Tratamiento común de tuberculosis pulmonar

Official reprint from UpToDate

www.uptodate.com ©2015 UpToDate

AuthorTimothy R Sterling, MD

Section EditorC Fordham von Reyn, MD

Deputy EditorElinor L Baron, MD, DTMH

Treatment of pulmonary tuberculosis in HIV-uninfected patients

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Jul 2015. | This topic last updated: May 28, 2015.

INTRODUCTION — The primary goals of tuberculosis (TB) treatment include [1]:

To achieve these objectives, combination therapy should be administered consisting of at least two drugs to which

the organism is susceptible. Successful treatment of individual cases facilitates reduction of transmission to others in

the community. Individual case management with directly observed therapy (DOT) is very important for facilitating

adherence and preventing the development of drug resistance and represents the standard of care in the United

States today [1]. Tuberculosis is a reportable disease, regardless of the organ(s) involved, and successful

management usually requires engagement of public health and TB laboratory services to assure safe completion of

therapy and minimize risk of secondary drug resistance and treatment failure or relapse.

The American Thoracic Society (ATS), Centers for Disease Control (CDC), and Infectious Disease Society of

America (IDSA) statement on the treatment of tuberculosis is a key summary of treatment guidelines in the United

States [1]. The International Standards for Tuberculosis Care provides important treatment recommendations for

international settings [2].

An overview of the medical therapy of tuberculosis, as well as features of specific antituberculous drugs, will be

provided here. Issues related to the treatment of latent M. tuberculosis infection and tuberculosis in HIV-infected

patients are discussed separately. (See "Treatment of latent tuberculosis infection in HIV-negative adults" and

"Treatment of latent tuberculosis infection in HIV-infected patients" and "Treatment of pulmonary tuberculosis in the

HIV-infected patient" and "Monitoring the HIV-infected patient on antituberculous medications".)

TREATMENT — Chemotherapy for tuberculosis became available with the introduction of streptomycin (SM) and

isoniazid (INH) in the 1940s and 1950s, respectively. Observation of treatment failure with single agents (due to the

emergence of drug resistance) and subsequent development of additional agents with activity against M.

tuberculosis have led to successful treatment with combination therapy.

Several trials were conducted in the 1970s and 1980s by the British Medical Research Council, British Thoracic

Association, and Hong Kong Chest Service to evaluate the optimal combination and duration of antituberculosis

therapy [3-8]. These studies established that the efficacy of short-course (six-month) regimens with the addition of

rifampin (RIF) and pyrazinamide (PZA) to a base regimen of daily isoniazid and streptomycin, that ethambutol (EMB)

was roughly as effective as SM (allowing all-oral therapy), and that PZA and EMB (or SM) was necessary only for

the first two months of a six-month regimen using INH and RIF throughout.

Initial therapy of tuberculosis should include four drugs; basic regimens for treating patients with tuberculosis caused

by organisms known or presumed to be drug susceptible are outlined in the Table (table 1) [1]. Each regimen has an

initial phase of two months followed by a choice of several options for the continuation phase of either four or seven

months. Drug doses are shown in the Tables (table 2 and table 3 and table 4).

The choice of treatment in the initial phase is usually empiric, as susceptibility data may not be available or become

available at the end of the initial phase of treatment. Susceptibility data should be available at the beginning of the

continuation phase and should be used to direct therapy if drug resistance is identified.

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Eradicating M. tuberculosis infection●

Preventing development of drug resistance●

Preventing relapse of disease●

Treatment of pulmonary tuberculosis in HIV-uninfected patients http://www.uptodate.com.wdg.biblio.udg.mx:2048/contents/treatment-of...

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Individual case management with directly observed therapy (DOT) is the preferred strategy for treatment of all

patients with tuberculosis to assure completion of appropriate therapy and prevent emergence of drug resistance.

DOT involves providing the antituberculosis drugs directly to the patient and watching as the patient swallows the

medications. (See "Adherence to tuberculosis treatment", section on 'Directly observed therapy'.)

Initial phase — The initial drug regimen is based on knowledge of the likely drug susceptibility. Four drugs (usually

isoniazid, rifampin, pyrazinamide, and ethambutol) are used in the initial phase of previously untreated tuberculosis

because of concern for INH resistance [9]. This regimen is intended to decrease the secondary development of

resistance to RIF in populations with a high rate of primary resistance to INH (4 percent or more). Treatment of

tuberculosis with organisms resistant to both INH and RIF (multidrug-resistant tuberculosis [MDR-TB]) is discussed

separately. (See "Diagnosis, treatment, and prevention of drug-resistant tuberculosis".)

Where drug resistance is suspected, expert consultation and supplemental testing using molecular methods for

identifying mutations within the MTb genome associated with drug resistance, such as the GenExpert-Rif or the

Centers for Disease Control and Prevention's Molecular Determination of Drug Resistance service should be

considered to help guide treatment decisions (see "Diagnosis of pulmonary tuberculosis in HIV-uninfected patients").

The initial phase of treatment usually consists of two months and may be administered in one of the following

schedules (table 1):

If susceptibility results indicate the isolate is sensitive to INH, RIF, and PZA, then EMB can be discontinued as it

does not affect or shorten the overall treatment duration [1]. If PZA cannot be included in the initial phase of

treatment (eg, in the setting of severe liver disease, gout, or, in the United States, pregnancy) the initial phase should

consist of INH, RIF, and EMB administered daily for two months and the total treatment duration extended (Regimen

4).

Sputum acid-fast bacilli (AFB) smears and cultures should be obtained at the time of completion of the initial phase

of treatment (eight weeks) in order to identify patients at increased risk of relapse [1]. Susceptibility testing should be

pursued for positive cultures from the initial respiratory isolate (and from each additional site of disease if possible)

and at three months into therapy if still culture positive at this point, along with a search for an explanation for

delayed culture conversion. Repeat chest radiography should be obtained at this time for patients with negative

initial cultures to evaluate for evidence of interval improvement. It may also be useful for patients with positive initial

cultures but is not essential. (See 'Monitoring' below.)

For cases in which it is not possible to establish a definitive laboratory diagnosis and presumptive therapy is initiated

(eg, based on signs and symptoms, chest radiograph, positive tuberculin skin test, epidemiologic exposure, etc),

treatment should be continued if initial cultures are found to be positive or there is a response to treatment (eg,

clinically and/or radiographically). If culture-negative tuberculosis (TB) is suspected, a total four-month course of

antituberculosis treatment should be administered (two months of INH, RIF, PZA, EMB followed by two months of

INH and RIF for HIV-uninfected patients). If there is no evidence of active disease, latent tuberculosis may be

inferred and treatment for latent tuberculosis infection (LTBI) should be continued accordingly. (See 'Culture-negative

TB' below and "Treatment of latent tuberculosis infection in HIV-negative adults", section on 'Continuation of LTBI

treatment after presumptive treatment for TB disease'.)

Continuation phase — The continuation phase of treatment for pulmonary tuberculosis is administered for four or

seven months and, in most cases, consists of INH and RIF (table 1). Most patients are treated with a four-month

continuation phase (total duration of treatment six months) [10].

The six-month rifampin-based treatment regimen is supported by US Public Health Service (USPHS) Trial 21, a

randomized trial of 1451 patients with pulmonary TB comparing the efficacy of six months of INH and RIF (with PZA

Daily for eight weeks (Regimens 1 and 4)●

Daily for two weeks, then twice weekly for six weeks (Regimen 2). Regimen 2a is frequently used by public

health departments because the twice-weekly dosing schedule facilitates administration of DOT.

●

Three times weekly for eight weeks (Regimen 3)●


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for the first two months) with nine months of INH and RIF [11]. Patients in the six-month regimen were more likely to

complete therapy (61 versus 51 percent), and relapse rates two years after completing therapy were similar in the

two groups (3.5 and 2.8 percent).

