Antimycobacterial Drugs-Henry F.Chambers,MD INTRODUCTION Mycobacteria are intrinsically resistant to most antibiotics.Because they grow slowly compared with other bacteria,antibiotics that are most active against growing cells are relatively ineffective. Mycobacterial cells can also be dormant and thus completely resistant to many drugs or killed only very slowly.The lipid-rich mycobacterial cell wall is impermeable to many agents. Mycobacterial species are intracellular pathogens,and organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly.Finally,mycobacteria are notorious for their ability to develop resistance.Combinations of two or more drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy.The response of mycobacterial infections to chemotherapy is slow,and treatment must be administered for months to years,depending on which drugs are used.The drugs used to treat tuberculosis,atypical mycobacterial infections,and leprosy are described in this chapter. DRUGS USED IN TUBERCULOSIS INTRODUCTION Isoniazid (INH),rifampin (or other rifamycin),pyrazinamide,ethambutol,and streptomycin are the five first-line agents for treatment of tuberculosis.Isoniazid and rifampin are the two most active drugs.An isoniazid-rifampin combination administered for 9 months will cure 95-98%of cases of tuberculosis caused by susceptible strains.The addition of pyrazinamide to an isoniazid-rifampin combination for the first 2 months allows the total duration of therapy to be reduced to 6 months without loss of efficacy.In practice,therapy is initiated with a four-drug regimen of isoniazid,rifampin,pyrazinamide,and either ethambutol or streptomycin until susceptibility of the clinical isolate has been determined.Neither ethambutol nor streptomycin adds substantially to the overall activity of the regimen (ie,the duration of treatment cannot be further reduced if either drug is used),but they provide additional coverage if the isolate proves to be resistant to isoniazid,rifampin,or both.The prevalence of isoniazid resistance among US clinical isolates is approximately 10%.Prevalence of resistance to both isoniazid and rifampin(ie, multiple drug resistance)is about 3%. ISONIAZID (INH) Introduction Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains.It is small(MW 137)and freely soluble in water.The structural similarity to pyridoxine is shown below
Antimycobacterial Drugs Henry F. Chambers, MD INTRODUCTION Mycobacteria are intrinsically resistant to most antibiotics. Because they grow slowly compared with other bacteria, antibiotics that are most active against growing cells are relatively ineffective. Mycobacterial cells can also be dormant and thus completely resistant to many drugs or killed only very slowly. The lipid-rich mycobacterial cell wall is impermeable to many agents. Mycobacterial species are intracellular pathogens, and organisms residing within macrophages are inaccessible to drugs that penetrate these cells poorly. Finally, mycobacteria are notorious for their ability to develop resistance. Combinations of two or more drugs are required to overcome these obstacles and to prevent emergence of resistance during the course of therapy. The response of mycobacterial infections to chemotherapy is slow, and treatment must be administered for months to years, depending on which drugs are used. The drugs used to treat tuberculosis, atypical mycobacterial infections, and leprosy are described in this chapter. DRUGS USED IN TUBERCULOSIS INTRODUCTION Isoniazid (INH), rifampin (or other rifamycin), pyrazinamide, ethambutol, and streptomycin are the five first-line agents for treatment of tuberculosis. Isoniazid and rifampin are the two most active drugs. An isoniazid-rifampin combination administered for 9 months will cure 95-98% of cases of tuberculosis caused by susceptible strains. The addition of pyrazinamide to an isoniazid-rifampin combination for the first 2 months allows the total duration of therapy to be reduced to 6 months without loss of efficacy. In practice, therapy is initiated with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin until susceptibility of the clinical isolate has been determined. Neither ethambutol nor streptomycin adds substantially to the overall activity of the regimen (ie, the duration of treatment cannot be further reduced if either drug is used), but they provide additional coverage if the isolate proves to be resistant to isoniazid, rifampin, or both. The prevalence of isoniazid resistance among US clinical isolates is approximately 10%. Prevalence of resistance to both isoniazid and rifampin (ie, multiple drug resistance) is about 3%. ISONIAZID (INH) Introduction Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains. It is small (MW 137) and freely soluble in water. The structural similarity to pyridoxine is shown below
In vitro,isoniazid inhibits most tubercle bacilli in a concentration of 0.2 mcg/mL or less and is bactericidal for actively growing tubercle bacilli.It is less effective against atypical mycobacterial species.Isoniazid penetrates into macrophages and is active against both extracellular and intracellular organisms. Mechanism of Action Basis of Resistance Isoniazid inhibits synthesis of mycolic acids,which are essential components of mycobacterial cell walls.Isoniazid is a prodrug that is activated by KatG,the mycobacterial catalase-peroxidase. The activated form of isoniazid forms a covalent complex with an acyl carrier protein(AcpM)and KasA,a beta-ketoacyl carrier protein synthetase,which blocks mycolic acid synthesis and kills the cell.Resistance to isoniazid is associated with mutations resulting in overexpression of inhA, which encodes an NADH-dependent acyl carrier protein reductase;mutation or deletion of the katG gene;promoter mutations resulting in overexpression of ahpC,a putative virulence gene involved in protection of the cell from oxidative stress;and mutations in kas4.Overproducers of inhA express low-level isoniazid resistance and cross-resistance to ethionamide.KatG mutants express high-level isoniazid resistance and often are not cross-resistant to ethionamide. Drug-resistant mutants are normally present in susceptible mycobacterial populations at about 1 bacillus in 106.Since tuberculous lesions often contain more than 108 tubercle bacilli,resistant mutants are readily selected out if isoniazid or any other drug is given as a single agent.The use of two independently acting drugs in combination is much more effective.The probability that a bacillus is resistant to both drugs is approximately 1 in 106 x 106,or I in 1012,several orders of magnitude greater than the number of infecting organisms.Thus,at least two (or more in certain cases)active agents should always be used to treat active tuberculosis to prevent emergence of resistance during therapy. Pharmacokinetics Isoniazid is readily absorbed from the gastrointestinal tract.A 300-mg oral dose (5 mg/kg in children)achieves peak plasma concentrations of 3-5 mcg/mL within 1-2 hours.Isoniazid diffuses readily into all body fluids and tissues.The concentration in the central nervous system and cerebrospinal fluid ranges between 20%and 100%of simultaneous serum concentrations. Metabolism of isoniazid,especially acetylation by liver N-acetyltransferase,is genetically determined(see Chapter 4).The average plasma concentration of isoniazid in rapid acetylators is about one third to one half of that in slow acetylators,and average half-lives are less than I hour and 3 hours,respectively.More rapid clearance of isoniazid by rapid acetylators is usually of no therapeutic consequence when appropriate doses are administered daily,but subtherapeutic concentrations may occur if drug is administered as a once-weekly dose or if there is malabsorption
