The earliest recorded human case of TB dates back 9000 years. Early treatment modalities, such as bloodletting, were replaced by sanatorium regimens in the late nineteenth century. The discovery of streptomycin in 1943 launched the era of antibiotic treatment for TB. Over subsequent decades, the discovery of additional agents and the use of multiple-drug regimens allowed progressive shortening of the treatment course from years to as little as 6 months with the regimen for drug-susceptible TB. Latent TB infection (LTBI) and active TB disease are diagnosed by history, physical examination, radiographic imaging, tuberculin skin test, interferon γ release assays, acid-fast staining, mycobacterial cultures, and/or new molecular diagnostics. LTBI is treated with isoniazid (optimally given daily or twice weekly for 9 months), rifampin (daily for 4 months), or isoniazid plus rifapentine (weekly for 3 months) (Table 205e-1).
TABLE 205e-1Regimens for the Treatment of Latent Tuberculosis Infection in Adults ||Download (.pdf) TABLE 205e-1Regimens for the Treatment of Latent Tuberculosis Infection in Adults
|Regimen ||Schedule ||Duration ||Comments |
|Isoniazid || |
300 mg/d (5 mg/kg)
Alternative: 900 mg twice weekly (15 mg/kg)
|9 months (6 months acceptable) || |
Supplement with pyridoxine (25–50 mg daily).
Twice-weekly regimens require directly observed therapy.
|Rifampin ||600 mg/d (10 mg/kg) ||4 months ||Broader efficacy studies are needed. |
|Isoniazid plus rifapentine ||900 mg (15 mg/kg) weekly + 900 mg weekly ||3 months || |
Directly observed therapy is recommended for once-weekly treatment.
This regimen may be supplemented with pyridoxine (25–50 mg/d).
For active or suspected TB disease, clinical factors, including HIV co-infection, symptom duration, radiographic appearance, and public health concerns about TB transmission, drive diagnostic testing and treatment initiation. Multiple-drug regimens are used for the treatment of TB disease (Table 205e-2). Initially, an intensive phase consisting of four drugs—isoniazid, rifampin, pyrazinamide, and ethambutol—given for 2 months is followed by a continuation phase of isoniazid and rifampin for 4 months, for a total treatment duration of 6 months. The continuation phase is extended to 7 months (for a total treatment duration of 9 months) if the 2-month course of pyrazinamide is not completed or, for patients with cavitary pulmonary TB, if sputum cultures remain positive beyond 2 months of treatment (delayed culture conversion).
Treatment of TB in individuals co-infected with HIV poses significant challenges, but some progress is being made. Recent data show improved survival when antiretroviral therapy (ART) is initiated early during TB treatment. Interactions of rifampin with protease inhibitors or non-nucleoside reverse transcriptase inhibitors are significant and require close monitoring and dose adjustments. The TB immune reconstitution inflammatory syndrome (IRIS) may appear as early as 1 week after initiation of ART and manifests as paradoxical worsening or unmasking of existing TB infection. Conservative management consists of continued administration of ART and TB medications. However, severe or debilitating IRIS has been anecdotally treated with varying doses of glucocorticoids. Intermittent therapy in patients co-infected with HIV and M. tuberculosis has been associated with low plasma levels of several key TB drugs and with higher rates of treatment failure or relapse; therefore, intermittent twice-weekly therapy for TB in HIV-co-infected individuals is not recommended.
Adherence to medications is critical in achieving a cure with antimycobacterial therapy. Consequently, directly observed therapy (DOT) by trained staff, either in the clinic or at home, is recommended to ensure adherence. In addition, monthly dispensing of TB medicines is recommended because monthly clinical monitoring for hepatotoxicity due to these medications is essential for all patients. Discontinuation of suspected offending agents at the onset of hepatitis symptoms reduces the risk of progression to fatal hepatitis. Clinical monitoring includes at least monthly assessment for symptoms (nausea, vomiting, abdominal discomfort, and unexplained fatigue) and signs (jaundice, dark urine, light stools, diffuse pruritus) of hepatotoxicity, although the latter represent comparatively late manifestations (Table 205e-3). The presence of such symptoms and signs mandates provisional discontinuation of potentially hepatotoxic agents. Biochemical testing of at least serum alanine aminotransferase and total bilirubin levels and exclusion of other causes of these abnormalities are also indicated during treatment for those at risk for hepatotoxicity (Table 205e-3). For patients with active TB, monthly mycobacterial cultures of sputum are recommended until it is certain that the organisms have been cleared and the patient has responded to therapy or until no sputum is available for culture.
TABLE 205e-2Simplified Approach to Treatment of Active Tuberculosis (TB) in Adults ||Download (.pdf) TABLE 205e-2Simplified Approach to Treatment of Active Tuberculosis (TB) in Adults
|Culture Results ||Intensive Phase ||Continuation Phase ||Extension of Total Treatment |
|Culture positive ||HRZE for 2 months, daily or intermittent (with dose adjustment) ||HR for 4 months, daily or 5 d/wk ||To 9 months, if 2 months of Z is not completed or culture conversion is prolonged and cavitation is evident on plain radiographa |
HR for 4 months, intermittent (with dose adjustment)
|Culture negative ||HRZE for 2 months ||2 months ||To 6 months, if patient is infected with HIV |
|Extrapulmonary ||HRZE for 2 months ||HR for 4–7 months, daily or 5 d/wkb ||To 9–12 months in TB meningitis. Some recommend 9 months for bone/joint TB. |
|Resistant to H ||QRZEc or, less often, RZES for 6 months ||… ||Prolonged culture conversion, cavitation |
|Resistant to R ||HZEQc (IAd) for 2 months ||HEQ(S) for 10–16 months ||Prolonged culture conversion, delayed response |
|Resistant to HRe ||ZEQc (IAd) ± alternative agentsf for 18–24 months ||… ||Prolonged culture conversion |
TABLE 205e-3Monitoring and Clinical Management of Tuberculosis Treatment in Adultsa ||Download (.pdf) TABLE 205e-3Monitoring and Clinical Management of Tuberculosis Treatment in Adultsa
|Drug ||Assessment ||Management |
|LTBI Treatment |
|With hepatic risk factorsb, check ALT and bilirubin at baseline. If ALT is ≥3 × ULN or total bilirubin is >2 × ULN, defer treatment and reevaluate. |
|Isoniazid ||Determine whether hepatic risk factors are present. If so, obtain baseline and periodic ALT and bilirubin values. ||If ALT is 5 × ULN (or 3 × ULN with symptoms)c or if bilirubin reaches jaundice levels (usually >2 × ULN), interrupt treatment. With normalization, consider an alternative agent. |
|Rifampin ||Same as above ||Same as above |
|TB Treatment |
|Check ALT, bilirubin, platelets, creatinine, and hepatitis panel for all patients at baseline. If hepatic risk factors are present, check ALT and bilirubin monthly. |
|Isoniazid ||If ALT is >5 × ULN (or >3 × ULN with hepatitis symptoms)c || |
Obtain history of alcohol consumption and concomitant drug use.