Intermittent drug administration facilitates supervision of therapy and has been shown to be as effective as daily

administration [1]. Twice-weekly dosing is frequently used by public health departments [Regimen 2a; (table 1)]. This

practice is supported by a study of 160 patients treated with two weeks of daily directly observed therapy (INH, RIF,

PZA, and EMB) followed by twice-weekly directly observed therapy for a total over 62 doses administered over 32

weeks; the relapse rate was 1.6 percent [12].

The continuation phase should be extended to seven months (nine months total duration of treatment) in the

following circumstances [1]:

This practice is based on evidence from USPHS Study 22, which demonstrated that, among patients on continuation

phase twice-weekly INH and RIF who had cavitation on initial chest radiograph and positive culture at the two month

juncture, nearly 21 percent relapsed [13]. Patients with only one of these factors (either cavitation or positive culture

at two months) had relapse rates of 5 to 6 percent; patients with neither risk factor had relapse rates of 2 percent. A

prolonged continuation phase for patients with cavitation and positive cultures at two months is supported by a study

of patients with silicotuberculosis in whom extending treatment to eight months greatly reduced the rate of relapse

(22 to 7 percent) [14].

A chest radiograph at completion of therapy provides a baseline against which subsequent examinations can be

compared but is not essential.

In the setting of culture-negative tuberculosis, the continuation phase can be shortened to two months using INH and

RIF (table 1) [1,15]. (See 'Culture-negative TB' below.)

Management of extrapulmonary tuberculosis consists of the same treatment regimen and duration as for pulmonary

tuberculosis. Exceptions include concomitant bone and joint disease (six to nine months of therapy) and central

nervous system disease (12 months of therapy). In addition, adjunctive corticosteroids are recommended in persons

with tuberculous meningitis [1] and patients with constrictive pericarditis and patients at high risk of constrictive

tuberculous pericarditis. These issues are discussed in further detail separately. (See "Skeletal tuberculosis" and

"Tuberculous pericarditis" and "Central nervous system tuberculosis".)

Monitoring — In the United States, it is recommended that sputum be obtained for microscopic examination and

culture at monthly intervals until two consecutive culture specimens are negative [1]. Obtaining sputum culture after

two months of treatment is particularly important because of the association with increased relapse risk if positive.

Results also have implications for the duration of the continuation phase of treatment. (See 'Continuation phase'

above.)

Treatment guidelines issued by the World Health Organization (WHO), which pertain to all global settings,

recommend repeat sputum smear two months after initiation of therapy. If smear positive, sputum smear microscopy

should be repeated at the end of the third month of treatment, and, if positive, sputum culture and drug susceptibility

testing should be performed [16].

A meta-analysis has noted that both microscopy and culture during tuberculosis treatment have low sensitivity and

modest specificity for predicting failure and relapse [17]; better markers are needed [18].

Interrupted therapy — Completion of treatment is determined by both the duration of therapy and the total number

of doses administered. In some cases, the specified number of doses cannot be administered within the target time

Patients with both cavitary pulmonary TB on initial chest radiograph and positive sputum culture after two

months of initial phase treatment. The decision to prolong the continuation phase for patients with either

cavitation or positive cultures (but not both) should be made on an individual basis.

●

Patients whose initial phase of treatment did not include PZA●


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period (eg, due to drug toxicity or nonadherence). In general, all of the doses for the initial phase should be delivered

within three months, the doses for the four-month continuation phase should be delivered within six months, and the

six-month continuation phase should be completed within nine months [1].

For circumstances in which the specified number of doses cannot be administered within the targeted period, a

determination should be made regarding continuing treatment for a longer duration or restarting treatment from the

beginning. Reinstitution of therapy must take into account the burden of disease, the point when the interruption

occurred, and the duration of the interruption (algorithm 1).

In general, continuous treatment is more important in the initial phase of therapy when the organism burden is

highest and the chance of developing drug resistance is greatest [19]. The earlier in the course treatment and the

longer the duration of interruption, the more serious the effect and the greater the need to restart therapy from the

beginning.

BASELINE AND FOLLOW-UP EVALUATION — Treatment of patients with tuberculosis requires careful monitoring

for adverse drug effects. Since hepatotoxicity may be caused by isoniazid (INH), rifampin (RIF) or pyrazinamide

(PZA), patients receiving antituberculous therapy with first-line drugs should undergo baseline measurement of

hepatic enzymes (transaminases and alkaline phosphatase) and bilirubin. In addition, testing for hepatitis B and C

should be pursued for patients with epidemiologic risk factors. Patients with hepatitis B carrier state (and normal

baseline transaminase levels) appear to be more likely to develop hepatotoxicity during antituberculous treatment

than patients without hepatitis B [20]. (See related topics.)

Other baseline tests prior to initiation of therapy should include complete blood count, serum creatinine, and uric acid

[1]. In addition, counseling and testing for HIV infection should be performed. When treatment includes ethambutol

(EMB), baseline testing of visual acuity and red-green color discrimination should be obtained.

Hepatic monitoring — Repeated monthly hepatic enzyme measurements are not necessary for patients with

normal baseline results and no risk for hepatitis. They should be obtained in the following settings:

Patients must be educated about the symptoms of hepatic toxicity, including anorexia, nausea, vomiting, dark urine,

icterus, rash, pruritus, fatigue, fever, abdominal discomfort (particularly right upper quadrant discomfort), easy

bruising or bleeding, and arthralgias [21]. Patients should be directly questioned at monthly visits for these

symptoms. In addition, they should immediately report any signs or symptoms that occur in the interval between the

monthly visits. All patients with such complaints should be fully evaluated, including serum testing for hepatic injury.

Hepatotoxicity — Hepatotoxicity may be caused by INH, RIF, or PZA. An asymptomatic increase in aspartate

transaminase (AST) concentration occurs in nearly 20 percent of patients treated with the standard four-drug

regimen; in most patients, asymptomatic aminotransferase elevations resolve spontaneously [22]. Occasionally,

there are also disproportionate increases in bilirubin and alkaline phosphatase; these are consistent with rifampin

hepatotoxicity.

In general, antituberculosis agents should be discontinued if a patient's transaminase level exceeds three times the

upper limit of normal in association with symptoms or five times the upper limit of normal in the absence of

symptoms [1]. Drug-induced hepatitis is a diagnosis of exclusion; other possible etiologies must also be assessed,

such as acetaminophen, alcohol, and hepatitis A, B, or C.

The optimal approach to resumption of antituberculous therapy is uncertain, and expert consultation should be

obtained. In general, in cases where there should be no interruption in therapy, three new drugs (eg, an

Abnormal baseline results●

A drug reaction is suspected●

Liver disease (eg, hepatitis B or C, alcohol abuse)●

Pregnancy and the first three months postpartum●

Combination therapy including pyrazinamide in continuation phase●

Other situations that may be associated with hepatic injury (eg, some medications, alcohol or drug abuse)●


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aminoglycoside and two oral agents such as EMB and a fluoroquinolone) could be started until the transaminase

concentration returns to less than two to three times the upper limit of normal (or to near baseline levels). In a study

of 1191 patients with hepatotoxicity due to first-line antituberculosis regimens, levofloxacin and moxifloxacin caused

no additional hepatotoxicity [23].

Thereafter, the first-line medications can be restarted one at a time. RIF (may be given together with EMB) should be

restarted first [21,22]. If there is no increase in hepatic transaminases after one week, INH may be restarted. If

symptoms recur or hepatic transaminases increase, the last drug added should be stopped. For those who have

experienced prolonged or severe hepatotoxicity but tolerate reintroduction with RIF and INH, rechallenge with PZA

may be hazardous. In this circumstance, PZA may be permanently discontinued, with treatment extended to nine

months. Although PZA can be reintroduced in some milder cases of hepatotoxicity [24] and a regimen of RIF, PZA,

and EMB can be given for six months [1], the benefit of a shorter treatment course may not outweigh the risk of

severe hepatotoxicity from PZA rechallenge. (See 'Interrupted therapy' above.)