In vitro, isoniazid inhibits most tubercle bacilli in a concentration of 0.2 mcg/mL or less and is bactericidal for actively growing tubercle bacilli. It is less effective against atypical mycobacterial species. Isoniazid penetrates into macrophages and is active against both extracellular and intracellular organisms. Mechanism of Action Basis of Resistance Isoniazid inhibits synthesis of mycolic acids, which are essential components of mycobacterial cell walls. Isoniazid is a prodrug that is activated by KatG, the mycobacterial catalase-peroxidase. The activated form of isoniazid forms a covalent complex with an acyl carrier protein (AcpM) and KasA, a beta-ketoacyl carrier protein synthetase, which blocks mycolic acid synthesis and kills the cell. Resistance to isoniazid is associated with mutations resulting in overexpression of inhA, which encodes an NADH-dependent acyl carrier protein reductase; mutation or deletion of the katG gene; promoter mutations resulting in overexpression of ahpC, a putative virulence gene involved in protection of the cell from oxidative stress; and mutations in kasA. Overproducers of inhA express low-level isoniazid resistance and cross-resistance to ethionamide. KatG mutants express high-level isoniazid resistance and often are not cross-resistant to ethionamide. Drug-resistant mutants are normally present in susceptible mycobacterial populations at about 1 bacillus in 10 6 . Since tuberculous lesions often contain more than 10 8 tubercle bacilli, resistant mutants are readily selected out if isoniazid or any other drug is given as a single agent. The use of two independently acting drugs in combination is much more effective. The probability that a bacillus is resistant to both drugs is approximately 1 in 10 6 10 6 , or 1 in 10 12 , several orders of magnitude greater than the number of infecting organisms. Thus, at least two (or more in certain cases) active agents should always be used to treat active tuberculosis to prevent emergence of resistance during therapy. Pharmacokinetics Isoniazid is readily absorbed from the gastrointestinal tract. A 300-mg oral dose (5 mg/kg in children) achieves peak plasma concentrations of 3-5 mcg/mL within 1-2 hours. Isoniazid diffuses readily into all body fluids and tissues. The concentration in the central nervous system and cerebrospinal fluid ranges between 20% and 100% of simultaneous serum concentrations. Metabolism of isoniazid, especially acetylation by liver N-acetyltransferase, is genetically determined (see Chapter 4). The average plasma concentration of isoniazid in rapid acetylators is about one third to one half of that in slow acetylators, and average half-lives are less than 1 hour and 3 hours, respectively. More rapid clearance of isoniazid by rapid acetylators is usually of no therapeutic consequence when appropriate doses are administered daily, but subtherapeutic concentrations may occur if drug is administered as a once-weekly dose or if there is malabsorption
Isoniazid metabolites and a small amount of unchanged drug are excreted mainly in the urine.The dose need not be adjusted in renal failure.Dose adjustment is not well defined in patients with severe preexisting hepatic insufficiency (isoniazid is contraindicated if it is the cause of the hepatitis)and should be guided by serum concentrations if a reduction in dose is contemplated. Clinical Uses The usual dosage of isoniazid is 5 mg/kg/d;a typical adult dose is 300 mg given once daily.Up to 10 mg/kg/d may be used for serious infections or if malabsorption is a problem.A 15 mg/kg dose, or 900 mg,may be used in a twice-weekly dosing regimen in combination with a second antituberculous agent (eg,rifampin 600 mg).Pyridoxine,25-50 mg/d,is recommended for those with conditions predisposing to neuropathy,an adverse effect of isoniazid.Isoniazid is usually given by mouth but can be given parenterally in the same dosage. Isoniazid as a single agent is also indicated for treatment of latent tuberculosis.The dosage is 300 mg/d(5 mg/kg/d)or 900 mg twice weekly for 9 months. Adverse Reactions The incidence and severity of untoward reactions to isoniazid are related to dosage and duration of administration. A.IMMUNOLOGIC REACTIONS Fever and skin rashes are occasionally seen.Drug-induced systemic lupus erythematosus has been reported. B.DIRECT TOXICITY Isoniazid-induced hepatitis is the most common major toxic effect.This is distinct from the minor increases in liver aminotransferases (up to three or four times normal),which do not require cessation of the drug and which are seen in 10-20%of patients,who usually are asymptomatic. Clinical hepatitis with loss of appetite,nausea,vomiting,jaundice,and right upper quadrant pain occurs in 1%of isoniazid recipients and can be fatal,particularly if the drug is not discontinued promptly.There is histologic evidence of hepatocellular damage and necrosis.The risk of hepatitis depends on age.It occurs rarely under age 20,in 0.3%of those aged 21-35,1.2%of those aged 36-50,and 2.3%for those aged 50 and above.The risk of hepatitis is greater in alcoholics and possibly during pregnancy and the postpartum period.Development of isoniazid hepatitis contraindicates further use of the drug. Peripheral neuropathy is observed in 10-20%of patients given dosages greater than 5 mg/kg/d but is infrequently seen with the standard 300 mg adult dose.It is more likely to occur in slow acetylators and patients with predisposing conditions such as malnutrition,alcoholism,diabetes, AIDS,and uremia.Neuropathy is due to a relative pyridoxine deficiency.Isoniazid promotes excretion of pyridoxine,and this toxicity is readily reversed by administration of pyridoxine in a