In most instances, discontinue isoniazid, pyrazinamide, rifampin, and other hepatotoxic drugs. Consider alternative agents. Obtain viral hepatitis serologies.
Rechallenge: With normalization of liver enzymes, rifampin and isoniazid may be sequentially reintroduced. With no recurrence of hepatotoxicity, pyrazinamide is not resumed in many cases. Alternative rechallenge protocols have been used.
|Rifampin ||If primary elevation is in bilirubin and alkaline phosphatase, most likely due to rifampin || |
Discontinue rifampin if total bilirubin reaches jaundice levels (usually >2 × ULN).
May try to reintroduce; if not tolerated, may substitute fluoroquinolone
|Ethambutol ||Decrease in visual acuity or color vision or appearance on monthly screening ||Discontinue ethambutol and repeat ocular exam. Peripheral neuropathy may be a precursor of ocular toxicity; if it occurs, consider repeat ocular exam. |
|Pyrazinamide ||If ALT is >5 × ULN (or >3 × ULN with symptoms)c ||Same as for isoniazid |
|Fluoroquinolone ||If QTc prolongation is discovered incidentally on ECG ||Repeat ECG and check electrolytes. If QTc is >500 on repeat ECG after electrolytes are corrected, consider stopping the fluoroquinolone or seek a cardiology consultation. |
|Aminoglycoside ||Abnormal results on audiometry testing, BUN, creatinine, electrolytes at baseline or on monthly check ||Discontinue aminoglycoside if not MDR-TB. As appropriate, assess renal function, correct electrolytes, or seek ENT consultation. |
If significant clinical improvement does not occur or the patient’s condition deteriorates over the course of therapy, possibilities include treatment failure due to nonadherence, poor medication absorption, or the development of resistance. For patients co-infected with HIV and M. tuberculosis, IRIS, which is a diagnosis of exclusion, should also be a consideration. Drug susceptibility testing should be repeated at this point. If resistance is documented or strongly suspected, at least two efficacious drugs to which the isolate is susceptible or which the patient has not already taken should be added to the therapeutic regimen.
Multidrug-resistant TB (MDR-TB) is defined as disease caused by a strain of M. tuberculosis that is resistant to both isoniazid and rifampin—the most efficacious of the first-line TB drugs. The risk of MDR-TB is elevated in patients presenting from geographic areas in which ≥5% of incident cases are MDR-TB and in patients previously treated for TB. Treatment regimens for MDR-TB generally include a late-generation fluoroquinolone and an injectable second-line agent (such as capreomycin, amikacin, or kanamycin). Regimens of at least five drugs are recommended for the treatment of MDR-TB. Both standardized and optimized/customized regimens are in use around the world. Extensively drug-resistant TB (XDR-TB) is defined as MDR-TB with additional resistance to any fluoroquinolone and at least one of the second-line injectable agents. Treatment of XDR-TB is individualized on the basis of complete phenotypic and, if possible, genotypic antimicrobial susceptibility testing. Therapeutic regimens for either MDR-TB or XDR-TB should be constructed with input from experienced clinicians who should continue the management of the disease.
FIRST-LINE ANTITUBERCULOSIS DRUGS
The following discussion of individual anti-TB agents focuses on treatment of TB in adults, unless otherwise noted. Several agents are being actively investigated during the current remarkable period of drug development for TB treatment.
Isoniazid is a critical drug for treatment of both TB disease and LTBI. Isoniazid has excellent bactericidal activity against both intracellular M. tuberculosis and extracellular, actively dividing organisms. This drug is bacteriostatic against slowly dividing organisms. In treatment of LTBI, isoniazid is considered the first-line agent because it is generally well tolerated, has well-established efficacy, and is inexpensive. In this setting, the drug is taken daily or intermittently (i.e., twice weekly) as DOT for 9 months. The 9-month course is more efficacious than the 6-month course (75–90% vs ≤65%), but extension of treatment to 12 months is not likely to provide further protection. A 6-month course of daily or intermittent isoniazid is considered second-line, but acceptable, therapy. A recent large open-label, multicenter, randomized, controlled trial showed that weekly DOT with isoniazid and rifapentine, administered over 3 months, was not inferior to daily isoniazid given for 9 months and had a higher treatment completion rate than the single-drug regimen.
For treatment of TB disease, isoniazid is used in combination with other agents to ensure killing of both actively dividing M. tuberculosis and slowly growing "persister" organisms. Unless the organism is resistant, the standard regimen includes isoniazid, rifampin, ethambutol, and pyrazinamide (Table 205e-2). Isoniazid is often given together with 25–50 mg of pyridoxine daily to prevent drug-related peripheral neuropathy.
Isoniazid is a prodrug activated by the mycobacterial KatG catalase-peroxidase; isoniazid is coupled with reduced nicotinamide adenine dinucleotide (NADH). The resulting isonicotinic acyl–NADH complex blocks the mycobacterial ketoenoylreductase known as InhA, binding to its substrate and inhibiting fatty acid synthase and ultimately mycolic acid synthesis. Mycolic acids are essential components of the mycobacterial cell wall. KatG activation of isoniazid also results in the release of free radicals that have antimycobacterial activity, including nitric oxide.