Alternative regimens — Expert consultation should be sought for the management of patients requiring

alternative regimens. Options for treatment of disease due to susceptible strains in the setting of drug intolerance

include [1]:

Other adverse effects

Ocular toxicity — Patients taking EMB should be questioned about possible visual disturbances, including

blurred vision or scotomata, at monthly intervals. Monthly testing of visual acuity and color discrimination is

recommended for patients taking doses greater than those listed in the Table (table 4) and for patients receiving the

drug for longer than two months.

Rash — All antituberculous drugs can cause rash. Minor pruritic rashes affecting a limited area can be managed

symptomatically with antihistamines and continuation of antituberculous therapy. A petechial rash in patients taking

rifampin should prompt consideration of hypersensitivity; if thrombocytopenia is present, rifampin should be stopped

and the platelet count monitored until it returns to baseline. In such circumstances, rifampin should not be resumed.

Generalized erythematous rash should prompt discontinuation of all drugs immediately (particularly if associated

with fever and/or mucous membrane involvement). In the setting of severe tuberculosis, three new drugs (eg, an

aminoglycoside or capreomycin and two oral agents) should be started. When the rash is substantially improved, the

first-line medications can be restarted one at a time, at intervals of two to three days. If no rash appears after the first

three drugs have been restarted, the fourth drug should not be restarted unless it is considered essential for therapy.

Drug fever — Fever observed in the setting of microbiological and radiographic improvement after several

For patients who cannot tolerate INH, a six-month regimen of RIF, PZA, and EMB may be given. This regimen

is nearly as efficacious as an INH-containing regimen [7,9]. Alternatively, RIF and EMB may be used for 12

months, preferably with PZA during at least the initial two months [7,25].

●

For patients who cannot tolerate rifampin, alternative regimens include 12 to 18 months of INH and EMB. A

fluoroquinolone (usually levofloxacin [500 to 1000 mg oral or intravenous once daily] or moxifloxacin [400 mg

oral or intravenous once daily]) can also be given, though such a regimen has not been studied. PZA could be

given during at least the first two months [26,27]. An injectable agent may be added for the first two to three

months in persons with extensive disease or to shorten the overall treatment duration to 12 months.

●

For patients who cannot tolerate PZA, nine months of INH and RIF should be administered (supplemented by

EMB until INH and RIF susceptibility are demonstrated). This approach requires that the M. tuberculosis strain

be susceptible to both INH and RIF [28].

●

For patients with severe unstable liver disease who require a regimen with no hepatotoxic agents, an injectable

agent (aminoglycoside or capreomycin), EMB, a fluoroquinolone, and another second-line oral drug may be

used for a duration of 18 to 24 months. The optimal approach as to the choice of agents or the duration of

treatment is uncertain.

●


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weeks of therapy should prompt consideration of drug fever; in such cases, patients generally look and feel well

despite high fever (often greater than 39°C). Eosinophilia may or may not be present. Other causes of fever include

tuberculosis (may persist as long as two months after therapy has been initiated) and paradoxical reaction in the

setting of HIV infection [29]. (See "Monitoring the HIV-infected patient on antituberculous medications".)

If alternative causes of fever are excluded, all drugs should be stopped; drug-related fever usually resolves within 24

hours. Once the fever has resolved, the protocol for restarting drugs should be followed as described in the

preceding section. (See 'Rash' above.)

ADVERSE OUTCOMES — Adverse outcomes include treatment failure (positive cultures after four months of

treatment) and relapse (recurrent tuberculosis at any time after completion of treatment with apparent cure). Repeat

sputum smear and culture two months after initiation of therapy is important for identifying patients at risk of relapse

and treatment failure. Patients with positive cultures three months after initiation of therapy should undergo careful

evaluation to determine the cause, and drug susceptibility testing should be repeated [1].

Possible reasons for adverse outcomes include impaired adherence to treatment (for patients who have not been

receiving directly observed therapy [DOT]), high burden of clinical disease (including presence of cavitary disease,

bilateral disease, and/or extrapulmonary disease), drug resistance, malabsorption, and malnourishment [13,30-32].

Relapse — Relapse is defined by recurrent tuberculosis at any time after completion of treatment and apparent cure

[1]. Recurrence of tuberculosis may occur either as a result of relapsed infection due to the same M. tuberculosis

strain or due to exogenous reinfection with a new strain [33]. One study from South Africa that employed genetic

testing of M. tuberculosis strains from predominantly HIV-uninfected or HIV–status unknown patients showed that 80

percent of smear-positive recurrent disease within the first year following successful therapy was due to relapse,

whereas reinfection accounted for 66 percent of cases that occurred after the first year [34]. Data were not available

from this study on the 50 percent of cases that were smear negative. In settings with high incidence of tuberculosis,

such as South Africa, exogenous reinfection is more likely to account for recurrent disease than in settings with low

rates of tuberculosis where recurrent disease is more likely due to relapse [11,33,35,36].

Most relapses occur within the first 6 to 12 months following completion of therapy. Among patients treated with

rifamycin-containing regimens using DOT, relapses generally occur with susceptible organisms. For other patients,

the risk of acquired drug resistance is substantial. If initial drug susceptibility testing was not performed and the

patient fails or relapses with a rifamycin-containing regimen given by DOT, there is high likelihood that the organisms

were resistant from the outset.

Treatment failure — Treatment failure is defined as continuous or recurrently positive cultures during the course of

appropriate antituberculous therapy [1]. After three months of a regimen containing isoniazid (INH) and rifampin

(RIF) for pulmonary tuberculosis caused by drug-susceptible organisms, 90 to 95 percent of patients have negative

cultures and demonstrate clinical improvement. Presumptive treatment should be continued in such circumstances.

Patients with positive cultures after three months of effective treatment must be evaluated carefully to identify the

cause of the delayed conversion. Patients whose sputum cultures remain positive after four months of treatment

should be considered treatment failures.

Management — If relapse or treatment failure occurs, early consultation with an expert should be pursued. A single

drug should never be added to a failing regimen, as this may lead to acquired resistance to the new drug.

Retreatment should be administered with DOT whenever feasible.

The clinical M. tuberculosis isolate should be sent promptly to a reference laboratory for drug susceptibility testing to

both first- and second-line agents. The Centers for Disease Control and Prevention's Molecular Detection of Drug

Resistance service may help guide treatment decisions, since turnaround time is rapid. Results of molecular tests for

drug resistance, however, must be confirmed using culture-based methods (see "Diagnosis of pulmonary

tuberculosis in HIV-uninfected patients").

The possibility of acquired drug resistance must be considered when determining the initial treatment regimen. The


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regimen should be based on the prior treatment regimen(s) and the severity of disease. Once the susceptibility test

results return, the treatment regimen should be based on the susceptibility of the organism identified.

For patients who did not receive DOT, were not treated with a rifamycin-based regimen, or had irregular treatment, it

is prudent to infer that drug resistance is present. An expanded regimen with INH, RIF, and pyrazinamide (PZA) plus

an additional two or three new drugs to which susceptibility could logically be inferred should be added in order to

minimize the probability of developing further resistance.

For patients whose epidemiologic circumstances provide strong suspicion of exogenous reinfection as the cause of

apparent relapse, the susceptibility profile of the putative source case may be used to guide selection of an initial

regimen, pending susceptibility results of the patient's own isolate.

For patients with drug-susceptible disease treated with DOT, initiation of the standard four-drug regimen may be

appropriate until drug susceptibility test results are available. However, in the setting of life-threatening forms of

tuberculosis (eg, meningitis or miliary disease), at least three additional drugs from different drug classes to which

the patient has not been exposed should be included in the empiric treatment regimen. Empiric retreatment

regimens may include a fluoroquinolone, an injectable agent such as capreomycin or amikacin, and an additional

oral agent such as paraaminosalicylic acid (PAS), cycloserine, or ethionamide. (See "Second-line antituberculous

therapy".)

Once drug susceptibility results are available, the treatment regimen can be adjusted according to the susceptibility

results. (See "Diagnosis, treatment, and prevention of drug-resistant tuberculosis" and "Second-line antituberculous

therapy".)