Isoniazid metabolites and a small amount of unchanged drug are excreted mainly in the urine. The dose need not be adjusted in renal failure. Dose adjustment is not well defined in patients with severe preexisting hepatic insufficiency (isoniazid is contraindicated if it is the cause of the hepatitis) and should be guided by serum concentrations if a reduction in dose is contemplated. Clinical Uses The usual dosage of isoniazid is 5 mg/kg/d; a typical adult dose is 300 mg given once daily. Up to 10 mg/kg/d may be used for serious infections or if malabsorption is a problem. A 15 mg/kg dose, or 900 mg, may be used in a twice-weekly dosing regimen in combination with a second antituberculous agent (eg, rifampin 600 mg). Pyridoxine, 25-50 mg/d, is recommended for those with conditions predisposing to neuropathy, an adverse effect of isoniazid. Isoniazid is usually given by mouth but can be given parenterally in the same dosage. Isoniazid as a single agent is also indicated for treatment of latent tuberculosis. The dosage is 300 mg/d (5 mg/kg/d) or 900 mg twice weekly for 9 months. Adverse Reactions The incidence and severity of untoward reactions to isoniazid are related to dosage and duration of administration. A. IMMUNOLOGIC REACTIONS Fever and skin rashes are occasionally seen. Drug-induced systemic lupus erythematosus has been reported. B. DIRECT TOXICITY Isoniazid-induced hepatitis is the most common major toxic effect. This is distinct from the minor increases in liver aminotransferases (up to three or four times normal), which do not require cessation of the drug and which are seen in 10-20% of patients, who usually are asymptomatic. Clinical hepatitis with loss of appetite, nausea, vomiting, jaundice, and right upper quadrant pain occurs in 1% of isoniazid recipients and can be fatal, particularly if the drug is not discontinued promptly. There is histologic evidence of hepatocellular damage and necrosis. The risk of hepatitis depends on age. It occurs rarely under age 20, in 0.3% of those aged 21-35, 1.2% of those aged 36-50, and 2.3% for those aged 50 and above. The risk of hepatitis is greater in alcoholics and possibly during pregnancy and the postpartum period. Development of isoniazid hepatitis contraindicates further use of the drug. Peripheral neuropathy is observed in 10-20% of patients given dosages greater than 5 mg/kg/d but is infrequently seen with the standard 300 mg adult dose. It is more likely to occur in slow acetylators and patients with predisposing conditions such as malnutrition, alcoholism, diabetes, AIDS, and uremia. Neuropathy is due to a relative pyridoxine deficiency. Isoniazid promotes excretion of pyridoxine, and this toxicity is readily reversed by administration of pyridoxine in a
dosage as low as 10 mg/d.Central nervous system toxicity,which is less common,includes memory loss,psychosis,and seizures.These may also respond to pyridoxine. Miscellaneous other reactions include hematologic abnormalities,provocation of pyridoxine deficiency anemia,tinnitus,and gastrointestinal discomfort.Isoniazid can reduce the metabolism of phenytoin,increasing its blood level and toxicity. RIFAMPIN Introduction Rifampin is a semisynthetic derivative of rifamycin,an antibiotic produced by Streptomyces mediterranei.It is active in vitro against gram-positive and gram-negative cocci,some enteric bacteria,mycobacteria,and chlamydia.Susceptible organisms are inhibited by less than 1 mcg/mL. Resistant mutants are present in all microbial populations at approximately 1 in 106 and are rapidly selected out if rifampin is used as a single drug,especially if there is active infection. There is no cross-resistance to other classes of antimicrobial drugs,but there is cross-resistance to other rifamycin derivatives,eg,rifabutin and rifapentine. Antimycobacterial Activity,Resistance,Pharmacokinetics Rifampin binds to the B subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis.Resistance results from any one of several possible point mutations in rpoB,the gene for the B subunit of RNA polymerase.These mutations result in reduced binding of rifampin to RNA polymerase.Human RNA polymerase does not bind rifampin and is not inhibited by it.Rifampin is bactericidal for mycobacteria.It readily penetrates most tissues and into phagocytic cells.It can kill organisms that are poorly accessible to many other drugs,such as intracellular organisms and those sequestered in abscesses and lung cavities. Rifampin is well absorbed after oral administration and excreted mainly through the liver into bile. It then undergoes enterohepatic recirculation,with the bulk excreted as a deacylated metabolite in feces and a small amount in the urine.Dosage adjustment for renal or hepatic insufficiency is not necessary.Usual doses result in serum levels of 5-7 mcg/mL.Rifampin is distributed widely in body fluids and tissues.Rifampin is relatively highly protein-bound,and adequate cerebrospinal fluid concentrations are achieved only in the presence of meningeal inflammation. Clinical Uses A.MYCOBACTERIAL INFECTIONS Rifampin,usually 600 mg/d(10 mg/kg/d)orally,must be administered with isoniazid or other antituberculous drugs to patients with active tuberculosis to prevent emergence of drug-resistant mycobacteria.In some short-course therapies,600 mg of rifampin are given twice weekly. Rifampin 600 mg daily or twice weekly for 6 months also is effective in combination with other agents in some atypical mycobacterial infections and in leprosy.Rifampin,600 mg daily for 4
dosage as low as 10 mg/d. Central nervous system toxicity, which is less common, includes memory loss, psychosis, and seizures. These may also respond to pyridoxine. Miscellaneous other reactions include hematologic abnormalities, provocation of pyridoxine deficiency anemia, tinnitus, and gastrointestinal discomfort. Isoniazid can reduce the metabolism of phenytoin, increasing its blood level and toxicity. RIFAMPIN Introduction Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Streptomyces mediterranei. It is active in vitro against gram-positive and gram-negative cocci, some enteric bacteria, mycobacteria, and chlamydia. Susceptible organisms are inhibited by less than 1 mcg/mL. Resistant mutants are present in all microbial populations at approximately 1 in 10 6 and are rapidly selected out if rifampin is used as a single drug, especially if there is active infection. There is no cross-resistance to other classes of antimicrobial drugs, but there is cross-resistance to other rifamycin derivatives, eg, rifabutin and rifapentine. Antimycobacterial Activity, Resistance, Pharmacokinetics Rifampin binds to the subunit of bacterial DNA-dependent RNA polymerase and thereby inhibits RNA synthesis. Resistance results from any one of several possible point mutations in rpoB, the gene for the