/ml or less. Small groups of patients with tuberculosis have been treated with 1 g of kanamycin daily; toxic effects have been common, including the risk of serious reactions, such as neuromuscular paralysis, respiratory depression, agranulocytosis, anaphylaxis, and nephrotoxicity.

Amikacin also is an aminoglycoside (seeChapter 46: Antimicrobial Agents: The Aminoglycosides). It is extremely active against several mycobacterial species and has a role in the treatment of disease caused by nontuberculous mycobacteria (seeBrown and Wallace, 2000).

Capreomycin CAPASTAT SULFATE) is an antimycobacterial cyclic peptide elaborated by Streptococcus capreolus. It consists of four active componentscapreomycins IA, IB, IIA, and IIB. The agent used clinically contains primarily IA and IB. Bacterial resistance to capreomycin develops when it is given alone; such microorganisms show cross-resistance with kanamycin and neomycin. Capreomycin is used only in conjunction with other appropriate antitubercular drugs in treatment of pulmonary tuberculosis when bactericidal agents cannot be tolerated or when causative organisms have become resistant.

Capreomycin must be given intramuscularly. The recommended daily dose is 15 to 30 mg/kg per day or up to 1 g for 60 to 120 days, followed by 1 g two to three times a week.

The reactions associated with the use of capreomycin are hearing loss, tinnitus, transient proteinuria, cylindruria, and nitrogen retention. Severe renal failure is rare. Eosinophilia is common. Leukocytosis, leukopenia, rashes, and fever have also been observed. Injections of the drug may be painful.

Chemotherapy of Tuberculosis

The availability of effective agents has so altered the treatment of tuberculosis that most patients are now treated in the ambulatory setting, often after diagnosis and initial therapy in a general hospital. Prolonged bed rest is not necessary or even helpful in speeding recovery. Patients must be seen at frequent intervals to follow the course of their disease and treatment. The local health department must be notified of all cases. Contacts should be investigated for the possibility of disease and for the appropriateness of prophylactic therapy with isoniazid.

The majority of cases of previously untreated tuberculosis in the United States is caused by microorganisms that are sensitive to isoniazid, rifampin, ethambutol, and streptomycin. To prevent the development of resistance to these agents that frequently occurs during the course of therapy of the individual patient, treatment must include at least two drugs to which the bacteria are sensitive. The standard 6-month treatment program for drug-sensitive tuberculosis usually is preferred for adults and children and consists of isoniazid, rifampin, and pyrazinamide for 2 months, followed by isoniazid and rifampin for 4 additional months. The combination of isoniazid and rifampin for 9 months is equally effective for drug-sensitive tuberculosis. Because of the increasing frequency of drug resistance, the Centers for Disease Control and Prevention (CDC) has recommended that initial therapy should be with a four-drug regimen (isoniazid, rifampin, pyrazinamide, and ethambutol or streptomycin) pending sensitivity results. Directly observed therapy is the most effective approach to ensure treatment completion rates of about 90% (Chaulk and Kazandjian, 1998).

Drug interactions are a special concern in patients receiving highly active antiretroviral therapy. The rifamycins accelerate the metabolism of protease inhibitors and nonnucleoside reverse transcriptase inhibitors. Of the rifamycins, rifabutin has the least effect on indinavir and nelfinavir serum levels.

Patients infected with the human immunodeficiency virus (HIV) may benefit from longer (9- to 12-month) treatment regimens (Havlir and Barnes, 1999). Treatment should be initiated with at least a four-drug regimen consisting of isoniazid, rifabutin, pyrazinamide, and ethambutol or streptomycin. In patients with a high likelihood of infection with multidrug-resistant strains, an initial five- or six-drug regimen may be appropriate (Lane et al., 1994; Gallant et al., 1994). Treatment should be continued for at least 6 months after three negative cultures have been obtained. If isoniazid or rifampin cannot be used, therapy should be continued for at least 18 months (12 months after cultures become negative). Chemoprophylaxis (seeChemoprophylaxis of Tuberculosis) should be undertaken if a patient with HIV infection has a positive tuberculin test (induration 5 mm), a history of a positive tuberculin skin test that was not treated with chemoprophylaxis, or recent close contact with a potentially infectious patient with tuberculosis. Isoniazid does not reduce the incidence of tuberculosis in anergic patients with HIV, so the earlier recommendation to treat such patients with chemoprophylaxis has been abandoned (Gordin et al., 1997).