SPECIAL CIRCUMSTANCES

Drug resistance — Initial drug regimens need to be modified in areas with a known high prevalence of

drug-resistant tuberculosis (TB) and in treatment of patients with known drug-resistant disease. These issues are

discussed in detail separately. (See "Epidemiology and molecular mechanisms of drug-resistant tuberculosis" and

"Diagnosis, treatment, and prevention of drug-resistant tuberculosis" and "Clinical manifestations, diagnosis, and

treatment of extensively drug-resistant tuberculosis".)

Culture-negative TB — In the United States, about 17 percent of reported new cases of pulmonary tuberculosis

have negative cultures [1]. Failure to isolate M. tuberculosis from appropriately collected specimens from patients

suspected to have pulmonary TB (on clinical or radiographic grounds) does not exclude a diagnosis of tuberculosis.

In such cases, presumptive therapy should be initiated as outlined in the preceding sections. At the end of the initial

phase, continuation phase treatment should be pursued if initial cultures are found to be positive or there is a

response to treatment (eg, clinically and/or radiographically). In the setting of culture-negative tuberculosis, the

continuation phase can be shortened to two months using INH and RIF (table 1) [1,37].

If there is no evidence of active disease, latent tuberculosis may be inferred and treatment for latent tuberculosis

infection (LTBI) should be continued accordingly. (See "Treatment of latent tuberculosis infection in HIV-negative

adults", section on 'Continuation of LTBI treatment after presumptive treatment for TB disease'.)

Children — Treatment of tuberculosis in children is discussed in detail separately. (See "Tuberculosis disease in

children".)

Pregnant women — Treatment of tuberculosis in pregnancy is discussed in detail separately. (See "Tuberculosis in

pregnancy".)

Diabetes — The incidence of TB among patients with diabetes has been noted to be approximately two- to fourfold

higher than in those without diabetes, although these data come from surveys performed prior to 1960 [38,39].

Data regarding the effect that underlying diabetes may have on efficacy of treatment for TB are limited. In a study of

737 Indonesian patients with pulmonary TB between 2000 and 2005, clinical characteristics and outcome were

compared between patients with and without underlying diabetes [40]. After six months of treatment, the odds ratio


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of having a positive sputum culture for M. tuberculosis was sevenfold higher in diabetic patients than in patients

without diabetes. The severity of disease at presentation was comparable in both groups. It is unclear whether better

glycemic control could improve sputum sterilization in diabetic patients.

Renal insufficiency — Alteration in dosing of antituberculosis agents, particularly ethambutol (EMB) and

pyrazinamide (PZA), is necessary in patients with renal insufficiency (table 5). Lengthening the dosing interval is

preferable over reducing the dose to optimize peak serum concentrations [1]. Administration of all antituberculosis

drugs immediately after hemodialysis facilitates directly observed therapy (DOT; three times weekly) and minimizes

premature removal of the drugs [41].

Patients with renal disease may have additional clinical conditions (such as diabetes with gastroparesis) that may

affect the absorption of antituberculous drugs or may be taking concurrent medications that interact with these

drugs. Therefore, a careful clinical and pharmacological assessment is necessary, and, in some cases, serum drug

concentration monitoring may be warranted to determine optimal drug dosing [42].

Hepatic disease — The treatment of tuberculosis in patients with unstable or advanced liver disease is challenging.

The likelihood of drug-induced hepatitis may be increased, and the implications of adverse drug effects for patients

with marginal hepatic reserve are potentially life threatening. Therefore, regimens with fewer potentially hepatotoxic

agents may be needed, together with expert consultation. However, standard antituberculosis therapy is generally

initiated in patients with underlying hepatic disease, and hepatic transaminases and bilirubin are monitored closely.

(See 'Alternative regimens' above.)

Tuberculosis itself may involve the liver, causing abnormal liver function that improves with effective treatment.

HIV infection — HIV infection is common in patients with tuberculosis. All persons suspected of having active

tuberculosis who are not known to be HIV infected should undergo HIV counseling and testing [43]. Issues related to

treatment of tuberculosis in the setting of HIV infection, including indications for HIV antiretroviral therapy, are

discussed in detail separately. (See "Treatment of pulmonary tuberculosis in the HIV-infected patient".)

Malnutrition — The role of micronutrient supplementation for patients with tuberculosis in developing countries is

uncertain. Supplementation has included a number of agents (including vitamins A, B complex, C, D, and selenium)

and has been associated with the following benefits [44-47]:

However, other studies have shown no effect on mortality or other outcomes [48-51]. These discordant findings may

be related to differences in the types of micronutrients supplemented, gender, age, and other factors including

effectiveness of antituberculosis therapy [52]. Further study is needed in resource-limited settings; results may or

may not be applicable to patients in developed areas.

The role of macronutrient supplementation (eg, supplemental calorie or protein intake) in the treatment of

tuberculosis is uncertain. In a small study of 36 HIV-uninfected subjects with TB, those who received high energy

supplements had significantly greater increases in body weight and total lean mass compared to controls, although

the effects on TB endpoints (cure, failure, death) are uncertain [53].

ANTITUBERCULOUS AGENTS — The major drugs used to treat tuberculosis, along with the appropriate doses,

are listed in the Tables (table 2 and table 3 and table 4) [54,55]. The first-line antituberculous medications should be

administered together as a single dose to optimize peak serum concentrations. Drugs should be administered on an

empty stomach if tolerated, but dosing with food is acceptable to ameliorate gastrointestinal upset and is preferable

to dividing doses or changing to second-line agents.

Isoniazid — Isoniazid (INH) is bactericidal, easily tolerated orally in a single daily dose, and inexpensive. The major

toxicity is hepatitis, which is age dependent; it is rare in persons younger than 20 years of age, and the risk

increases with age and alcohol use. (See "Isoniazid: An overview" and "Isoniazid hepatotoxicity".)

Enhanced rate of smear conversion●

Reduced risk of TB recurrence●

Reduced mortality in HIV-infected individuals●


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Peripheral neuropathy can occur due to isoniazid and can be minimized by using pyridoxine. The risk is increased in

persons with conditions that may be associated with neuropathy, such as nutritional deficiency, diabetes, HIV

infection, renal failure, and alcoholism, as well as for pregnant and breastfeeding women. Pyridoxine

supplementation (25 to 50 mg per day in adults) is recommended for high-risk patients with these conditions to help

prevent neuropathy [43].

Rifampin — Rifampin (RIF) is bactericidal for M. tuberculosis; it is given as a single daily oral dose and is well

tolerated. Hepatic toxicity is less common than with INH. Rifampin induces hepatic microsomal enzymes and may

increase hepatic clearance, decreasing the effectiveness of several drugs, including oral contraceptives, warfarin,

methadone, corticosteroids, and HIV antiretroviral therapy. Rifampin is excreted as a red-orange compound in urine,

tears, sweat, and stool, and may permanently stain contact lenses. (See "Rifamycins (rifampin, rifabutin,

rifapentine)".)

The other rifamycins used to treat tuberculosis, including rifapentine and rifabutin, are used in special circumstances

and are discussed separately. (See "Rifamycins (rifampin, rifabutin, rifapentine)".)

Pyrazinamide — Pyrazinamide (PZA) is bactericidal for M. tuberculosis at an acidic pH (eg, inside cells). It is

effective orally as a single daily dose; gastrointestinal upset is fairly common. The major toxicity is hepatic injury [56].

Hyperuricemia is a frequent consequence of PZA use due to decreased renal uric acid excretion; gouty flares may

also occur. (See "Pyrazinamide: An overview".)

Ethambutol — Ethambutol (EMB) is mostly bacteriostatic at standard doses, although it may have some

bactericidal effect. It is administered as a single daily oral dose and is usually well tolerated. The major toxicity is

optic neuritis, which is relatively uncommon with standard dosing. (See "Ethambutol: An overview".)