subunit of RNA polymerase. These mutations result in reduced binding of rifampin to RNA polymerase. Human RNA polymerase does not bind rifampin and is not inhibited by it. Rifampin is bactericidal for mycobacteria. It readily penetrates most tissues and into phagocytic cells. It can kill organisms that are poorly accessible to many other drugs, such as intracellular organisms and those sequestered in abscesses and lung cavities. Rifampin is well absorbed after oral administration and excreted mainly through the liver into bile. It then undergoes enterohepatic recirculation, with the bulk excreted as a deacylated metabolite in feces and a small amount in the urine. Dosage adjustment for renal or hepatic insufficiency is not necessary. Usual doses result in serum levels of 5-7 mcg/mL. Rifampin is distributed widely in body fluids and tissues. Rifampin is relatively highly protein-bound, and adequate cerebrospinal fluid concentrations are achieved only in the presence of meningeal inflammation. Clinical Uses A. MYCOBACTERIAL INFECTIONS Rifampin, usually 600 mg/d (10 mg/kg/d) orally, must be administered with isoniazid or other antituberculous drugs to patients with active tuberculosis to prevent emergence of drug-resistant mycobacteria. In some short-course therapies, 600 mg of rifampin are given twice weekly. Rifampin 600 mg daily or twice weekly for 6 months also is effective in combination with other agents in some atypical mycobacterial infections and in leprosy. Rifampin, 600 mg daily for 4
months as a single drug,is an alternative to isoniazid prophylaxis for patients with latent tuberculosis only who are unable to take isoniazid or who have had exposure to a case of active tuberculosis caused by an isoniazid-resistant,rifampin-susceptible strain. B.OTHER INDICATIONS Rifampin has other uses.An oral dosage of 600 mg twice daily for 2 days can eliminate meningococcal carriage.Rifampin,20 mg/kg/d for 4 days,is used as prophylaxis in contacts of children with Haemophilus influenzae type b disease.Rifampin combined with a second agent is used to eradicate staphylococcal carriage.Rifampin combination therapy is also indicated for treatment of serious staphylococcal infections such as osteomyelitis and prosthetic valve endocarditis. Adverse Reactions Rifampin imparts a harmless orange color to urine,sweat,tears,and contact lenses (soft lenses may be permanently stained).Occasional adverse effects include rashes,thrombocytopenia,and nephritis.It may cause cholestatic jaundice and occasionally hepatitis.Rifampin commonly causes light-chain proteinuria.If administered less often than twice weekly,rifampin causes a flu-like syndrome characterized by fever,chills,myalgias,anemia,and thrombocytopenia and sometimes is associated with acute tubular necrosis.Rifampin strongly induces most cytochrome P450 isoforms(CYPs 1A2,2C9,2C19,2D6,and 3A4),which increases the elimination of numerous other drugs including methadone,anticoagulants,cyclosporine,some anticonvulsants,protease inhibitors,some nonnucleoside reverse transcriptase inhibitors,contraceptives,and a host of others.Administration of rifampin results in significantly lower serum levels of these drugs ETHAMBUTOL Introduction Ethambutol is a synthetic,water-soluble,heat-stable compound,the dextro-isomer of the structure shown below,dispensed as the dihydrochloride salt. Susceptible strains of Mycobacterium tuberculosis and other mycobacteria are inhibited in vitro by ethambutol.1-5 mg/mL.Ethambutol inhibits mycobacterial arabinosyl transferases,which are encoded by the embC4B operon.Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan,an essential component of the mycobacterial cell wall.Resistance to ethambutol is due to mutations resulting in overexpression of emb gene products or within the embB structural gene. Ethambutol is well absorbed from the gut.After ingestion of 25 mg/kg,a blood level peak of 2-5 mcg/mL is reached in 2-4 hours.About 20%of the drug is excreted in feces and 50%in urine in unchanged form.Ethambutol accumulates in renal failure,and the dose should be reduced by half if creatinine clearance is less than 10 mL/min.Ethambutol crosses the blood-brain barrier only if the meninges are inflamed.Concentrations in cerebrospinal fluid are highly variable,ranging from 4%to 64%of serum levels in the setting of meningeal inflammation
months as a single drug, is an alternative to isoniazid prophylaxis for patients with latent tuberculosis only who are unable to take isoniazid or who have had exposure to a case of active tuberculosis caused by an isoniazid-resistant, rifampin-susceptible strain. B. OTHER INDICATIONS Rifampin has other uses. An oral dosage of 600 mg twice daily for 2 days can eliminate meningococcal carriage. Rifampin, 20 mg/kg/d for 4 days, is used as prophylaxis in contacts of children with Haemophilus influenzae type b disease. Rifampin combined with a second agent is used to eradicate staphylococcal carriage. Rifampin combination therapy is also indicated for treatment of serious staphylococcal infections such as osteomyelitis and prosthetic valve endocarditis. Adverse Reactions Rifampin imparts a harmless orange color to urine, sweat, tears, and contact lenses (soft lenses may be permanently stained). Occasional adverse effects include rashes, thrombocytopenia, and nephritis. It may cause cholestatic jaundice and occasionally hepatitis. Rifampin commonly causes light-chain proteinuria. If administered less often than twice weekly, rifampin causes a flu-like syndrome characterized by fever, chills, myalgias, anemia, and thrombocytopenia and sometimes is associated with acute tubular necrosis. Rifampin strongly induces most cytochrome P450 isoforms (CYPs 1A2, 2C9, 2C19, 2D6, and 3A4), which increases the elimination of numerous other drugs including methadone, anticoagulants, cyclosporine, some anticonvulsants, protease inhibitors, some nonnucleoside reverse transcriptase inhibitors, contraceptives, and a host of others. Administration of rifampin results in significantly lower serum levels of these drugs. ETHAMBUTOL Introduction Ethambutol is a synthetic, water-soluble, heat-stable compound, the dextro-isomer of the structure shown below, dispensed as the dihydrochloride salt. Susceptible strains of Mycobacterium tuberculosis and other mycobacteria are inhibited in vitro by ethambutol, 1-5 mg/mL. Ethambutol inhibits mycobacterial arabinosyl transferases, which are encoded by the embCAB operon. Arabinosyl transferases are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell wall. Resistance to ethambutol is due to mutations resulting in overexpression of emb gene products or within the embB structural gene. Ethambutol is well absorbed from the gut. After ingestion of 25 mg/kg, a blood level peak of 2-5 mcg/mL is reached in 2-4 hours. About 20% of the drug is excreted in feces and 50% in urine in unchanged form. Ethambutol accumulates in renal failure, and the dose should be reduced by half if creatinine clearance is less than 10 mL/min. Ethambutol crosses the blood-brain barrier only if the meninges are inflamed. Concentrations in cerebrospinal fluid are highly variable, ranging from 4% to 64% of serum levels in the setting of meningeal inflammation