Therapy of Specific Types of Tuberculosis

Therapy for uncomplicated drug-sensitive pulmonary tuberculosis consists of isoniazid (5 mg/kg, up to 300 mg per day), rifampin (10 mg/kg per day, up to 600 mg daily), and pyrazinamide (15 to 30 mg/kg per day or a maximum of 2 g per day). Pyridoxine, 15 to 50 mg per day, also should be included for most adults to minimize adverse reactions to isoniazid (Snider, 1980). Isoniazid, rifampin, and pyrazinamide are given for 2 months; isoniazid and rifampin are then continued for 4 additional months. Children are treated similarly; doses are isoniazid, 10 mg/kg per day (300 mg maximum); rifampin, 10 to 20 mg/kg per day (600 mg maximum); pyrazinamide, 15 to 30 mg/kg per day (2 g maximum; Bass et al., 1994). Surgery is rarely indicated (Haas, 2000). The multidrug regimen of isoniazid, rifampin, and ethambutol is considered safe during pregnancy.

Certain patients should receive at least four drugs initially to ensure that the microorganisms will be susceptible to at least two of the agents. These patients include (1) those known to have been exposed to drug-resistant microorganisms; (2) Asians and Hispanics, especially if they are recent immigrants; (3) those with miliary tuberculosis or other extrapulmonary disease; (4) those with meningitis; (5) those with extensive pulmonary disease; and (6) those with HIV infection. The microorganisms should be cultured for determination of their sensitivity to antimicrobial agents, but results will not be available for several weeks. The fourth agent may be either ethambutol (usual adult dose of 15 mg/kg once per day) or streptomycin (1 g daily). The dosage of streptomycin is reduced to 1 g twice weekly after 2 months. Some physicians prefer to institute ethambutol therapy with a dose of 25 mg/kg per day for the first 60 days and then to reduce the dose to 15 mg/kg per day, particularly for those who have received previous therapy.

Clinical improvement is readily discernible in the vast majority of patients with pulmonary tuberculosis if the treatment is appropriate. Efficacy usually becomes obvious within the first 2 weeks of therapy and is evidenced by a reduction of fever, decrease in cough, gain in weight, and increase in the sense of well-being. Progressive radiological improvement also is evident. Over 90% of patients who receive optimal treatment will have negative cultures within 3 to 6 months, depending on the severity of the disease. Cultures that remain positive after 6 months frequently yield resistant microorganisms; the value of using an alternative therapeutic program should then be considered.

Failure of chemotherapy may be due to (1) irregular or inadequate therapy (resulting in persistent or resistant mycobacteria) caused by poor patient compliance during the protracted therapeutic regimen; (2) the use of a single drug, with interruption necessitated by toxicity or hypersensitivity; (3) an inadequate initial regimen; or (4) the primary resistance of the microorganism.

Problems in Chemotherapy

Bacterial Resistance to Drugs

One of the more important problems in the chemotherapy of tuberculosis is bacterial resistance. The primary reason for development of drug resistance is poor patient compliance. To prevent noncompliance and the attendant development of drug-resistant tuberculosis, directly observed therapy is advisable for most patients. For directly observed therapy, a health care provider observes the patient ingest the medications 2 to 5 times weekly (Barnes and Barrows, 1993; Chaulk and Kazandjian, 1998).

Where drug resistance is suspected but sensitivities are not yet known (as in patients who have undergone several courses of treatment), therapy should be instituted with five or six drugs, including two or three that the patient has not received in the past. Such a program might include isoniazid, rifampin, ethambutol, streptomycin, pyrazinamide, and ethionamide. Some physicians include isoniazid in the therapeutic regimen, even if microorganisms are resistant, because of some evidence that disease with isoniazid-resistant mycobacteria does not 'progress' during such therapy. Others prefer to discontinue isoniazid to lessen the possibility of toxicity. Therapy should be continued for at least 24 months.

Nontuberculous (Atypical) Mycobacteria

These microorganisms (not including M. avium complex, which is discussed later) have been recovered from a variety of lesions in human beings (Brown and Wallace, 2000). Because they frequently are resistant to many of the commonly used agents, they must be examined for sensitivity in vitro and drug therapy selected on this basis. In some instances, surgical removal of the infected tissue followed by long-term treatment with effective agents is necessary.