Fixed dose combinations — Fixed dose combinations (FDC) containing INH and RIF (Rifamate), and INH, RIF,

and PZA (Rifater) are available. These combinations decrease the likelihood of inappropriate ingestion of a single

drug and may decrease the development of drug resistance during therapy. They are often used when directly

observed therapy (DOT) cannot be provided.

A four-drug FDC (containing rifampicin, isoniazid, pyrazinamide, and ethambutol) was compared with a regimen of

four separately administered medications in a noninferiority trial among 1585 adults at 11 sites in Africa, Asia, and

Latin America; the patients enrolled were predominantly HIV uninfected [57]. The four-drug FDC satisfied

noninferiority criteria in two of three analyses. The potential advantages related to administration and adherence

using the FDC may make this a preferred approach compared with non-FDC regimens, particularly in resource-

limited settings where DOT is not provided.

Fluoroquinolones — The fluoroquinolones have shown promise as antituberculosis agents that could potentially

shorten treatment duration [58]. However, three published phase III clinical trials have shown that shorter

fluoroquinolone-containing regimens were inferior to standard six-month therapy:

Shortening treatment with a moxifloxacin-containing regimen to four months was not effective in a randomized

trial including 1931 patients with uncomplicated, smear-positive tuberculosis [59]. The study demonstrated that

each of two moxifloxacin-containing regimens (one included isoniazid, rifampin, pyrazinamide, and

moxifloxacin for 17 weeks; the other included rifampin, pyrazinamide, ethambutol, and moxifloxacin for 17

weeks) was inferior to the standard control regimen of two months of isoniazid, rifampin, pyrazinamide, and

ethambutol followed by four months of isoniazid and rifampin. Both moxifloxacin-containing regimens had

higher rates of negative sputum cultures at two months, despite higher rates of tuberculosis failure or relapse

within 18 months of randomization (the primary study endpoint). Prior data had been conflicting regarding

whether substitution of moxifloxacin for ethambutol (in addition to treatment with isoniazid, rifampin, and

pyrazinamide) hastens sputum culture conversion at eight weeks [60-62].

●

Shortening treatment with a regimen containing moxifloxacin for four months and rifapentine for two months

was not effective in randomized trial including 827 patients with smear-positive tuberculosis [63]. Patients were

treated with one of three regimens: a control regimen (two months of ethambutol, isoniazid, rifampin, and

●


9 de 23 03/08/2015 07:11 p.m.

Pending further data, fluoroquinolones should be used only in persons with intolerance of or resistance to first-line

agents [1]. The optimal duration of tuberculosis regimens that include fluoroquinolones is uncertain.

The possibility of fluoroquinolone resistance should be considered in patients who have received fluoroquinolone

monotherapy for treatment of other infections prior to diagnosis of tuberculosis [65]. Among 116 patients with

tuberculosis who had fluoroquinolone exposure in the 12 months prior to diagnosis, fluoroquinolone resistance was

observed in 2.5 percent of cases [65]. Among patients with more than 10 days of fluoroquinolone exposure that

occurred more than 60 days before tuberculosis diagnosis, fluoroquinolone resistance was observed in 20 percent of

cases.

Second-line drugs — A number of other drugs may be used to treat tuberculosis when the major drugs are not

tolerated or when drug resistance is present. These drugs are less effective and more toxic than the major

antituberculous drugs outlined above and should be used only by medical personnel who have experience in treating

such patients with these agents. (See "Second-line antituberculous therapy".)

RESOURCE-LIMITED SETTINGS — In general, the approach outlined in the preceding section should be utilized

as feasible. Documents summarizing recommendations in countries where mycobacterial laboratory facilities (for

culture and susceptibility testing) and chest radiography are not widely available have been issued by the World

Health Organization (WHO) and the International Union against Tuberculosis and Lung Disease (IUATLD) [16,66].

These organizations recommend a control strategy called "DOTS" (Directly Observed Treatment, Short Course) in

which direct observation therapy is one of five key elements. The components include [67]:

The International Standards for Tuberculosis Care also provide important guidelines for tuberculosis management in

all settings [2].

Evaluation — The acid-fast bacilli (AFB) smear is the primary tool in resource-limited settings for diagnosis,

classification, and monitoring response to therapy, as access to reliable culture facilities is limited and the AFB

smear identifies patients who are most likely to transmit infection. However, smear conversion is not always a useful

pyrazinamide administered daily, followed by four months of daily isoniazid and rifampin), a four-month regimen

(in which isoniazid in the control regimen was replaced by moxifloxacin administered daily for two months,

followed by moxifloxacin and 900 mg of rifapentine administered twice weekly for two months), and a six-month

regimen (in which isoniazid was replaced by daily moxifloxacin for two months, followed by one weekly dose of

moxifloxacin and 1200 mg of rifapentine for four months). The six-month regimen was as effective as the

control regimen; the four-month regimen was inferior to the control regimen. The primary endpoint was a

composite of unfavorable outcomes, including treatment failure, relapse, and death up to 18 months after

randomization.

Shortening treatment with a gatifloxacin-containing regimen for four months was not effective in a randomized

trial including 1836 patients with smear-positive tuberculosis [64]. A standard six-month regimen was compared

with a four-month regimen in which gatifloxacin (400 mg per day) was substituted for ethambutol during the

intensive phase and continued, along with rifampin and isoniazid, during the continuation phase. The

four-month regimen was inferior to the standard regimen, based on the primary composite endpoint of

unfavorable outcomes 24 months after the end of treatment.

●

Government commitment to sustained tuberculosis (TB) control activities●

Case detection by sputum smear microscopy among patients self reporting to health services●

Standardized treatment regimen of six to eight months for at least all confirmed sputum smear-positive cases,

with directly observed therapy for at least the initial two months

●

A regular, uninterrupted supply of all essential antituberculosis drugs●

A standardized recording and reporting system that allows assessment of treatment results for each patient

and of the TB control program overall

●


10 de 23 03/08/2015 07:11 p.m.

determining factor for identifying patients with multidrug-resistant tuberculosis (MDR-TB). In one study of 93 adults in

Peru, persistent 60-day smear positivity had a positive predictive value for detecting multidrug resistance of only 67

percent [68]. Drug susceptibility testing is not performed routinely for new patients in the setting of limited funds and

facilities.

Xpert MTB/RIF is a rapid diagnostic test performed directly on sputum that can detect tuberculosis and resistance to

rifampin [69]. This use of this test is increasing in resource-limited settings. (See "Diagnosis, treatment, and

prevention of drug-resistant tuberculosis", section on 'Rapid testing'.)

The WHO recommends susceptibility testing for patients who fail the initial treatment regimen (eg, sputum smear

positive in month five of treatment or later) and for those who fail a supervised treatment regimen. Assessment of

cure is based on clinical response and on sputum AFB smear (or culture when available) at completion of treatment.

Chest radiography is recommended by the WHO and IUATLD only for patients with negative sputum smears and is

not recommended for follow-up.

Treatment — In resource-limited settings, the WHO favors an initial phase of daily isoniazid (INH), rifampin (RIF),

pyrazinamide (PZA), and ethambutol (EMB) for two months followed by a continuation phase of INH and RIF for four

months by directly observed therapy (DOT) [16]. Although daily dosing throughout the entire course of therapy is

preferred, a thrice-weekly regimen can be considered in the continuation phase if each dose is directly observed

[16].

An alternative regimen in which an initial phase of daily INH, RIF, PZA, and EMB for two months is followed by a

continuation phase of INH and EMB for six months should be phased out because of decreased effectiveness [16].

Monitoring and follow-up — Follow-up laboratory testing is not recommended by the WHO or IUATLD, though

patients should be followed regularly to assess for response to therapy and possible adverse events. Patients should

be taught to recognize the symptoms associated with drug toxicity and report them promptly.

Patients with initial positive smears have repeat smear examination at two months, five months, and at completion of

treatment (either six or eight months) [16,66]. The IUATLD recommends that, for patients with positive smears at two

months, the initial phase should be extended for one month.

Relapse and failure — The approach in the setting of relapse and failure in the absence of susceptibility testing

data is an area of considerable controversy. The WHO and IUATLD have standard retreatment regimens [16,66].