As with all antituberculous drugs,resistance to ethambutol emerges rapidly when the drug is used alone.Therefore,ethambutol is always given in combination with other antituberculous drugs. Clinical Use Ethambutol hydrochloride,15-25 mg/kg,is usually given as a single daily dose in combination with isoniazid or rifampin.The higher dose is recommended for treatment of tuberculous meningitis.The dose of ethambutol is 50 mg/kg when a twice-weekly dosing schedule is used. Adverse Reactions Hypersensitivity to ethambutol is rare.The most common serious adverse event is retrobulbar neuritis,resulting in loss of visual acuity and red-green color blindness.This dose-related side effect is more likely to occur at doses of 25 mg/kg/d continued for several months.At 15 mg/kg/d or less,visual disturbances are very rare.Periodic visual acuity testing is desirable if the 25 mg/kg/d dosage is used.Ethambutol is relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination. PYRAZINAMIDE Introduction Pyrazinamide (PZA)is a relative of nicotinamide,stable,and slightly soluble in water.It is inactive at neutral pH,but at pH 5.5 it inhibits tubercle bacilli and some other mycobacteria at concentrations of approximately 20 mcg/mL.The drug is taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment of lysosomes. Pyrazinamide is converted to pyrazinoic acid-the active form of the drug-by mycobacterial pyrazinamidase,which is encoded by pnc4.The drug target and mechanism of action are unknown.Resistance may be due to impaired uptake of pyrazinamide or mutations in pncA4 that impair conversion of pyrazinamide to its active form. Clinical Use Serum concentrations of 30-50 mcg/mL at 1-2 hours after oral administration are achieved with dosages of 25 mg/kg/d.Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed in body tissues,including inflamed meninges.The half-life is 8-11 hours.The parent compound is metabolized by the liver,but metabolites are renally cleared;therefore,pyrazinamide should be administered at 25-35 mg/kg three times weekly(not daily)in hemodialysis patients and those in whom the creatinine clearance is less than 30 mL/min.In patients with normal renal function,a dose of 40-50 mg/kg is used for thrice-weekly or twice-weekly treatment regimens. Pyrazinamide is an important front-line drug used in conjunction with isoniazid and rifampin in short-course (ie,6-month)regimens as a "sterilizing"agent active against residual intracellular
As with all antituberculous drugs, resistance to ethambutol emerges rapidly when the drug is used alone. Therefore, ethambutol is always given in combination with other antituberculous drugs. Clinical Use Ethambutol hydrochloride, 15-25 mg/kg, is usually given as a single daily dose in combination with isoniazid or rifampin. The higher dose is recommended for treatment of tuberculous meningitis. The dose of ethambutol is 50 mg/kg when a twice-weekly dosing schedule is used. Adverse Reactions Hypersensitivity to ethambutol is rare. The most common serious adverse event is retrobulbar neuritis, resulting in loss of visual acuity and red-green color blindness. This dose-related side effect is more likely to occur at doses of 25 mg/kg/d continued for several months. At 15 mg/kg/d or less, visual disturbances are very rare. Periodic visual acuity testing is desirable if the 25 mg/kg/d dosage is used. Ethambutol is relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination. PYRAZINAMIDE Introduction Pyrazinamide (PZA) is a relative of nicotinamide, stable, and slightly soluble in water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli and some other mycobacteria at concentrations of approximately 20 mcg/mL. The drug is taken up by macrophages and exerts its activity against mycobacteria residing within the acidic environment of lysosomes. Pyrazinamide is converted to pyrazinoic acidthe active form of the drugby mycobacterial pyrazinamidase, which is encoded by pncA. The drug target and mechanism of action are unknown. Resistance may be due to impaired uptake of pyrazinamide or mutations in pncA that impair conversion of pyrazinamide to its active form. Clinical Use Serum concentrations of 30-50 mcg/mL at 1-2 hours after oral administration are achieved with dosages of 25 mg/kg/d. Pyrazinamide is well absorbed from the gastrointestinal tract and widely distributed in body tissues, including inflamed meninges. The half-life is 8-11 hours. The parent compound is metabolized by the liver, but metabolites are renally cleared; therefore, pyrazinamide should be administered at 25-35 mg/kg three times weekly (not daily) in hemodialysis patients and those in whom the creatinine clearance is less than 30 mL/min. In patients with normal renal function, a dose of 40-50 mg/kg is used for thrice-weekly or twice-weekly treatment regimens. Pyrazinamide is an important front-line drug used in conjunction with isoniazid and rifampin in short-course (ie, 6-month) regimens as a "sterilizing" agent active against residual intracellular
organisms that may cause relapse.Tubercle bacilli develop resistance to pyrazinamide fairly readily,but there is no cross-resistance with isoniazid or other antimycobacterial drugs. Adverse Reactions Major adverse effects of pyrazinamide include hepatotoxicity (in 1-5%of patients),nausea, vomiting,drug fever,and hyperuricemia.The latter occurs uniformly and is not a reason to halt therapy.Hyperuricemia may provoke acute gouty arthritis. STREPTOMYCIN Introduction The mechanism of action and other pharmacologic features of streptomycin are discussed in Chapter 45.The typical adult dose is 1 g/d(15 mg/kg/d).If the creatinine clearance is less than 30 mL/min or the patient is on hemodialysis,the dose is 15 mg/kg two or three times a week.Most tubercle bacilli are inhibited by streptomycin,1-10 mcg/mL,in vitro.Nontuberculosis species of mycobacteria other than Mycobacterium avium complex (MAC)and Mycobacterium kansasii are resistant.All large populations of tubercle bacilli contain some streptomycin-resistant mutants.On average,I in 108 tubercle bacilli can be expected to be resistant to streptomycin at levels of 10-100 mcg/mL.Resistance is due to a point mutation in either the rpsL gene encoding the S12 ribosomal protein gene or the rrs gene encoding 16S ribosomal rRNA,which