Isoniazid (INH), rifampin (or other rifamycin), pyrazinamide, and ethambutol are the traditional first-line agents for treatment of tuberculosis (Table 47–1). Isoniazid and rifampin are the most active drugs. An isoniazid-rifampin combination administered for 9 months will cure 95–98% of cases of tuberculosis caused by susceptible strains. An initial intensive phase of treatment is recommended for the first 2 months due to the prevalence of resistant strains. The addition of pyrazinamide during this intensive phase allows the total duration of therapy to be reduced to 6 months without loss of efficacy. In practice, therapy is usually initiated with a four-drug regimen of isoniazid, rifampin, pyrazinamide, and ethambutol until susceptibility of the clinical isolate has been determined. In susceptible isolates, the continuation phase consists of an additional 4 months with isoniazid and rifampin (Table 47–2). Neither ethambutol nor other drugs such as streptomycin adds substantially to the overall activity of the regimen (ie, the duration of treatment cannot be further reduced if another drug is used), but the fourth drug provides additional coverage if the isolate proves to be resistant to isoniazid, rifampin, or both. If therapy is initiated after the isolate is known to be susceptible to isoniazid and rifampin, ethambutol does not need to be added. The prevalence of isoniazid resistance among clinical isolates in the USA is approximately 10%. Prevalence of resistance to both isoniazid and rifampin (which is termed multidrug resistance) ranged from 1 to 1.6% from the years 2000 to 2013 in the USA. Multidrug resistance is much more prevalent in many other parts of the world. Resistance to rifampin alone is rare.
TABLE 47–1Antimicrobials used in the treatment of tuberculosis. ||Download (.pdf) TABLE 47–1 Antimicrobials used in the treatment of tuberculosis.
TABLE 47–2Recommended treatment for drug-susceptible tuberculosis. ||Download (.pdf) TABLE 47–2 Recommended treatment for drug-susceptible tuberculosis.
|Regimen (in order of preference) ||Intensive Phase (min duration = 8 weeks) ||Continuation Phase (min duration = 18 weeks)1 ||Comments |
|Drugs ||Dosing Interval ||Drugs ||Dosing Interval |
|1 || |
|7 days per week2 || |
|7 days per week2 ||Preferred regimen. |
|2 || |
|7 days per week2 || |
|3 days per week ||Preferred alternative if less frequent DOT is needed. |
|3 || |
|3 days per week || |
|3 days per week ||Caution in patients with HIV and/or cavitary disease due to concerns for treatment failure, relapse, drug resistance. |
|4 || |
7 days per week × 2 weeks, then
2 days per week × 6 weeks
|2 days per week ||Avoid in patients with HIV or those with smear-positive and/ or cavitary disease. |
Isoniazid is the most active drug for the treatment of tuberculosis caused by susceptible strains. It is a small molecule (molecular weight 137) that is freely soluble in water. The structural similarity to pyridoxine is shown below.
In vitro, isoniazid inhibits most tubercle bacilli at a concentration of 0.2 mcg/mL or less and is bactericidal for actively growing tubercle bacilli. It is less effective against nontuberculous mycobacteria. 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. 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 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 106. Since tuberculous lesions often contain more than 108 tubercle bacilli, resistant mutants are readily selected 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 initially resistant to both drugs is approximately 1 in 106 × 106, or 1 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.
Isoniazid is readily absorbed from the gastrointestinal tract, optimally on an empty stomach; peak concentrations may be decreased by up to 50% when taken with a fatty meal. 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 in the urine. The dosage need not be adjusted in renal failure. Dose adjustment is not well defined in patients with severe preexisting hepatic insufficiency and should be guided by serum concentrations if a reduction in dose is contemplated. Isoniazid inhibits several cytochrome P450 enzymes, leading to increased concentrations of such medications as phenytoin, carbamazepine, and benzodiazepines. However, when used in combination with rifampin, a potent CYP enzyme inducer, the concentrations of these medications are usually decreased.
The typical 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 to three times-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, and the duration is usually 9 months.