Individualized regimens must be determined depending on clinical circumstances [70].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and

“Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5 to 6 grade

reading level, and they answer the four or five key questions a patient might have about a given condition. These

articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the

Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the

10 to 12 grade reading level and are best for patients who want in-depth information and are comfortable with

some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these

topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on

“patient info” and the keyword(s) of interest.)

SUMMARY AND RECOMMENDATIONS

th th

th th

Beyond the Basics topics (see "Patient information: Tuberculosis (Beyond the Basics)")●

The primary goals of tuberculosis treatment include eradicating M. tuberculosis, preventing development of

drug resistance, and preventing relapse of infection. Directly observed therapy (DOT) is the preferred strategy

for treatment of all patients with tuberculosis to assure completion of appropriate therapy and prevent

emergence of drug resistance. (See 'Introduction' above.)

●


11 de 23 03/08/2015 07:11 p.m.

Use of UpToDate is subject to the Subscription and License Agreement.

REFERENCES

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1.

Hopewell PC, Pai M, Maher D, et al. International standards for tuberculosis care. Lancet Infect Dis 2006;6:710.

2.

Controlled clinical trial of four short-course (6-month) regimens of chemotherapy for treatment of pulmonary

tuberculosis. Second report. Lancet 1973; 1:1331.

3.

Controlled trial of 6-month and 9-month regimens of daily and intermittent streptomycin plus isoniazid pluspyrazinamide for pulmonary tuberculosis in Hong Kong. The results up to 30 months. Am Rev Respir Dis

1977; 115:727.

4.

Short-course chemotherapy in pulmonary tuberculosis. A controlled trial by the British Thoracic andTuberculosis Association. Lancet 1976; 2:1102.

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The initial phase of treatment usually consists of two months; we recommend initial therapy with four drugs

(Grade 1B). The regimen typically consists of isoniazid, rifampin, pyrazinamide, and ethambutol (table 1). Drug

doses are shown in the Tables (table 2 and table 3 and table 4 and table 5). Sputum acid-fast bacilli (AFB)

smears and cultures should be obtained at the time of initiation and completion of the initial phase of treatment;

the latter will help identify patients at increased risk of relapse. (See 'Initial phase' above.)

●

The continuation phase in most cases consists of isoniazid and rifampin administered for four months (six

months total duration of treatment) (table 1). Intermittent drug administration facilitates supervision of therapy

and has been shown to be as effective as daily administration in most patients. The continuation phase should

be extended to seven months (nine months total duration of treatment) in the circumstances outlined above.

(See 'Continuation phase' above.)

●

In general, continuous treatment is most important in the initial phase of therapy, when the organism burden is

highest and the chance of developing drug resistance is greatest. The earlier in the course and the longer the

duration of treatment interruption, the more serious the effect and the greater the need to restart therapy from

the beginning. (See 'Interrupted therapy' above.)

●

Treatment requires careful monitoring for adverse drug effects. Baseline laboratory evaluation should include

measurement of hepatic enzymes (transaminases, bilirubin, and alkaline phosphatase), complete blood count,

serum creatinine, and uric acid. Testing for hepatitis B and C should be pursued for patients with epidemiologic

risk factors, and counseling and testing for HIV infection should be performed on all patients. Visual acuity and

red-green color discrimination testing should be obtained when treatment includes ethambutol. (See 'Baseline

and follow-up evaluation' above.)

●

Patients must be educated about the symptoms of hepatic toxicity. In general, antituberculosis agents should

be discontinued if a patient's transaminase level exceeds three times the upper limit of normal in association

with symptoms or five times the upper limit of normal in the absence of symptoms. Alternative treatment

regimens are available for patients who cannot tolerate or are resistant to first-line therapy. (See 'Hepatic

monitoring' above.)

●

Adverse outcomes include treatment failure (positive cultures after four months of treatment) and relapse

(recurrent tuberculosis at any time after completion of treatment with apparent cure). If relapse or treatment

failure occurs, early consultation with specialty expertise should be pursued. A single drug should never be

added to a failing regimen, as this may lead to acquired resistance to the new drug. (See 'Adverse outcomes'

above.)

●


12 de 23 03/08/2015 07:11 p.m.

A controlled trial of six months chemotherapy in pulmonary tuberculosis. Second report: results during the 24months after the end of chemotherapy. British Thoracic Association. Am Rev Respir Dis 1982; 126:460.

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Controlled trial of 2, 4, and 6 months of pyrazinamide in 6-month, three-times-weekly regimens for smear-positive pulmonary tuberculosis, including an assessment of a combined preparation of isoniazid, rifampin, andpyrazinamide. Results at 30 months. Hong Kong Chest Service/British Medical Research Council. Am RevRespir Dis 1991; 143:700.

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Mitchison DA, Nunn AJ. Influence of initial drug resistance on the response to short-course chemotherapy ofpulmonary tuberculosis. Am Rev Respir Dis 1986; 133:423.

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Johnson JL, Hadad DJ, Dietze R, et al. Shortening treatment in adults with noncavitary tuberculosis and2-month culture conversion. Am J Respir Crit Care Med 2009; 180:558.

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Combs DL, O'Brien RJ, Geiter LJ. USPHS Tuberculosis Short-Course Chemotherapy Trial 21: effectiveness,toxicity, and acceptability. The report of final results. Ann Intern Med 1990; 112:397.

11.

Cohn DL, Catlin BJ, Peterson KL, et al. A 62-dose, 6-month therapy for pulmonary and extrapulmonarytuberculosis. A twice-weekly, directly observed, and cost-effective regimen. Ann Intern Med 1990; 112:407.

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Benator D, Bhattacharya M, Bozeman L, et al. Rifapentine and isoniazid once a week versus rifampicin andisoniazid twice a week for treatment of drug-susceptible pulmonary tuberculosis in HIV-negative patients: arandomised clinical trial. Lancet 2002; 360:528.

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A controlled clinical comparison of 6 and 8 months of antituberculosis chemotherapy in the treatment ofpatients with silicotuberculosis in Hong Kong. Hong Kong Chest Service/tuberculosis Research Centre,Madras/British Medical Research Council. Am Rev Respir Dis 1991; 143:262.

14.

Efficacy of various durations of isoniazid preventive therapy for tuberculosis: five years of follow-up in the IUATtrial. International Union Against Tuberculosis Committee on Prophylaxis. Bull World Health Organ 1982;60:555.

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WHO. Treatment of tuberculosis guidelines (4th edition). whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf (Accessed on June 11, 2010).

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Horne DJ, Royce SE, Gooze L, et al. Sputum monitoring during tuberculosis treatment for predicting outcome:systematic review and meta-analysis. Lancet Infect Dis 2010; 10:387.

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Datta S, Sherman JM, Bravard MA, et al. Clinical evaluation of tuberculosis viability microscopy for assessingtreatment response. Clin Infect Dis 2015; 60:1186.

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Mitchison DA. Role of individual drugs in the chemotherapy of tuberculosis. Int J Tuberc Lung Dis 2000; 4:796.19.

Lee BH, Koh WJ, Choi MS, et al. Inactive hepatitis B surface antigen carrier state and hepatotoxicity duringantituberculosis chemotherapy. Chest 2005; 127:1304.

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Saukkonen JJ, Cohn DL, Jasmer RM, et al. An official ATS statement: hepatotoxicity of antituberculosistherapy. Am J Respir Crit Care Med 2006; 174:935.

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Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991;99:465.

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Ho CC, Chen YC, Hu FC, et al. Safety of fluoroquinolone use in patients with hepatotoxicity induced byanti-tuberculosis regimens. Clin Infect Dis 2009; 48:1526.

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Døssing M, Wilcke JT, Askgaard DS, Nybo B. Liver injury during antituberculosis treatment: an 11-year study.Tuber Lung Dis 1996; 77:335.

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Bobrowitz ID. Ethambutol-isoniazid versus streptomycin-ethambutol-isoniazid in original treatment of cavitarytuberculosis. Am Rev Respir Dis 1974; 109:548.