alters the ribosomal binding site. Streptomycin penetrates into cells poorly and is active mainly against extracellular tubercle bacilli. Streptomycin crosses the blood-brain barrier and achieves therapeutic concentrations with inflamed meninges. Clinical Use in Tuberculosis Streptomycin sulfate is used when an injectable drug is needed or desirable,principally in individuals with severe,possibly life-threatening forms of tuberculosis,eg,meningitis and disseminated disease,and in treatment of infections resistant to other drugs.The usual dosage is 15 mg/kg/d intramuscularly or intravenously daily for adults(20-40 mg/kg/d,not to exceed 1-1.5 g for children)for several weeks,followed by 1-1.5 g two or three times weekly for several months.Serum concentrations of approximately 40 mcg/mL are achieved 30-60 minutes after intramuscular injection of a 15 mg/kg dose.Other drugs are always given in combination to prevent emergence of resistance Adverse Reactions Streptomycin is ototoxic and nephrotoxic.Vertigo and hearing loss are the most common side effects and may be permanent.Toxicity is dose-related,and the risk is increased in the elderly.As with all aminoglycosides,the dose must be adjusted according to renal function (see Chapter 45)
organisms that may cause relapse. Tubercle bacilli develop resistance to pyrazinamide fairly readily, but there is no cross-resistance with isoniazid or other antimycobacterial drugs. Adverse Reactions Major adverse effects of pyrazinamide include hepatotoxicity (in 1-5% of patients), nausea, vomiting, drug fever, and hyperuricemia. The latter occurs uniformly and is not a reason to halt therapy. Hyperuricemia may provoke acute gouty arthritis. STREPTOMYCIN Introduction The mechanism of action and other pharmacologic features of streptomycin are discussed in Chapter 45. The typical adult dose is 1 g/d (15 mg/kg/d). If the creatinine clearance is less than 30 mL/min or the patient is on hemodialysis, the dose is 15 mg/kg two or three times a week. Most tubercle bacilli are inhibited by streptomycin, 1-10 mcg/mL, in vitro. Nontuberculosis species of mycobacteria other than Mycobacterium avium complex (MAC) and Mycobacterium kansasii are resistant. All large populations of tubercle bacilli contain some streptomycin-resistant mutants. On average, 1 in 10 8 tubercle bacilli can be expected to be resistant to streptomycin at levels of 10-100 mcg/mL. Resistance is due to a point mutation in either the rpsL gene encoding the S12 ribosomal protein gene or the rrs gene encoding 16S ribosomal rRNA, which alters the ribosomal binding site. Streptomycin penetrates into cells poorly and is active mainly against extracellular tubercle bacilli. Streptomycin crosses the blood-brain barrier and achieves therapeutic concentrations with inflamed meninges. Clinical Use in Tuberculosis Streptomycin sulfate is used when an injectable drug is needed or desirable, principally in individuals with severe, possibly life-threatening forms of tuberculosis, eg, meningitis and disseminated disease, and in treatment of infections resistant to other drugs. The usual dosage is 15 mg/kg/d intramuscularly or intravenously daily for adults (20-40 mg/kg/d, not to exceed 1-1.5 g for children) for several weeks, followed by 1-1.5 g two or three times weekly for several months. Serum concentrations of approximately 40 mcg/mL are achieved 30-60 minutes after intramuscular injection of a 15 mg/kg dose. Other drugs are always given in combination to prevent emergence of resistance. Adverse Reactions Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing loss are the most common side effects and may be permanent. Toxicity is dose-related, and the risk is increased in the elderly. As with all aminoglycosides, the dose must be adjusted according to renal function (see Chapter 45)
Toxicity can be reduced by limiting therapy to no more than 6 months whenever possible. ALTERNATIVE SECOND-LINE DRUGS FOR TUBERCULOSIS Introduction The alternative drugs listed below are usually considered only (1)in case of resistance to first-line agents;(2)in case of failure of clinical response to conventional therapy;(3)in case of serious treatment-limiting adverse drug reactions;and(4)when expert guidance is available to deal with the toxic effects.For many of the second-line drugs listed in the following text,the dosage, emergence of resistance,and long-term toxicity have not been fully established. Ethionamide Ethionamide is chemically related to isoniazid and also blocks the synthesis of mycolic acids.It is poorly water-soluble and available only in oral form.It is metabolized by the liver. Most tubercle bacilli are inhibited in vitro by ethionamide,2.5 mcg/mL or less.Some other species of mycobacteria also are inhibited by ethionamide,10 mcg/mL.Serum concentrations in plasma and tissues of approximately 20 mcg/mL are achieved by a dosage of 1 g/d.Cerebrospinal fluid concentrations are equal to those in serum. Ethionamide is administered at an initial dose of 250 mg once daily,which is increased in 250-mg increments to the recommended dosage of 1 g/d(or 15 mg/kg/d),if possible.The 1 g/d dosage, although theoretically desirable,is poorly tolerated because of the intense gastric irritation and neurologic symptoms that commonly occur,and one often must settle for a total daily dose of 500-750 mg.Ethionamide is also hepatotoxic.Neurologic symptoms may be alleviated by pyridoxine. Resistance to ethionamide as a single agent develops rapidly in vitro and in vivo.There can be low-level cross-resistance between isoniazid and ethionamide. Capreomycin Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus.Daily injection of I g intramuscularly results in blood levels of 10 mcg/mL or more. Such concentrations in vitro are inhibitory for many mycobacteria,including multidrug-resistant strains of M tuberculosis. Capreomycin (15 mg/kg/d)is an important injectable agent for treatment of drug-resistant tuberculosis.Strains of M tuberculosis that are resistant to streptomycin or amikacin (eg,the multidrug-resistant W strain)usually are susceptible to capreomycin.Resistance to capreomycin, when it occurs,may be due to an rrs mutation