The minimal inhibitory concentrations (MICs) of isoniazid for wild-type (untreated) susceptible strains are <0.1 μg/mL for M. tuberculosis and 0.5–2 μg/mL for Mycobacterium kansasii.
Isoniazid is the hydrazide of isonicotinic acid, a small, water-soluble molecule. The usual adult oral daily dose of 300 mg results in peak serum levels of 3–5 μg/mL within 30 min to 2 h after ingestion—well in excess of the MICs for most susceptible strains of M. tuberculosis. Both oral and IM preparations of isoniazid reach effective levels in the body, although antacids and high-carbohydrate meals may interfere with oral absorption. Isoniazid diffuses well throughout the body, reaching therapeutic concentrations in body cavities and fluids, with concentrations in cerebrospinal fluid (CSF) comparable to those in serum.
Isoniazid is metabolized in the liver via acetylation by N-acetyltransferase 2 (NAT2) and hydrolysis. Both fast- and slow-acetylation phenotypes occur; patients who are “fast acetylators” may have lower serum levels of isoniazid, whereas “slow acetylators” may have higher levels and experience more toxicity. Satisfactory isoniazid levels are attained in the majority of homozygous fast NAT2 acetylators given a dose of 6 mg/kg and in the majority of homozygous slow acetylators given only 3 mg/kg. Genotyping is increasingly being used to characterize isoniazid-related pharmacogenomic responses.
Isoniazid’s interactions with other drugs are due primarily to its inhibition of the cytochrome P450 system. Among the drugs with significant isoniazid interactions are warfarin, carbamazepine, benzodiazepines, acetaminophen, clopidogrel, maraviroc, dronedarone, salmeterol, tamoxifen, eplerenone, and phenytoin.
The recommended daily dose for the treatment of TB in the United States is 5 mg/kg for adults and 10–20 mg/kg for children, with a maximal daily dose of 300 mg for both. For intermittent therapy in adults (usually twice per week), the dose is 15 mg/kg, with a maximal daily dose of 900 mg. Isoniazid does not require dosage adjustment in patients with renal disease. When the 12-dose, 3-month weekly LTBI regimen is used, the dose of isoniazid is 15 mg/kg, with a maximal dose of 900 mg, and the drug is coadministered with rifapentine.
Although isoniazid, along with rifampin, is the mainstay of TB treatment regimens, ~7% of clinical M. tuberculosis isolates in the United States are resistant. Rates of primary isoniazid resistance among untreated patients are significantly higher in many populations born outside the United States. Five separate pathways for isoniazid resistance have been elucidated. Most strains have amino acid changes in either the catalase-peroxidase gene (katG) or the mycobacterial ketoenoylreductase gene (inhA). Less frequently, alterations in kasA, the gene for an enzyme involved in mycolic acid elongation, and loss of NADH dehydrogenase 2 activity confer isoniazid resistance. In 20–30% of isoniazid-resistant M. tuberculosis isolates, increased expression of efflux pump genes, such as efpA, mmpL7, mmr, p55, and the Tap-like gene Rv1258c, has been implicated as the underlying mechanism of resistance.
Although isoniazid is generally well tolerated, drug-induced liver injury and peripheral neuropathy are significant adverse effects associated with this agent. Isoniazid may cause asymptomatic transient elevation of aminotransferase levels (often termed hepatic adaptation) in up to 20% of recipients. Other adverse reactions include rash (2%), fever (1.2%), anemia, acne, arthritic symptoms, a systemic lupus erythematosus–like syndrome, optic atrophy, seizures, and psychiatric symptoms. Symptomatic hepatitis occurs in fewer than 0.1% of persons treated with isoniazid alone for LTBI, and fulminant hepatitis with hepatic failure occurs in fewer than 0.01%. Isoniazid-associated hepatitis is idiosyncratic, but its incidence increases with age, with daily alcohol consumption, and in women who are within 3 months postpartum.
In patients who have liver disorders or HIV infection, who are pregnant or in the 3-month postpartum period, who have a history of liver disease (e.g., hepatitis B or C, alcoholic hepatitis, or cirrhosis), who use alcohol regularly, who have multiple medical problems, or who have other risk factors for chronic liver disease, the risks and benefits of treatment for LTBI should be weighed. If treatment is undertaken, these patients should have serum concentrations of alanine aminotransferase (ALT) determined at baseline. Routine baseline hepatic ALT testing based solely on an age of >35 years is optional and depends on individual concerns. Monthly biochemical monitoring during isoniazid treatment is indicated for patients whose baseline liver function tests yield abnormal results and for persons at risk for hepatic disease, including the groups just mentioned. Guidelines recommend that isoniazid be discontinued in the presence of hepatitis symptoms or jaundice and an ALT level three times the upper limit of normal or in the absence of symptoms with an ALT level five times the upper limit of normal (Table 205e-3).
Peripheral neuropathy associated with isoniazid occurs in up to 2% of patients given 5 mg/kg. Isoniazid appears to interfere with pyridoxine (vitamin B6) metabolism. The risk of isoniazid-related neurotoxicity is greatest for patients with preexisting disorders that also pose a risk of neuropathy, such as HIV infection; for those with diabetes mellitus, alcohol abuse, or malnutrition; and for those simultaneously receiving other potentially neuropathic medications, such as stavudine. These patients should be given prophylactic pyridoxine (25–50 mg/d).
Rifampin is a semisynthetic derivative of Amycolatopsis rifamycinica (formerly known as Streptomyces mediterranei). The most active antimycobacterial agent available, rifampin is the keystone of first-line treatment for TB. Introduced in 1968, this drug eventually permitted dramatic shortening of the TB treatment course. Rifampin has both sterilizing and bactericidal activity against dividing and nondividing M. tuberculosis. The drug is also active against an array of other organisms, including some gram-positive and gram-negative bacteria, Legionella, M. kansasii, and Mycobacterium marinum.