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Ziganshina LE, Vizel AA, Squire SB. Fluoroquinolones for treating tuberculosis. Cochrane Database Syst Rev2005; :CD004795.

26.

Gosling RD, Uiso LO, Sam NE, et al. The bactericidal activity of moxifloxacin in patients with pulmonarytuberculosis. Am J Respir Crit Care Med 2003; 168:1342.

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Kiblawi SS, Jay SJ, Stonehill RB, Norton J. Fever response of patients on therapy for pulmonary tuberculosis.Am Rev Respir Dis 1981; 123:20.

29.

Sterling TR, Alwood K, Gachuhi R, et al. Relapse rates after short-course (6-month) treatment of tuberculosisin HIV-infected and uninfected persons. AIDS 1999; 13:1899.

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Chang KC, Leung CC, Yew WW, et al. A nested case-control study on treatment-related risk factors for earlyrelapse of tuberculosis. Am J Respir Crit Care Med 2004; 170:1124.

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Korenromp EL, Scano F, Williams BG, et al. Effects of human immunodeficiency virus infection on recurrence

of tuberculosis after rifampin-based treatment: an analytical review. Clin Infect Dis 2003; 37:101.

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Verver S, Warren RM, Beyers N, et al. Rate of reinfection tuberculosis after successful treatment is higher thanrate of new tuberculosis. Am J Respir Crit Care Med 2005; 171:1430.

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Marx FM, Dunbar R, Enarson DA, et al. The temporal dynamics of relapse and reinfection tuberculosis aftersuccessful treatment: a retrospective cohort study. Clin Infect Dis 2014; 58:1676.

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Dutt AK, Moers D, Stead WW. Smear- and culture-negative pulmonary tuberculosis: four-month short-coursechemotherapy. Am Rev Respir Dis 1989; 139:867.

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Root H. The association of diabetes and tuberculosis. N Engl J Med 1934; 210:1.38.

BOUCOT KR, DILLON ES, COOPER DA, et al. Tuberculosis among diabetics: the Philadelphia survey. AmRev Tuberc 1952; 65:1.

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40.

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Peloquin CA. Using therapeutic drug monitoring to dose the antimycobacterial drugs. Clin Chest Med 1997;

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Recomm Rep 1998; 47:1.

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Villamor E, Mugusi F, Urassa W, et al. A trial of the effect of micronutrient supplementation on treatmentoutcome, T cell counts, morbidity, and mortality in adults with pulmonary tuberculosis. J Infect Dis 2008;

197:1499.

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Karyadi E, West CE, Schultink W, et al. A double-blind, placebo-controlled study of vitamin A and zincsupplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status.

Am J Clin Nutr 2002; 75:720.

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Range N, Changalucha J, Krarup H, et al. The effect of multi-vitamin/mineral supplementation on mortalityduring treatment of pulmonary tuberculosis: a randomised two-by-two factorial trial in Mwanza, Tanzania. Br JNutr 2006; 95:762.

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Martineau AR, Timms PM, Bothamley GH, et al. High-dose vitamin D(3) during intensive-phase antimicrobialtreatment of pulmonary tuberculosis: a double-blind randomised controlled trial. Lancet 2011; 377:242.

47.

Range N, Andersen AB, Magnussen P, et al. The effect of micronutrient supplementation on treatmentoutcome in patients with pulmonary tuberculosis: a randomized controlled trial in Mwanza, Tanzania. Trop MedInt Health 2005; 10:826.

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Semba RD, Kumwenda J, Zijlstra E, et al. Micronutrient supplements and mortality of HIV-infected adults withpulmonary TB: a controlled clinical trial. Int J Tuberc Lung Dis 2007; 11:854.

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Wejse C, Gomes VF, Rabna P, et al. Vitamin D as supplementary treatment for tuberculosis: a double-blind,randomized, placebo-controlled trial. Am J Respir Crit Care Med 2009; 179:843.

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Daley P, Jagannathan V, John KR, et al. Adjunctive vitamin D for treatment of active tuberculosis in India: arandomised, double-blind, placebo-controlled trial. Lancet Infect Dis 2015; 15:528.

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Benn CS, Friis H, Wejse C. Should micronutrient supplementation be integrated into the case management oftuberculosis? J Infect Dis 2008; 197:1487.

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Paton NI, Chua YK, Earnest A, Chee CB. Randomized controlled trial of nutritional supplementation in patientswith newly diagnosed tuberculosis and wasting. Am J Clin Nutr 2004; 80:460.

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Small PM, Fujiwara PI. Management of tuberculosis in the United States. N Engl J Med 2001; 345:189.54.

Handbook of anti-tuberculosis agents. Introduction. Tuberculosis (Edinb) 2008; 88:85.55.

Yee D, Valiquette C, Pelletier M, et al. Incidence of serious side effects from first-line antituberculosis drugsamong patients treated for active tuberculosis. Am J Respir Crit Care Med 2003; 167:1472.

56.

Lienhardt C, Cook SV, Burgos M, et al. Efficacy and safety of a 4-drug fixed-dose combination regimencompared with separate drugs for treatment of pulmonary tuberculosis: the Study C randomized controlledtrial. JAMA 2011; 305:1415.

57.

Ziganshina LE, Titarenko AF, Davies GR. Fluoroquinolones for treating tuberculosis (presumed drug-sensitive).Cochrane Database Syst Rev 2013; 6:CD004795.

58.

Gillespie SH, Crook AM, McHugh TD, et al. Four-month moxifloxacin-based regimens for drug-sensitivetuberculosis. N Engl J Med 2014; 371:1577.

59.

Burman WJ, Goldberg S, Johnson JL, et al. Moxifloxacin versus ethambutol in the first 2 months of treatment

for pulmonary tuberculosis. Am J Respir Crit Care Med 2006; 174:331.

60.

Conde MB, Efron A, Loredo C, et al. Moxifloxacin versus ethambutol in the initial treatment of tuberculosis: adouble-blind, randomised, controlled phase II trial. Lancet 2009; 373:1183.

61.

Dorman SE, Johnson JL, Goldberg S, et al. Substitution of moxifloxacin for isoniazid during intensive phasetreatment of pulmonary tuberculosis. Am J Respir Crit Care Med 2009; 180:273.

62.

Jindani A, Harrison TS, Nunn AJ, et al. High-dose rifapentine with moxifloxacin for pulmonary tuberculosis. NEngl J Med 2014; 371:1599.

63.

Merle CS, Fielding K, Sow OB, et al. A four-month gatifloxacin-containing regimen for treating tuberculosis. NEngl J Med 2014; 371:1588.

64.

Devasia RA, Blackman A, Gebretsadik T, et al. Fluoroquinolone resistance in Mycobacterium tuberculosis: theeffect of duration and timing of fluoroquinolone exposure. Am J Respir Crit Care Med 2009; 180:365.

65.

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66.

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67.

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68.

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69.

Mitnick C, Bayona J, Palacios E, et al. Community-based therapy for multidrug-resistant tuberculosis in Lima,Peru. N Engl J Med 2003; 348:119.

70.

Topic 8015 Version 31.0


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GRAPHICS

Drug regimens for active tuberculosis in adults caused by

drug-susceptible organisms

Initial phase Continuation phase Range of

total doses

(minimal

duration)

Rating*Drugs

Interval and doses

(minimal duration)Drugs

Interval and

doses

(minimal

duration)

Regimen 1

INH

RIF

PZA

EMB

7 days per week for 56

doses (8 weeks), or


doses (8 weeks)

1a.

INH/RIF

7 days per week

for 126 doses (18

weeks), or

5 days per week

for 90 doses (18

weeks)

182 to 130 (26

weeks)

A

1b.

INH/RIF

Twice weekly for

36 doses (18

weeks)

92 to 76 (26

weeks)

A

1c.