Toxicity can be reduced by limiting therapy to no more than 6 months whenever possible. ALTERNATIVE SECOND-LINE DRUGS FOR TUBERCULOSIS Introduction The alternative drugs listed below are usually considered only (1) in case of resistance to first-line agents; (2) in case of failure of clinical response to conventional therapy; (3) in case of serious treatment-limiting adverse drug reactions; and (4) when expert guidance is available to deal with the toxic effects. For many of the second-line drugs listed in the following text, the dosage, emergence of resistance, and long-term toxicity have not been fully established. Ethionamide Ethionamide is chemically related to isoniazid and also blocks the synthesis of mycolic acids. It is poorly water-soluble and available only in oral form. It is metabolized by the liver. Most tubercle bacilli are inhibited in vitro by ethionamide, 2.5 mcg/mL or less. Some other species of mycobacteria also are inhibited by ethionamide, 10 mcg/mL. Serum concentrations in plasma and tissues of approximately 20 mcg/mL are achieved by a dosage of 1 g/d. Cerebrospinal fluid concentrations are equal to those in serum. Ethionamide is administered at an initial dose of 250 mg once daily, which is increased in 250-mg increments to the recommended dosage of 1 g/d (or 15 mg/kg/d), if possible. The 1 g/d dosage, although theoretically desirable, is poorly tolerated because of the intense gastric irritation and neurologic symptoms that commonly occur, and one often must settle for a total daily dose of 500-750 mg. Ethionamide is also hepatotoxic. Neurologic symptoms may be alleviated by pyridoxine. Resistance to ethionamide as a single agent develops rapidly in vitro and in vivo. There can be low-level cross-resistance between isoniazid and ethionamide. Capreomycin Capreomycin is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus. Daily injection of 1 g intramuscularly results in blood levels of 10 mcg/mL or more. Such concentrations in vitro are inhibitory for many mycobacteria, including multidrug-resistant strains of M tuberculosis. Capreomycin (15 mg/kg/d) is an important injectable agent for treatment of drug-resistant tuberculosis. Strains of M tuberculosis that are resistant to streptomycin or amikacin (eg, the multidrug-resistant W strain) usually are susceptible to capreomycin. Resistance to capreomycin, when it occurs, may be due to an rrs mutation
Capreomycin is nephrotoxic and ototoxic.Tinnitus,deafness,and vestibular disturbances occur. The injection causes significant local pain,and sterile abscesses may occur. Dosing of capreomycin is the same as that of streptomycin.Toxicity is reduced if 1 g is given two or three times weekly after an initial response has been achieved with a daily dosing schedule Cycloserine Cycloserine is an inhibitor of cell wall synthesis and is discussed in Chapter 43.Concentrations of 15-20 mcg/mL inhibit many strains of M tuberculosis.The dosage of cycloserine in tuberculosis is 0.5-1 g/d in two divided doses.Cycloserine is cleared renally,and the dose should be reduced by half if creatinine clearance is less than 50 mL/min. The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including depression and psychotic reactions.Pyridoxine 150 mg/d should be given with cycloserine because this ameliorates neurologic toxicity.Adverse effects,which are most common during the first 2 weeks of therapy,occur in 25%or more of patients,especially at higher doses. Side effects can be minimized by monitoring peak serum concentrations.The peak concentration is reached 2-4 hours after dosing.The recommended range of peak concentrations is 20-40 mcg/mL Aminosalicylic Acid (PAS) Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against M tuberculosis.It is structurally similar to p-aminobenzoic aid (PABA)and to the sulfonamides (see Chapter 46) Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid,1-5 mcg/mL.Aminosalicylic acid is readily absorbed from the gastrointestinal tract.Serum levels are 50 mcg/mL or more after a 4-g oral dose.The dosage is 8-12 g/d orally for adults and 300 mg/kg/d for children.The drug is widely distributed in tissues and body fluids except the cerebrospinal fluid.Aminosalicylic acid is rapidly excreted in the urine,in part as active aminosalicylic acid and in part as the acetylated compound and other metabolic products.Very high concentrations of aminosalicylic acid are reached in the urine,which can result in crystalluria. Aminosalicylic acid is used infrequently now because other oral drugs are better tolerated. Gastrointestinal symptoms are common and may be diminished by giving the drug with meals and with antacids.Peptic ulceration and hemorrhage may occur.Hypersensitivity reactions manifested by fever,joint pains,skin rashes,hepatosplenomegaly,hepatitis,adenopathy,and granulocytopenia often occur after 3-8 weeks of aminosalicylic acid therapy,making it necessary to stop aminosalicylic acid administration temporarily or permanently Kanamycin Amikacin
Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness, and vestibular disturbances occur. The injection causes significant local pain, and sterile abscesses may occur. Dosing of capreomycin is the same as that of streptomycin. Toxicity is reduced if 1 g is given two or three times weekly after an initial response has been achieved with a daily dosing schedule. Cycloserine Cycloserine is an inhibitor of cell wall synthesis and is discussed in Chapter 43. Concentrations of 15-20 mcg/mL inhibit many strains of M tuberculosis. The dosage of cycloserine in tuberculosis is 0.5-1 g/d in two divided doses. Cycloserine is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min. The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including depression and psychotic reactions. Pyridoxine 150 mg/d should be given with cycloserine because this ameliorates neurologic toxicity. Adverse effects, which are most common during the first 2 weeks of therapy, occur in 25% or more of patients, especially at higher doses. Side effects can be minimized by monitoring peak serum concentrations. The peak concentration is reached 2-4 hours after dosing. The recommended range of peak concentrations is 20-40 mcg/mL. Aminosalicylic Acid (PAS) Aminosalicylic acid is a folate synthesis antagonist that is active almost exclusively against M tuberculosis. It is structurally similar to p-aminobenzoic aid (PABA) and to the sulfonamides (see Chapter 46). Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid, 1-5 mcg/mL. Aminosalicylic acid is readily absorbed from the gastrointestinal tract. Serum levels are 50 mcg/mL or more after a 4-g oral dose. The dosage is 8-12 g/d orally for adults and 300 mg/kg/d for children. The drug is widely distributed in tissues and body fluids except the cerebrospinal fluid. Aminosalicylic acid is rapidly excreted in the urine, in part as active aminosalicylic acid and in part as the acetylated compound and other metabolic products. Very high concentrations of aminosalicylic acid are reached in the urine, which can result in crystalluria. Aminosalicylic acid is used infrequently now because other oral drugs are better tolerated. Gastrointestinal symptoms are common and may be diminished by giving the drug with meals and with antacids. Peptic ulceration and hemorrhage may occur. Hypersensitivity reactions manifested by fever, joint pains, skin rashes, hepatosplenomegaly, hepatitis, adenopathy, and granulocytopenia often occur after 3-8 weeks of aminosalicylic acid therapy, making it necessary to stop aminosalicylic acid administration temporarily or permanently. Kanamycin Amikacin