Rifampin, administered for 4 months, is also an alternative agent to isoniazid for the treatment of LTBI, although efficacy data are scant at this time. A 3-month course of rifampin alone has been found to be similar in efficacy to a 6-month course of isoniazid. Although the efficacy of the 4-month regimen of rifampin is under study, comparison of this regimen with 9 months of isoniazid in randomized safety and tolerability studies suggests fewer adverse events, including hepatotoxicity; less treatment interruption; a higher completion rate; and greater cost-effectiveness.
Rifampin exerts both intracellular and extracellular bactericidal activity. Like other rifamycins, rifampin specifically binds to and inhibits mycobacterial DNA-dependent RNA polymerase, blocking RNA synthesis. Susceptible strains of M. tuberculosis as well as M. kansasii and M. marinum are inhibited by rifampin concentrations of 1 μg/mL.
Rifampin is a fat-soluble, complex macrocyclic molecule readily absorbed after oral administration. Serum levels of 10–20 μg/mL are achieved 2.5 h after the usual adult oral dose of 10 mg/kg (given without food). Rifampin has a half-life of 1.5–5 h. The drug distributes well throughout most body tissues, including CSF. Rifampin turns body fluids such as urine, saliva, sputum, and tears a reddish-orange color—an effect that offers a simple means of assessing patients’ adherence to this medication. Rifampin is excreted primarily through the bile and enters the enterohepatic circulation; <30% of a dose is renally excreted.
As a potent inducer of the hepatic cytochrome P450 system, rifampin can decrease the half-life of some drugs, such as digoxin, warfarin, phenytoin, prednisone, cyclosporine, methadone, oral contraceptives, clarithromycin, azole antifungal agents, quinidine, antiretroviral protease inhibitors, and non-nucleoside reverse transcriptase inhibitors. The Centers for Disease Control and Prevention has issued guidelines for the management of drug interactions during treatment of HIV and M. tuberculosis co-infection (www.cdc.gov/tb/publications/guidelines/TB_HIV_Drugs/default.htm).
The daily dosage of rifampin is 10 mg/kg for adults and 10–20 mg/kg for children, with a maximum of 600 mg/d for both. The drug is given once daily, twice weekly, or three times weekly. No adjustments of dose or frequency are necessary in patients with renal insufficiency.
Resistance to rifampin in M. tuberculosis, Mycobacterium leprae, and other organisms is the consequence of spontaneous, mostly missense point mutations in a core region of the bacterial gene coding for the β subunit of RNA polymerase (rpoB). RNA polymerase altered in this manner is no longer subject to inhibition by rifampin. Most rapidly and slowly growing NTM harbor intrinsic resistance to rifampin, for which the mechanism has yet to be determined.
Adverse events associated with rifampin are infrequent and generally mild. Hepatotoxicity due to rifampin alone is uncommon in the absence of preexisting liver disease and often consists of isolated hyperbilirubinemia rather than aminotransferase elevation. Other adverse reactions include rash, pruritus, gastrointestinal symptoms, and pancytopenia. Rarely, a hypersensitivity reaction may occur with intermittent therapy, manifesting as fever, chills, malaise, rash, and—in some instances—renal and hepatic failure.
Ethambutol is a bacteriostatic antimycobacterial agent first synthesized in 1961. A component of the standard first-line regimen, ethambutol provides synergy with the other drugs in the regimen and is generally well tolerated. Susceptible species include M. tuberculosis, M. marinum, M. kansasii, and organisms of the Mycobacterium avium complex (MAC); however, among first-line drugs, ethambutol is the least potent against M. tuberculosis. This agent is also used in combination with other agents in the continuation phase of treatment when patients cannot tolerate isoniazid or rifampin or are infected with organisms resistant to either of the latter drugs.
Ethambutol is bacteriostatic against M. tuberculosis. Its primary mechanism of action is the inhibition of the arabinosyltransferases involved in cell wall synthesis, which probably inhibits the formation of arabinogalactan and lipoarabinomannan. The MIC of ethambutol for susceptible strains of M. tuberculosis is 0.5–2 μg/mL.
From a single dose of ethambutol, 75–80% is absorbed within 2–4 h of administration. Serum levels peak at 2–4 μg/mL after the standard adult daily dose of 15 mg/kg. Ethambutol is well distributed throughout the body except in the CSF; a dosage of 25 mg/kg is necessary for attainment of a CSF level half of that in serum. For intermittent therapy, the dosage is 50 mg/kg twice weekly. To prevent toxicity, the dosage must be lowered and the frequency of administration reduced for patients with renal insufficiency.
Ethambutol is usually well tolerated and has no significant interactions with other drugs. Optic neuritis, the most serious adverse effect reported, typically presents as reduced visual acuity, central scotoma, and loss of the ability to see green (or, less commonly, red). The cause of this neuritis is unknown, but it may be due to an effect of ethambutol on the amacrine and bipolar cells of the retina. Symptoms typically develop several months after initiation of therapy, but ocular toxicity soon after initiation of ethambutol has been described. The risk of ocular toxicity is dose dependent, occurring in 1–5% of patients, and can be increased by renal insufficiency. The routine use of ethambutol in younger children is not recommended because monitoring for visual complications can be difficult. If drug-resistant TB is suspected, ethambutol can be used for treatment of children.
All patients starting therapy with ethambutol should have a baseline test for visual acuity, visual fields, and color vision and should undergo an examination of the optic fundus. Visual acuity and color vision should be monitored monthly or less often as needed. Cessation of ethambutol in response to early symptoms of ocular toxicity usually results in reversal of the deficit within several months. Recovery of all visual function may take up to 1 year. In the elderly and in patients whose symptoms are not recognized early, deficits may be permanent. Some experts think that supplementation with hydroxocobalamin (vitamin B12) is beneficial for patients with ethambutol-related ocular toxicity. Other adverse effects of ethambutol are rare. Peripheral sensory neuropathy occurs in rare instances.