INH/RPT

Once weekly for

18 doses (18

weeks)

74 to 58 (26

weeks)

B

Regimen 2

INH

RIF

PZA

EMB


doses (2 weeks), then

twice weekly for 12 doses

(6 weeks), or


doses (2 weeks) , then

twice weekly for 12 doses

(6 weeks)

2a.

INH/RIF

Twice weekly for

36 doses (18

weeks)

62 to 58 (26

weeks)

A

2b.

INH/RPT

Once weekly for

18 doses (18

weeks)

44 to 40 B

Regimen 3

INH

RIF

PZA

EMB

Three times weekly for 24

doses (8 weeks)

3a.

INH/RIF

Three times

weekly for 54

doses (18 weeks)

78 (26 weeks) B

Regimen 4

INH

RIF

EMB


doses (8 weeks), or


doses (8 weeks)

4a.

INH/RIF

7 days per week

for 217 doses (31

weeks), or

5 days per week

for 155 doses (31

weeks)

273 to 195 (39

weeks)

C

• •Δ

◊

◊

§

◊ §

◊

◊


16 de 23 03/08/2015 07:11 p.m.

4b.

INH/RIF

Twice weekly for

62 doses (31

weeks)

118 to 102 (39

weeks)

C

INH: isoniazid; RIF: rifampin; PZA: pyrazinamide; EMB: ethambutol; RPT: rifapentine.

* Definitions of ratings: A: preferred; B: acceptable alternative; C: offer when A and B cannot be given.

• When directly observed therapy (DOT) is used, drugs may be given five days per week and the necessary

number of doses adjusted accordingly. Although there are no studies that compare five with seven daily

doses, extensive experience indicates that this would be an effective practice.

Δ Patients with cavitation on initial chest radiograph and positive cultures at completion of two months of

therapy should receive a seven-month (31-week; either 217 doses [daily] or 62 doses [twice weekly])

continuation phase.

◊ Five-day-a-week administration is always given by DOT.

§ Options 1c and 2b should be used only in HIV-negative patients who have negative sputum smears at the

time of completion of two months of therapy and who do not have cavitation on the initial chest radiograph

(see text). For patients started on this regimen and found to have a positive culture from the two month

specimen, treatment should be extended an extra three months.

Data from Am J Respir Crit Care Med 2003; 167:603.

Graphic 50102 Version 5.0


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Doses of first-line antituberculosis drugs for adults*

Drug PreparationDoses

Daily 1x/week 2x/week 3x/week

First-line drugs

Isoniazid Tablets (50 mg, 100

mg, 300 mg); elixir

(50 mg/5 mL);

aqueous solution (100

mg/mL) for

intravenous or

intramuscular

injection

5 mg/kg (300

mg)

15 mg/kg

(900 mg)

15 mk/kg

(900 mg)

15 mg/kg

(900 mg)

Rifampin Capsule (150 mg, 300

mg); powder may be

suspended for oral

administration;

aqueous solution for

intravenous injection

10 mg/kg (600

mg)

- 10 mg/kg

(600 mg)

10 mg/kg

(600 mg)

Rifabutin Capsule (150 mg) 5 mg/kg (300

mg)

- 5 mg/kg

(300 mg)

5 mg/kg

(300 mg)

Rifapentine Tablet (150 mg, film

coated)

- 10 mg/kg

(continuation

phase) (600

mg)

- -

Pyrazinamide Tablet (500 mg,

scored)

Weight-based

dosing

summarized in

separate table

Ethambutol Tablet (100 mg, 400

mg)

Weight-based

dosing

summarized in

separate table

* Doses per weight is based on ideal body weight. For purposes of this document, adult dosing begins at

age 15 years.

Data from: Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease

Control and Prevention/Infectious Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit

Care Med 2003; 167:603.



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Suggested pyrazinamide doses, using whole tablets, for adults

weighing 40 to 90 kilograms

Weight (kg)*

40 to 55 56 to 75 76 to 90

Daily, mg (mg/kg) 1000 (18.2 to 25) 1500 (20 to 26.8) 2000 (22.2 to 26.3)

Thrice weekly, mg

(mg/kg)

1500 (27.3 to 37.5) 2500 (33.3 to 44.6) 3000 (33.3 to 39.5)

Twice weekly, mg

(mg/kg)

2000 (36.4 to 50) 3000 (40 to 53.6) 4000 (44.4 to 52.6)

* Based on estimated lean body weight.

¶ Maximum dose regardless of weight.

Reproduced with permission from: Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic

Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of

tuberculosis. Am J Respir Crit Care Med 2003; 167:603. Official Journal of the American Thoracic Society.

Copyright ©2003 American Thoracic Society.


¶

¶

¶


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Suggested ethambutol doses, using whole tablets, for adults weighing

40 to 90 kilograms

Weight, kg*

40 to 55 56 to 75 76 to 90

Daily, mg (mg/kg) 800 (14.5 to 20) 1200 (16 to 21.4) 1600 (17.8 to 22.1)

Thrice weekly, mg

(mg/kg)

1200 (21.8 to 30) 2000 (26.7 to 35.7) 2400 (26.7 to 31.6)

Twice weekly, mg

(mg/kg)

2000 (36.4 to 50) 2800 (37.3 to 50) 4000 (44.4 to 52.6)

* Based on estimated lean body weight.

¶ Maximum dose regardless of weight.

Am J Respir Crit Care Med 2003; 167:603.


¶

¶

¶


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Management of treatment interruptions for patients

with tuberculosis

* Patients who were initially acid-fast bacilli (AFB) smear positive should receive

additional therapy.

• Recheck smears and cultures (if positive, check drug susceptibility results). Start

directly observed therapy (DOT) if not already being used.

Δ If repeat culture is positive, restart four-drug regimen while waiting for drug

susceptibility results. If repeat culture is negative, continue therapy to complete

regimen within nine months of original start date.

◊ If repeat culture is positive, continue four-drug regimen while waiting for drug

susceptibility results. If repeat culture is negative, consider stopping therapy if

patient has received a total of nine months of therapy.

Reproduced with permission from: Blumberg HM, Burman WJ, Chaisson RE, et al.

American Thoracic Society/Centers for Disease Control and Prevention/Infectious

Diseases Society of America: Treatment of tuberculosis. Am J Respir Crit Care Med

2003; 167:603. Official Journal of the American Thoracic Society. Copyright ©2003

American Thoracic Society.



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Dosing recommendations for adult patients with reduced renal function

DrugChange in

frequency?

Recommended dose and frequency for patients

with CrCl <30 ml/min or for patients receiving

intermittent hemodialysis

Isoniazid No change 300 mg PO once daily, or 900 mg PO three times per week

Rifampin No change 600 mg PO once daily, or 600 mg PO three times per week

Pyrazinamide Yes 25 to 35 mg/kg (IBW) per dose PO three times per week (NOT

daily); max 2.5 g per dose.

Ethambutol Yes 15 to 25 mg/kg (IBW) per dose PO three times per week (NOT

daily); max 1.6 g per dose

Standard doses are given unless there is intolerance.

On the day of hemodialysis, medications should be administered after hemodialysis.

Monitoring of serum drug concentrations should be considered to ensure adequate drug absorption

without excessive accumulation and to assist in avoiding toxicity.

CrCl: Creatinine clearance by Cockcroft-Gault equation (see "Calculator: Creatinine clearance estimate by

Cockcroft-Gault equation); PO: by mouth; IBW: ideal body weight.

Reproduced with permission from: Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic

Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: Treatment of

tuberculosis. Am J Respir Crit Care Med 2003; 167:603. Official Journal of the American Thoracic Society.

Copyright ©2003 American Thoracic Society.



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Disclosures: Timothy R Sterling, MD Other Financial Interest: Otsuka [Data Safety Monitoring Board for a clinical trial, treatment ofdrug-resistant TB (delaminid)]. C Fordham von Reyn, MD Nothing to disclose. Elinor L Baron, MD, DTMH Nothing to disclose.

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through amulti-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content isrequired of all authors and must conform to UpToDate standards of evidence.

Conflict of interest policy

Disclosures


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Tratamiento común de tuberculosis pulmonar

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