The aminoglycoside antibiotics are discussed in Chapter 45.Kanamycin has been used for treatment of tuberculosis caused by streptomycin-resistant strains,but the availability of less toxic alternatives (eg,capreomycin and amikacin)has rendered it obsolete. The role of amikacin in treatment of tuberculosis has increased with the increasing incidence and prevalence of multidrug-resistant tuberculosis.Prevalence of amikacin-resistant strains is low (less than 5%),and most multidrug-resistant strains remain amikacin-susceptible.M tuberculosis is inhibited at concentrations of 1 mcg/mL or less.Amikacin is also active against atypical mycobacteria.There is no cross-resistance between streptomycin and amikacin,but kanamycin resistance often indicates resistance to amikacin as well.Serum concentrations of 30-50 mcg/mL are achieved 30-60 minutes after a 15 mg/kg intravenous infusion.Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrug-resistant strains.Amikacin must be used in combination with at least one and preferably two or three other drugs to which the isolate is susceptible for treatment of drug-resistant cases. The recommended dosages are the same as that for streptomycin. Fluoroquinolones In addition to their activity against many gram-positive and gram-negative bacteria(discussed in Chapter 46),ciprofloxacin,levofloxacin,gatifloxacin,and moxifloxacin inhibit strains of M tuberculosis at concentrations less than 2 mcg/mL.They are also active against atypical mycobacteria.Moxifloxacin is the most active against M tuberculosis by weight in vitro. Levofloxacin tends to be slightly more active than ciprofloxacin against M tuberculosis,whereas ciprofloxacin is slightly more active against atypical mycobacteria. Fluoroquinolones are an important addition to the drugs available for tuberculosis,especially for strains that are resistant to first-line agents.Resistance,which may result from any one of several single point mutations in the gyrase A subunit,develops rapidly if a fluoroquinolone is used as a single agent;thus,the drug must be used in combination with two or more other active agents.The standard dosage of ciprofloxacin is 750 mg orally twice a day.The dosage of levofloxacin is 500-750 mg once a day.The dosage of moxifloxacin is 400 mg once a day. Linezolid Linezolid (discussed in Chapter 44)inhibits strains of M tuberculosis in vitro at concentrations of 4 to 8 mcg/mL.It achieves good intracellular concentrations,and it is active in murine models of tuberculosis.Linezolid has been used in combination with other second-and third-line drugs to treat patients with tuberculosis caused by multidrug-resistant strains.Conversion of sputum cultures to negative was associated with linezolid use in these cases,and some may have been cured.Significant and at times treatment-limiting adverse effects,including bone marrow suppression and irreversible peripheral and optic neuropathy,have been reported with the prolonged courses of therapy that are necessary for treatment of tuberculosis.A 600-mg (adult) dose administered once a day (half of that used for treatment of other bacterial infections)seems to be sufficient and may limit the occurrence of these adverse effects.Although linezolid may
The aminoglycoside antibiotics are discussed in Chapter 45. Kanamycin has been used for treatment of tuberculosis caused by streptomycin-resistant strains, but the availability of less toxic alternatives (eg, capreomycin and amikacin) has rendered it obsolete. The role of amikacin in treatment of tuberculosis has increased with the increasing incidence and prevalence of multidrug-resistant tuberculosis. Prevalence of amikacin-resistant strains is low (less than 5%), and most multidrug-resistant strains remain amikacin-susceptible. M tuberculosis is inhibited at concentrations of 1 mcg/mL or less. Amikacin is also active against atypical mycobacteria. There is no cross-resistance between streptomycin and amikacin, but kanamycin resistance often indicates resistance to amikacin as well. Serum concentrations of 30-50 mcg/mL are achieved 30-60 minutes after a 15 mg/kg intravenous infusion. Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrug-resistant strains. Amikacin must be used in combination with at least one and preferably two or three other drugs to which the isolate is susceptible for treatment of drug-resistant cases. The recommended dosages are the same as that for streptomycin. Fluoroquinolones In addition to their activity against many gram-positive and gram-negative bacteria (discussed in Chapter 46), ciprofloxacin, levofloxacin, gatifloxacin, and moxifloxacin inhibit strains of M tuberculosis at concentrations less than 2 mcg/mL. They are also active against atypical mycobacteria. Moxifloxacin is the most active against M tuberculosis by weight in vitro. Levofloxacin tends to be slightly more active than ciprofloxacin against M tuberculosis, whereas ciprofloxacin is slightly more active against atypical mycobacteria. Fluoroquinolones are an important addition to the drugs available for tuberculosis, especially for strains that are resistant to first-line agents. Resistance, which may result from any one of several single point mutations in the gyrase A subunit, develops rapidly if a fluoroquinolone is used as a single agent; thus, the drug must be used in combination with two or more other active agents. The standard dosage of ciprofloxacin is 750 mg orally twice a day. The dosage of levofloxacin is 500-750 mg once a day. The dosage of moxifloxacin is 400 mg once a day. Linezolid Linezolid (discussed in Chapter 44) inhibits strains of M tuberculosis in vitro at concentrations of 4 to 8 mcg/mL. It achieves good intracellular concentrations, and it is active in murine models of tuberculosis. Linezolid has been used in combination with other second- and third-line drugs to treat patients with tuberculosis caused by multidrug-resistant strains. Conversion of sputum cultures to negative was associated with linezolid use in these cases, and some may have been cured. Significant and at times treatment-limiting adverse effects, including bone marrow suppression and irreversible peripheral and optic neuropathy, have been reported with the prolonged courses of therapy that are necessary for treatment of tuberculosis. A 600-mg (adult) dose administered once a day (half of that used for treatment of other bacterial infections) seems to be sufficient and may limit the occurrence of these adverse effects. Although linezolid may