Ethambutol resistance in M. tuberculosis and NTM is associated primarily with missense mutations in the embB gene that encodes for arabinosyltransferase. Mutations have been found in resistant strains at codon 306 in 50–70% of cases. Mutations at embB306 can cause significantly increased MICs of ethambutol, resulting in clinical resistance.
A nicotinamide analog, pyrazinamide is an important bactericidal drug used in the initial phase of TB treatment. Its administration for the first 2 months of therapy with rifampin and isoniazid allows treatment duration to be shortened from 9 months to 6 months and decreases rates of relapse.
Pyrazinamide’s antimycobacterial activity is essentially limited to M. tuberculosis. The drug is more active against slowly replicating organisms than against actively replicating organisms. Pyrazinamide is a prodrug that is converted by the mycobacterial pyrimidase to the active form, pyrazinoic acid (POA). This agent is active only in acidic environments (pH <6.0), as are found within phagocytes or granulomas. The exact mechanism of action of POA is unclear, but fatty acid synthetase I may be the primary target in M. tuberculosis. Susceptible strains of M. tuberculosis are inhibited by pyrazinamide concentrations of 16–50 μg/mL at pH 5.5.
Pyrazinamide is well absorbed after oral administration, with peak serum concentrations of 20–60 μg/mL at 1–2 h after ingestion of the recommended adult daily dose of 15–30 mg/kg (maximum, 2 g/d). It distributes well to various body compartments, including CSF, and is an important component of treatment for tuberculous meningitis. The serum half-life of the drug is 9–11 h with normal renal and hepatic function. Pyrazinamide is metabolized in the liver to POA, 5-hydroxypyrazinamide, and 5-hydroxy-POA. A high proportion of pyrazinamide and its metabolites (~70%) is excreted in the urine. The dosage must be adjusted according to the level of renal function in patients with reduced creatinine clearance.
At the higher dosages used previously, hepatotoxicity was seen in as many as 15% of patients treated with pyrazinamide. However, at the currently recommended dosages, hepatotoxicity now occurs less commonly when this drug is administered with isoniazid and rifampin during the treatment of TB. Older age, active liver disease, HIV infection, and low albumin levels may increase the risk of hepatotoxicity. The use of pyrazinamide with rifampin for the treatment of LTBI is no longer recommended because of unacceptable rates of hepatotoxicity and death in this setting. Hyperuricemia is a common adverse effect of pyrazinamide therapy that usually can be managed conservatively. Clinical gout is rare.
Although pyrazinamide is recommended by international TB organizations for routine use in pregnancy, it is not recommended in the United States because of inadequate teratogenicity data.
The basis of pyrazinamide resistance in M. tuberculosis is a mutation in the pncA gene coding for pyrazinamidase, the enzyme that converts the prodrug to active POA. Resistance to pyrazinamide is associated with loss of pyrazinamidase activity, which prevents conversion of pyrazinamide to POA. Of pyrazinamide-resistant M. tuberculosis isolates, 72–98% have mutations in pncA. Conventional methods of testing for susceptibility to pyrazinamide may produce both false-negative and false-positive results because the high-acidity environment required for the drug's activation also inhibits the growth of M. tuberculosis. There is some controversy as to the clinical significance of in vitro pyrazinamide resistance.
Rifabutin, a semisynthetic derivative of rifamycin S, inhibits mycobacterial DNA-dependent RNA polymerase. Rifabutin is recommended in place of rifampin for the treatment of HIV-co-infected individuals who are taking protease inhibitors or non-nucleoside reverse transcriptase inhibitors, particularly nevirapine. Rifabutin’s effect on hepatic enzyme induction is less pronounced than that of rifampin. Protease inhibitors may cause significant increases in rifabutin levels through inhibition of hepatic metabolism. Rifabutin is more active in vitro than rifampin against MAC organisms and other NTM, but its clinical superiority has not been established.
Like rifampin, rifabutin is lipophilic and is absorbed rapidly after oral administration, reaching peak serum levels 2–4 h after ingestion. Rifabutin distributes best to tissues, reaching levels 5–10 times higher than those in plasma. Unlike rifampin, rifabutin and its metabolites are partially cleared by the hepatic microsomal system. Rifabutin’s slow clearance results in a mean serum half-life of 45 h—much longer than the 3- to 5-h half-life of rifampin. Clarithromycin (but not azithromycin) and fluconazole appear to increase rifabutin levels by inhibiting hepatic metabolism.
Rifabutin is generally well tolerated, with adverse effects occurring at higher doses. The most common adverse events are gastrointestinal; other reactions include rash, headache, asthenia, chest pain, myalgia, and insomnia. Less common adverse reactions include fever, chills, a flulike syndrome, anterior uveitis, hepatitis, Clostridium difficile–associated diarrhea, a diffuse polymyalgia syndrome, and yellow skin discoloration (“pseudo-jaundice”). Laboratory abnormalities include neutropenia, leukopenia, thrombocytopenia, and increased levels of liver enzymes. Approximately 80% of patients who develop rifampin-related adverse events are able to complete TB treatment with rifabutin.
Similar to rifampin resistance, resistance to rifabutin is mediated by some mutations in rpoB.
Rifapentine is a semisynthetic cyclopentyl rifamycin, sharing a mechanism of action with rifampin. Rifapentine is lipophilic and has a prolonged half-life that permits weekly or twice-weekly dosing. Therefore, this drug is the subject of intensive clinical investigation aimed at determining optimal dosing and frequency of administration. Currently, rifapentine is an alternative to rifampin in the continuation phase of treatment for noncavitary drug-susceptible pulmonary TB in HIV-seronegative patients who have negative sputum smears at completion of the initial phase of treatment. When administered in these specific circumstances, rifapentine (10 mg/kg, up to 600 mg) is given once weekly with isoniazid. Because of higher rates of relapse, this regimen is not recommended for patients with TB disease and HIV co-infection. A large randomized controlled trial recently demonstrated that, for latent TB, a 12-dose (3-month) regimen of weekly DOT with a weight-based dose of isoniazid and rifapentine was noninferior to daily isoniazid for 9 months. Although the rate of permanent drug discontinuation due to adverse events was higher with rifapentine/isoniazid, this regimen had a higher treatment completion rate than daily isoniazid in this study. The efficacy of this combination regimen in HIV-infected individuals not receiving ART and in children <12 years of age is under study. The regimen is not recommended for pregnant women, for persons with hypersensitivity reactions to isoniazid or rifampin, or for HIV-infected individuals taking ART.