M. kansasii causes disease similar to that caused by M. tuberculosis, but it may be milder. The microorganisms may be resistant to isoniazid. Therapy with isoniazid, rifampin, and ethambutol has been successful (Pezzia et al., 1981; Lane et al., 1994). M. marinum causes skin lesions. A combination of rifampin and ethambutol is probably effective; minocycline (Loria, 1976) or tetracycline is active in vitro and is used by some physicians (Izumi et al., 1977). M. scrofulaceum is an uncommon cause of cervical lymphadenitis. Surgical excision still seems to be the therapy of choice (Lincoln and Gilberg, 1972). Microbes of the M. fortuitum complex (including Mycobacterium chelonei) are usually saprophytes, but they may cause chronic lung disease and infections of skin and soft tissues. The microorganisms are highly resistant to most drugs, but amikacin, cefoxitin, and tetracyclines are active in vitro (Sanders et al., 1977; Sanders, 1982).

Chemoprophylaxis of Tuberculosis

There are several approaches to the chemoprophylaxis of tuberculosis. The classical prophylaxis with 12 months of isoniazid resulted in a 75% reduction in the risk of active tuberculosis (from an incidence of 14.3% to 3.6% over 5 years). A 6-month course of isoniazid therapy was nearly as effective, with a 65% risk reduction and a lower incidence of isoniazid-induced hepatitis (IUAT, 1982). Recently, a 2-month regimen of daily rifampin and pyrazinamide was shown to be as effective as 12 months of isoniazid in one study of HIV-infected individuals (Halsey et al., 1998).

Prophylactic therapy can effectively prevent the development of active tuberculosis in certain instances (Haas, 2000). There are three categories of patients for whom prophylactic therapy should be considered: those exposed to tuberculosis but who have no evidence of infection; those with infection [positive tuberculin test: more than 5 mm (HIV infected) or 10 mm (not immunocompromised) of induration to 5 units of purified protein derivative (PPD)] and no apparent disease; and those with a history of tuberculosis but in whom the disease is presently 'inactive' (seeBass et al., 1994; Stead and To, 1987; Wilkinson et al., 1998; Gordin et al., 1997; Gallant et al., 1994). The main risk of chemoprophylaxis is isoniazid-induced hepatitis, which is much more common about the age of 35. Some authorities argue that monitored isoniazid prophylaxis minimizes the risk of toxicity even in patients over the age of 35 (Salpeter et al., 1997).

Household contacts and other close associates of patients with tuberculosis who have negative tuberculin tests should receive isoniazid for at least 6 months after the contact has been broken, regardless of age. This is especially important for children. If the tuberculin skin test becomes positive, therapy should be continued for 12 months.

Persons without apparent disease whose skin test has converted from negative to positive within the preceding 2 years should probably receive isoniazid for 12 months regardless of age. These patients are considered to be 'infected' but not to have clinical disease. Some authorities believe that persons with positive skin tests, no matter when they became so, who are under 35 years of age, or who are at risk of infection because of such factors as infection with HIV, immunosuppressive therapy, leukemia, lymphoma, or silicosis should receive isoniazid for 1 year (Bass et al., 1994; Gallant et al., 1994). For individuals over 35 years of age, the risk of isoniazid toxicity may outweigh the potential benefit of therapy.

Patients with old 'inactive' tuberculosis who have not received adequate chemotherapy in the past should be considered for 1 year of treatment with isoniazid (seeComstock, 1983). HIV-infected intravenous drug abusers with a positive skin test have an approximately 8% chance per year of developing active tuberculosis (Selwyn et al., 1989). Isoniazid prophylaxis in HIV-infected persons appears to be as effective as in nonimmunocompromised persons (Wilkinson et al., 1998). The CDC recommends that isoniazid prophylaxis be continued for 12 months. Prophylaxis should be given to HIV-infected persons with more than 5 mm of induration to 5 units of PPD. A 1991 CDC recommendation that anergic HIV-infected persons from populations at risk for tuberculosis receive prophylaxis was reversed in 1997, when it was shown to be without foundation (Gordin et al., 1997; Whalen et al., 1997). Persons infected with HIV who are exposed to multidrug-resistant tuberculosis should receive prophylaxis with high-dose ethambutol and pyrazinamide, with or without a fluoroquinolone (Gallant et al., 1994).

Prophylaxis with isoniazid is contraindicated for patients who have active hepatic disease or who have had reactions to the drug. The recent demonstration of the comparable efficacy of a 2-month course of rifampin and pyrazinamide (in HIV-infected adults) offers a potential alternative to isoniazid prophylaxis (Halsey et al., 1998). In pregnant women, prophylaxis usually should be delayed until after delivery. For prophylaxis, isoniazid generally is given to adults in a daily dose of 300 mg. Children should receive 10 mg/kg to a maximal daily dose of 300 mg.