The incidence and severity of untoward reactions to isoniazid are related to dosage and duration of administration.
Fever and skin rashes are occasionally seen. Drug-induced systemic lupus erythematosus has been reported.
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 age 21–35, 1.2% of those age 36–50, and 2.3% for those age 50 and above. The risk of hepatitis is greater in individuals with alcohol dependence 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 it is infrequently seen with the standard 300-mg adult dose. Peripheral neuropathy 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, ataxia, and seizures. These effects may also respond to pyridoxine.
Miscellaneous other reactions include hematologic abnormalities, provocation of pyridoxine deficiency anemia, tinnitus, and gastrointestinal discomfort.
Rifampin is a semisynthetic derivative of rifamycin, an antibiotic produced by Amycolatopsis rifamycinica, formerly named Streptomyces mediterranei. It is active in vitro against Gram-positive organisms, some Gram-negative organisms, such as Neisseria and Haemophilus species, mycobacteria, and chlamydiae. Susceptible organisms are inhibited by less than 1 mcg/mL. Resistant mutants are present in all microbial populations at approximately 1 in 106 organisms and are rapidly selected out if rifampin is used as a single drug, especially in a patient with 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.
Mechanism of Action, Resistance, & Pharmacokinetics
Rifampin binds to the β 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 β 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 penetrates 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 excreted 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. The drug is relatively highly protein-bound, and adequate cerebrospinal fluid concentrations are achieved only in the presence of meningeal inflammation.
Rifampin strongly induces most cytochrome P450 isoforms (CYP1A2, 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 or integrase strand transfer inhibitors, contraceptives, and a host of others (see Chapters 4 and 66). Co-administration of rifampin results in significantly lower serum levels of these drugs.
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 is 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 for patients with latent tuberculosis 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.
Rifampin has other uses in bacterial infections. An oral dosage of 600 mg twice daily for 2 days can eliminate meningococcal carriage. Rifampin, 20 mg/kg (maximum 600 mg) once daily for 4 days, is used as prophylaxis in contacts of children with Haemophilus influenzae type b disease. Rifampin combined with a second agent is sometimes used to eradicate staphylococcal carriage. Rifampin combination therapy is also used for treatment of serious staphylococcal infections such as osteomyelitis, prosthetic joint infections, and prosthetic valve endocarditis.
Rifampin imparts a harmless orange color to urine, sweat, and tears (soft contact lenses may be permanently stained). Occasional adverse effects include rashes, thrombocytopenia, and nephritis. Rifampin may cause cholestatic jaundice and occasionally hepatitis, and it commonly causes light-chain proteinuria. If administered less often than twice weekly, rifampin may cause a flu-like syndrome characterized by fever, chills, myalgias, anemia, and thrombocytopenia. Its use has been associated with acute tubular necrosis.
Ethambutol is a synthetic, water-soluble, heat-stable compound, the dextro-isomer of the structure shown below, dispensed as the dihydrochloride salt.
Mechanism of Action & Clinical Uses
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. Susceptible strains of Mycobacterium tuberculosis and other mycobacteria are inhibited in vitro by ethambutol, 1–5 mcg/mL.
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 to three times weekly if creatinine clearance is less than 30 mL/min. Ethambutol crosses the blood-brain barrier only when 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. Ethambutol hydrochloride, 15–25 mg/kg, is usually given as a single daily dose in combination with isoniazid, rifampin, and pyrazinamide during the initial intensive phase of active tuberculosis treatment. The higher dose may be used for treatment of tuberculous meningitis. Higher doses have been used with intermittent dosing regimens for directly observed therapy; for example, 25–30 mg/kg three times weekly or 50 mg/kg administered twice weekly. Ethambutol is also used in combination with other agents for the treatment of nontuberculous mycobacterial infections, such as Mycobacterium avium complex (MAC) or M. kansasii; the typical dose for these infections is 15 mg/kg once daily.
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 adverse effect is more likely to occur at dosages of 25 mg/kg/d continued for several months. At 15 mg/kg/d or less, visual disturbances occur in approximately 2% of patients, typically after at least one month of treatment. Experts recommend baseline and monthly visual acuity and color discrimination testing, with particular attention to patients on higher doses or with impaired renal function. Ethambutol is relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination.