Rifapentine’s absorption is improved when the drug is taken with food. After oral administration, rifapentine reaches peak serum concentrations in 5–6 h and achieves a steady state in 10 days. The half-life of rifapentine and its active metabolite, 25-desacetyl rifapentine, is ~13 h. The administered dose is excreted via the liver (70%).
The adverse-effects profile of rifapentine is similar to that of other rifamycins. Rifapentine is teratogenic in animal models and is relatively contraindicated in pregnancy.
Rifapentine resistance is mediated by mutations in rpoB. Mutations that cause resistance to rifampin also cause resistance to rifapentine.
Streptomycin was the first antimycobacterial agent used for the treatment of TB. Derived from Streptomyces griseus, streptomycin is bactericidal against dividing M. tuberculosis organisms but has only low-level early bactericidal activity. This drug is administered only by the IM and IV routes. In developed nations, streptomycin is used infrequently because of its toxicity, the inconvenience of injections, and drug resistance. In developing countries, however, streptomycin is used because of its low cost.
Streptomycin inhibits protein synthesis by binding at a site on the 30S mycobacterial ribosome.
Serum levels of streptomycin peak at 25–45 μg/mL after a 1-g dose. This agent penetrates poorly into the CSF, reaching levels that are only 20% of serum levels. The usual daily dose of streptomycin (given IM either daily or 5 days per week) is 15 mg/kg for adults and 20–40 mg/kg for children, with a maximum of 1 g/d for both. For patients ≥60 years of age, 10 mg/kg is the recommended daily dose, with a maximum of 750 mg/d. Because streptomycin is eliminated almost exclusively by the kidneys, its use in patients with renal impairment should be avoided or implemented with caution, with lower doses and less frequent administration.
Adverse reactions occur frequently with streptomycin (10–20% of patients). Ototoxicity (primarily vestibulotoxicity), neuropathy, and renal toxicity are the most common and the most serious. Renal toxicity, usually manifested as nonoliguric renal failure, is less common with streptomycin than with other frequently used aminoglycosides, such as gentamicin. Manifestations of vestibular toxicity include loss of balance, vertigo, and tinnitus. Patients receiving streptomycin must be monitored carefully for these adverse effects, undergoing audiometry at baseline and monthly thereafter.
Spontaneous mutations conferring resistance to streptomycin are relatively common, occurring in 1 in 106 organisms. In the two-thirds of streptomycin-resistant M. tuberculosis strains exhibiting high-level resistance, mutations have been identified in one of two genes: a 16S rRNA gene (rrs) or the gene encoding ribosomal protein S12 (rpsL). Both targets are believed to be involved in streptomycin ribosomal binding. However, low-level resistance, which is seen in about one-third of resistant isolates, has no associated resistance mutation. A gene (gidB) that confers low-level resistance to streptomycin has recently been identified. Strains of M. tuberculosis resistant to streptomycin generally are not cross-resistant to capreomycin or amikacin. Streptomycin is not used for the treatment of MDR-TB or XDR-TB because of (1) the high prevalence of streptomycin resistance among strains resistant to isoniazid and (2) the unreliability of drug susceptibility testing.
SECOND-LINE ANTITUBERCULOSIS DRUGS
Second-line antituberculosis agents are indicated for treatment of drug-resistant TB, for patients who are intolerant or allergic to first-line agents, and when first-line supplemental agents are unavailable.
Fluoroquinolones inhibit mycobacterial DNA gyrase and topoisomerase IV, preventing cell replication and protein synthesis, and are bactericidal. The later-generation fluoroquinolones levofloxacin and moxifloxacin are the most active against M. tuberculosis and are recommended for the treatment of MDR-TB. They are also being investigated for their potential to shorten the course of treatment for TB. In a recent trial, gatifloxacin, which had been withdrawn from the market because of significant dysglycemia, was assessed for treatment shortening; although its inclusion in the TB treatment regimen did not shorten the duration of therapy from 6 to 4 months, the drug did not cause dysglycemia in TB patients who took it thrice weekly for 4 months. Ciprofloxacin and ofloxacin are no longer recommended for the treatment of TB because of poor efficacy. Despite the documented resistance of the infecting strains to these and other early-generation fluoroquinolones, use of a later-generation fluoroquinolone in patients with XDR-TB has been associated with favorable outcomes. Fluoroquinolones are also considered safe alternatives for patients who develop treatment-limiting adverse effects due to first-line agents. Levofloxacin and moxifloxacin have both been used effectively in the treatment of MDR-TB. The optimal dose of levofloxacin for this indication is being actively studied, but doses of at least 750 mg are commonly used.
The fluoroquinolones are well absorbed orally, reach high serum levels, and distribute well into body tissues and fluids. Their absorption is decreased by co-ingestion with products containing multivalent cations, such as antacids. Adverse effects are relatively infrequent (0.5–10% of patients) and include gastrointestinal intolerance, rashes, dizziness, and headache. Most studies of fluoroquinolone side effects have been based on relatively short-term administration for bacterial infections, but trials have now shown the relative safety and tolerability of fluoroquinolones administered for months during TB treatment in adults. Although the potential to prolong the QTc interval, leading to cardiac arrhythmias, has been a source of concern with fluoroquinolones, cessation of treatment due to this adverse effect is rare. There is increasing interest in the use of fluoroquinolones in children, which has traditionally been avoided because of the risks of tendon rupture and cartilage damage, because the benefits in treatment of drug-resistant TB may outweigh the risks.
Mycobacterial resistance can develop rapidly when a fluoroquinolone is inadvertently administered alone. Empirical fluoroquinolone therapy for presumed community-acquired pneumonia is associated with increased fluoroquinolone resistance in M. tuberculosis. Mutations in the genes encoding for DNA gyrase (gyrA and gyrB) are implicated in the majority of cases—but not all cases—of clinical resistance to fluoroquinolones.
Capreomycin, a cyclic peptide antibiotic derived from Streptomyces capreolus, is an important first-choice second-line agent used for treatment of MDR-TB, particularly when additional resistance to aminoglycosides is documented. Capreomycin is administered by the IM route; an inhaled preparation is under study. A dose of 15 mg/kg per day is given five to seven times per week (maximal daily dose, 1 g) and results in peak blood levels of 20–40 μg/mL. The dosage may be reduced to 1 g two or three times per week 2–4 months after mycobacterial cultures become negative. For individuals ≥60 years of age, the dose should be reduced to 10 mg/kg per day (maximal daily dose, 750 mg). For patients with renal insufficiency, the drug should be given intermittently and at lower dosage (12–15 mg/kg two or three times per week). A minimal duration of 3 months is recommended for MDR-TB treatment. Penetration of capreomycin into the CSF is believed to be poor.
The mechanism of capreomycin’s action is not well understood but involves interference with the mycobacterial ribosome and inhibition of protein synthesis. Resistance to capreomycin is associated with mutations that inactivate a ribosomal methylase (tlyA) or that encode genes for the 16S ribosomal subunit (rrs). Cross-resistance to kanamycin and amikacin is common with rrs but not always with tylA mutations. However, some strains that are resistant to streptomycin, kanamycin, and amikacin generally remain susceptible to capreomycin.
Adverse effects of capreomycin are relatively common. Significant hypokalemia and hypomagnesemia as well as oto- and renal toxicity have been reported.
Amikacin and kanamycin are aminoglycosides that exert mycobactericidal activity by binding to the 16S ribosomal subunit. The spectrum of antibiotic activity for amikacin and kanamycin includes M. tuberculosis, several NTM species, and aerobic gram-negative and gram-positive bacteria. Although amikacin is highly active against M. tuberculosis, it is used only infrequently because of its significant side effects. The usual daily adult dosage of both amikacin and kanamycin is 15–30 mg/kg given IM or IV (maximal daily dose, 1 g), with a reduction to 10 mg/kg for patients ≥60 years old. For patients with renal insufficiency, the dose and frequency should be reduced (12–15 mg/kg two or three times per week). Mycobacterial resistance is due to mutations in the genes encoding the 16S ribosomal RNA gene. Cross-resistance among kanamycin, amikacin, and capreomycin is common. Isolates resistant to streptomycin are frequently susceptible to amikacin or kanamycin. Adverse effects of amikacin include ototoxicity (in up to 10% of recipients, with auditory dysfunction occurring more commonly than vestibulotoxicity), nephrotoxicity, and neurotoxicity. Kanamycin has a similar side-effects profile, but adverse reactions are thought to be less frequent and less severe.
Ethionamide is a derivative of isonicotinic acid. Its mechanism of action is through inhibition of the inhA gene product enoyl–acyl carrier protein (acp) reductase, which is involved in mycolic acid synthesis. Ethionamide is bacteriostatic against metabolically active M. tuberculosis and some NTM. It is used in the treatment of drug-resistant TB, but its use is limited by severe gastrointestinal reactions (including abdominal pain, nausea, and vomiting) as well as significant central and peripheral neurologic side effects, reversible hepatitis (in ~5% of recipients), hypersensitivity reactions, and hypothyroidism. Ethionamide should be taken with food to reduce gastrointestinal effects and with pyridoxine (50–100 mg/d) to limit neuropathic side effects.
Cycloserine is an analog of the amino acid d-alanine and prevents cell wall synthesis. It inhibits the action of enzymes, including alanine racemase, that are involved in the production of peptidoglycans. Cycloserine is active against a range of bacteria, including M. tuberculosis. Mechanisms of mycobacterial resistance are not well understood, but overexpression of alanine racemase can confer resistance in Mycobacterium smegmatis. Cycloserine is well absorbed after oral administration and is widely distributed throughout body fluids, including CSF. The usual adult dosage is 250 mg two or three times per day. Serious potential side effects include seizures and psychosis (with suicide in some cases), peripheral neuropathy, headache, somnolence, and allergic reactions. Drug levels are monitored to achieve optimal dosing and to reduce the risk of adverse effects, especially in patients with renal failure. Cycloserine should be administered as DOT only with caution and with support from experienced TB physicians to patients with epilepsy, active alcohol abuse, severe renal insufficiency, or a history of depression or psychosis.
Para-aminosalicylic acid (PAS, 4-aminosalicylic acid) is an oral agent used in the treatment of MDR- and XDR-TB. Its bacteriostatic activity is due to inhibition of folate synthesis and of iron uptake. PAS has relatively little activity as an anti-TB agent. Adverse effects may include high-level nausea, vomiting, and diarrhea. PAS may cause hemolysis in patients with glucose-6-phosphate dehydrogenase deficiency. The drug should be taken with acidic foods to improve absorption. Enteric-coated PAS granules (4 g orally every 8 h) appear to be better tolerated than other formulations and produce higher therapeutic blood levels. PAS has a short half-life (1 h), and 80% of the dose is excreted in the urine.
Clofazimine is a fat-soluble riminophenazine dye used primarily in the treatment of leprosy worldwide. It is currently gaining popularity in the management of MDR- and XDR-TB because of its low cost and intracellular and extracellular activity. By increasing reactive oxygen species and causing membrane destabilization, clofazimine may promote killing of antibiotic-tolerant M. tuberculosis persister organisms. In addition to antimicrobial activity, the drug has other pharmacologic properties—e.g., anti-inflammatory, pro-oxidative, and immunopharmacologic. Clofazimine has a half-life of ~70 days in humans, and average steady-state concentrations are achieved at ~1 month. Ingestion with fatty meals can improve its low and variable rates of absorption (45–62%). Common side effects include gastrointestinal intolerance and reversible orange-to-brownish discoloration of the skin, bodily fluids, and secretions. Dose adjustment may be necessary in patients with severe hepatic impairment. Clofazimine is being studied as part of a regimen developed in Bangladesh for potential shortening of the MDR-TB treatment course. A recent meta-analysis suggested that inclusion of clofazimine in a multidrug regimen for treatment of MDR-TB was associated with a favorable outcome. Newer analogues with improved pharmacokinetics and alternative formulations of clofazimine (liposomal, nanosuspension, inhalational) are being studied.