Pyrazinamide (PZA) is a relative of nicotinamide, and it is used only for treatment of tuberculosis. It is stable and slightly soluble in water. It is inactive at neutral pH, but at pH 5.5 it inhibits tubercle bacilli 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.
Mechanism of Action & Clinical Uses
Pyrazinamide is converted to pyrazinoic acid—the active form of the drug—by mycobacterial pyrazinamidase, which is encoded by pncA. Pyrazinoic acid disrupts mycobacterial cell membrane metabolism and transport functions. Resistance may be due to impaired uptake of pyrazinamide or mutations in pncA that impair conversion of PZA to its active form.
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, PZA 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 30–50 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.
Major adverse effects of PZA include hepatotoxicity (in 1–5% of patients), nausea, vomiting, drug fever, photosensitivity, and hyperuricemia. The latter occurs uniformly and is not a reason to halt therapy if patients are asymptomatic.
SECOND-LINE DRUGS FOR TUBERCULOSIS
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; and (3) in case of serious treatment-limiting adverse drug reactions. Expert guidance is desirable in dealing with the toxic effects of these second-line drugs. For many drugs listed in the following text, the dosage, emergence of resistance, and long-term toxicity have not been fully established.
The mechanism of action and other pharmacologic features of streptomycin, an aminoglycoside, are discussed in Chapter 45. The typical adult dosage 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 dosage is 15 mg/kg two or three times per week. Most tubercle bacilli are inhibited by streptomycin, 1–10 mcg/mL, in vitro. Nontuberculous 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 108 tubercle bacilli can be expected to be resistant to streptomycin at levels of 10–100 mcg/mL. Resistance may be due to a point mutation in either the rpsL gene encoding the S12 ribosomal protein or the rrs gene encoding 16S ribosomal RNA, which alters the ribosomal binding site.
Streptomycin penetrates into cells poorly and is active mainly against extracellular tubercle bacilli. The drug 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 and in the 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 for children, not to exceed 1 g) for several weeks, followed by 15 mg/kg 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.
Streptomycin is ototoxic and nephrotoxic. Vertigo and hearing loss are the most common adverse 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.
Ethionamide is chemically related to isoniazid and similarly blocks the synthesis of mycolic acids. It is poorly water soluble and available only for oral use. 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 1-5 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, though theoretically desirable, is poorly tolerated because of gastric irritation and neurologic symptoms, often limiting the tolerable daily dose to 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 is a peptide protein synthesis inhibitor antibiotic obtained from Streptomyces capreolus. Daily injection of 15 mg/kg intramuscularly results in peak serum levels of 35–45 mcg/mL 2 hours after a dose. 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 usually are susceptible to capreomycin, though some data suggest cross-resistance with strains resistant to amikacin and kanamycin. Resistance to capreomycin, when it occurs, has been associated with rrs, eis, or tlyA gene mutations.
Capreomycin is nephrotoxic and ototoxic. Tinnitus, deafness, and vestibular disturbances occur. The injection causes significant local pain, and sterile abscesses may develop.
Typical dosing of capreomycin is 15 mg/kg/day initially, which is then reduced to two or three times weekly after an initial response has been achieved with a daily dosing schedule. The intermittent dosing regimen may minimize risk of toxicity.
Cycloserine—a structural analog of D-alanine—inhibits cell wall synthesis, as discussed in Chapter 43. Concentrations of 15–20 mcg/mL inhibit many strains of M tuberculosis. The usual dosage of cycloserine in tuberculosis is 0.5–1 g/d in two divided oral doses. The drug is widely distributed to tissues, including the central nervous system. This drug is cleared renally, and the dose should be reduced by half if creatinine clearance is less than 50 mL/min. Alternatively, it may be reduced to 500 mg three times weekly.
The most serious toxic effects are peripheral neuropathy and central nervous system dysfunction, including depression and psychoses. Pyridoxine, 100 mg or more per day, 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 leading to peak concentrations greater than 35 mcg/mL. Adverse 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 20–35 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-amino-benzoic acid (PABA) and is thought to have a similar mechanism of action to the sulfonamides (see Chapter 46). In the USA, PAS is commercially available as a 4-g packet of delayed-release granules. In order to protect the integrity of the delayed-release coating, the granules must be administered sprinkled over applesauce or yogurt, or swirled in fruit juice and swallowed whole.
Tubercle bacilli are usually inhibited in vitro by aminosalicylic acid, 1–5 mcg/mL. The granule formulation of aminosalicylic acid results in improved absorption from the gastrointestinal tract. Peak serum levels are expected to be 20–60 mcg/mL 6 hours after a 4 g oral dose. The dosage is 8–12 g/d orally for adults and 300 mg/kg/d for children, administered in two or three divided doses. 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 PAS and in part as the acetylated compound and other metabolic products. To avoid accumulation in renal impairment, the maximum dose is 4 g twice daily when creatinine clearance is less than 30 mL/min. Very high concentrations of aminosalicylic acid are reached in the urine, which can result in crystalluria.
Aminosalicylic acid is used infrequently in the USA because other oral drugs are better tolerated. Gastrointestinal symptoms are common but occur less frequently with the delayed-release granules; they 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 PAS therapy, making it necessary to stop administration temporarily or permanently.
The aminoglycoside antibiotics are discussed in Chapter 45. Kanamycin had been used for treatment of tuberculosis caused by streptomycin-resistant strains, but it is no longer available in the USA, and less toxic alternatives (eg, capreomycin and amikacin) have taken its place.
Amikacin is playing a greater role in the treatment of tuberculosis due to the prevalence of multidrug-resistant strains. Prevalence of amikacin-resistant strains is low (<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. Peak serum concentrations of 30–45 mcg/mL are achieved 30–60 minutes after a 15-mg/kg intravenous infusion or intramuscular injection. Amikacin is indicated for treatment of tuberculosis suspected or known to be caused by streptomycin-resistant or multidrug-resistant strains. This drug 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 dosage is 15 mg/kg once daily initially, followed by intermittent dosing two or three times per week.
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 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. The World Health Organization recommends using a later generation fluoroquinolone such as moxifloxacin or levofloxacin. Resistance, which may result from 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 additional active agents. Typically, resistance to one fluoroquinolone indicates class resistance. However, moxifloxacin may retain some activity in strains resistant to ofloxacin. The dosage of levofloxacin is 500–750 mg once a day, and some clinicians increase to 1000 mg daily if tolerated. The dosage of moxifloxacin is 400 mg once a day. Some experts recommend checking peak serum concentrations. Expected levels at about two hours post-dose are 8–12 mcg/mL for levofloxacin and 3–5 mcg/mL for moxifloxacin.
Linezolid (discussed in Chapter 44) inhibits strains of M tuberculosis in vitro at concentrations of 4–8 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. Significant 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. Experts recommend supplemental pyridoxine for patients treated with linezolid. Although linezolid may prove to be an important new agent for treatment of tuberculosis, at this point it should be used only for multidrug-resistant strains that also are resistant to several other first- and second-line agents. It is generally avoided in patients on concomitant serotonergic agents due to concern for serotonin syndrome.
Rifabutin is derived from rifamycin and is related to rifampin. It has significant activity against M tuberculosis, MAC, and Mycobacterium fortuitum (see below). Its activity is similar to that of rifampin, and cross-resistance with rifampin is virtually complete. Some rifampin-resistant strains may appear susceptible to rifabutin in vitro, but a clinical response is unlikely because the molecular basis of resistance, rpoB mutation, is the same. Rifabutin is both substrate and inducer of cytochrome P450 enzymes. Because it is a less potent inducer, rifabutin is often used in place of rifampin for treatment of tuberculosis in patients with HIV infection who are receiving antiretroviral therapy with a protease inhibitor, a nonnucleoside reverse transcriptase inhibitor (eg, efavirenz), or an integrase strand transfer inhibitor (eg dolutegravir), drugs that also are cytochrome P450 or UDP glucuronosyltransferase (UGT) substrates.