NEWER ANTITUBERCULOSIS DRUGS
Linezolid is an oxazolidinone used primarily for the treatment of drug-resistant gram-positive bacterial infections. However, this drug is active in vitro against M. tuberculosis and NTM. Several case series have suggested that linezolid may help clear mycobacteria relatively rapidly when included in a regimen for the treatment of complex cases of MDR- and XDR-TB. Linezolid’s mechanism of action is disruption of protein synthesis by binding to the 50S bacterial ribosome. Linezolid has nearly 100% oral bioavailability, with good penetration into tissues and fluids, including CSF. Clinical resistance to linezolid has been reported, but the mechanism is unclear. Adverse effects may include optic and peripheral neuropathy, pancytopenia, and lactic acidosis. Linezolid is a weak monoamine oxidase inhibitor and can be associated with the serotonin syndrome when given concomitantly with serotonergic drugs (primarily antidepressants such as selective serotonin-reuptake inhibitors). A recent meta-analysis showed that ~80% of patients with MDR- or XDR-TB can be successfully treated with linezolid-containing anti-TB regimens; however, significant adverse events attributed to linezolid were reported. For MDR-TB treatment, linezolid is usually administered at a dose of 600 mg (or less in some cases) once daily, which appears to be effective. The single daily dose is associated with fewer adverse events than twice-a-day dosing.
PNU 100480 and AZD 5847, modified versions of oxazolidinones and protein synthesis inhibitors, are undergoing phase 1 trials and appear to have greater efficacy than linezolid against M. tuberculosis. However, the adverse effect profiles of these compounds compared with that of linezolid need further investigation.
Amoxicillin-Clavulanate and Carbapenems
β-Lactam agents are largely ineffective for the treatment of M. tuberculosis because of resistance conferred by a hydrolyzing class A β-lactamase. Because clavulanate may theoretically inhibit the β-lactamase, amoxicillin-clavulanate has been used in the treatment of MDR-TB; however, it is a comparatively weak agent. Carbapenems are poor substrates for class A β-lactamases found in M. tuberculosis. Accordingly, meropenem and imipenem have in vitro activity against M. tuberculosis, and their use to treat MDR- and XDR-TB has been reported anecdotally. Nevertheless, the need to administer carbapenems by the IV route and lack of information on the drugs' long-term side effects have restricted their use to certain severe cases only.
Bedaquiline (TMC207 or R207910) is a new diarylquinoline with a novel mechanism of action: inhibition of the mycobacterial ATP synthetase proton pump. TMC207 is bactericidal for drug-susceptible and MDR strains of M. tuberculosis. Resistance has been reported and is due to point mutations in the atpE gene encoding for subunit c of ATP synthetase. A phase 2 randomized controlled clinical trial in MDR-TB patients demonstrated substantial improvement in 2-month culture-conversion rates as well as a reduction in acquired resistance to companion drugs. This drug is metabolized by the hepatic cytochrome CYP3A4. Rifampin lowers TMC207 levels by 50%, and protease inhibitors also interact significantly with this drug. The oral bioavailability of TMC207 appears to be excellent. The dosage is 400 mg/d for the first 2 weeks and then 200 mg thrice weekly. The elimination half-life is long (>14 days). A single dose of this drug can inhibit the growth of M. tuberculosis for up to 1 week through a combination of long plasma half-life, high-level tissue penetration, and long tissue half-life. Bedaquiline added to a background regimen improved the 2-month sputum culture conversion rate in multicenter, randomized placebo-controlled trials, and these results led to approval by the U.S. Food and Drug Administration (FDA). However, a higher death rate in one trial was observed in the bedaquiline arm than in the control arm (11.4% vs 2.5%); the result was a “black box” warning from the FDA, which also included QT prolongation. The Centers for Disease Control and Prevention has made a provisional recommendation for the use of bedaquiline for 24 weeks in adults with laboratory-confirmed pulmonary MDR-TB when no other effective treatment regimen can be provided.
The prodrugs delamanid (OPC-67683) and PA 824 are novel nitro-dihydro-imidazooxazole derivatives that are activated by M. tuberculosis–specific flavin-dependent nitroreductases whose antimycobacterial activity is attributable to inhibition of mycolic acid biosynthesis. These drugs are currently in phase 2 clinical trials and show potential in shortening treatment duration through their activity against nonreplicating drug-susceptible and drug-resistant mycobacteria. Delamanid was shown in a randomized, placebo-controlled, multinational clinical trial to significantly improve the culture conversion rate at 2 months. QT prolongation occurred significantly more often in delamanid-treated patients, but no clinically relevant events were reported.
SQ109, an ethambutol analogue with a 1,2-diamine pharmacophore, is the most promising of the diamines for TB treatment. It is activated by mycobacterial cytochrome enzymes and inhibits mycobacterial cell-wall synthesis by an unknown mechanism. It has a high tissue protein-binding capacity with a very long half-life (~61 h) in humans. In vitro studies have demonstrated that SQ109 has low MICs against both susceptible and resistant M. tuberculosis strains as well as a synergistic effect when administered with isoniazid and rifampin. The drug is under study in clinical trials for TB treatment.
LL3858, a pyrrole derivative, has entered clinical trials examining its utility in the treatment of drug-susceptible and drug-resistant TB. The drug’s mechanism of action is unknown. However, because it is active against M. tuberculosis strains that are resistant to available anti-TB drugs, its target is thought to differ from those of currently used agents.