The typical dosage of rifabutin is 300 mg/d unless the patient is receiving a protease inhibitor, in which case the dosage should be reduced, typically by half. If efavirenz (also a cytochrome P450 inducer) is used, the recommended dosage of rifabutin is 600 mg/d. Rifabutin may accumulate in severe renal impairment, and the dose should be reduced by half if creatinine clearance is less than 30 mL/min. Rifabutin is associated with similar rates of hepatotoxicity or rash compared to rifampin; it can also cause leukopenia, thrombocytopenia, and optic neuritis.
Rifapentine is another analog of rifampin. It is active against both M tuberculosis and MAC. As with all rifamycins, it is a bacterial RNA polymerase inhibitor, and cross-resistance between rifampin and rifapentine is complete. Like rifampin, rifapentine is a potent inducer of cytochrome P450 enzymes, and it has the same drug interaction profile; however, when rifapentine is administered intermittently, induction of metabolism of other medications is less pronounced compared to rifampin. Toxicity is similar to that of rifampin. Rifapentine and its microbiologically active metabolite, 25-desacetylrifapentine, have an elimination half-life of 13 hours. Rifapentine, 600 mg (10 mg/kg) once or twice weekly, has been used for treatment of tuberculosis caused by rifampin-susceptible strains during the continuation phase (ie, after the first 2 months of therapy and ideally after conversion of sputum cultures to negative); however, this regimen has decreased efficacy compared with the standard rifampin-based regimen. Revised guidelines for treatment of drug-susceptible tuberculosis published in 2016 recommend against it. In particular, its use should be avoided in patients at higher risk of failure, including those with positive cultures at the end of the intensive treatment phase and those with evidence of cavitation on chest radiographs. Rifapentine should not be used to treat active tuberculosis in patients with HIV infection because of an unacceptably high relapse rate with rifampin-resistant organisms. Rifapentine in combination with isoniazid, typically both dosed at 900 mg once weekly for 3 months (12 doses each in total), is an effective short course treatment for latent tuberculosis infection.
Bedaquiline, a diarylquinoline, is the first drug with a novel mechanism of action against M tuberculosis to be approved since 1971. Bedaquiline inhibits adenosine 5′-triphosphate (ATP) synthase in mycobacteria, has in vitro activity against both replicating and nonreplicating bacilli, and has bactericidal and sterilizing activity in the murine model of tuberculosis. Cross-resistance has been reported between bedaquiline and clofazimine, likely via upregulation of the multisubstrate efflux pump, MmpL5.
Peak plasma concentration and plasma exposure to bedaquiline increase approximately twofold when administered with high-fat food. Bedaquiline is highly protein-bound (>99%), is metabolized chiefly through the cytochrome P450 system, and is excreted primarily via the feces. The mean terminal half-life of bedaquiline and its major metabolite (M2), which is four to six times less active in terms of antimycobacterial potency, is approximately 5.5 months. This long elimination phase probably reflects slow release of bedaquiline and M2 from peripheral tissues. CYP3A4 is the major isoenzyme involved in the metabolism of bedaquiline, and potent inhibitors or inducers of this enzyme cause clinically significant drug interactions.
Current recommendations state that bedaquiline, in combination with at least three other active medications, may be used for 24 weeks of treatment in adults with laboratory-confirmed pulmonary tuberculosis if the isolate is resistant to both isoniazid and rifampin. The recommended dosage for bedaquiline is 400 mg once daily orally for 2 weeks, followed by 200 mg three times a week for 22 weeks taken orally with food in order to maximize absorption. The most common adverse effects, occurring at rates of 25% or more, are nausea, arthralgia, and headache. Bedaquiline has been associated with both hepatotoxicity and cardiac toxicity. The FDA has issued a black-box warning related to the risk of QTc prolongation and associated mortality. It should be reserved for patients who do not have other treatment options and used with caution in patients with other risk factors for cardiac conduction abnormalities.