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## Complete Summary

#### GUIDELINE TITLE

Treatment of tuberculosis.

#### BIBLIOGRAPHIC SOURCE(S)

Neff M. ATS, CDC, and IDSA update recommendations on the treatment of
tuberculosis. Am Fam Physician 2003 Nov 1;68(9):1854, 1857-8, 1861-2.
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14620606)

Treatment of tuberculosis. MMWR Recomm Rep 2003 Jun 20;52(RR-11):1-77.
\[534 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12836625)

#### GUIDELINE STATUS

This is the current release of the guideline.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse (NGC)**: This guideline
references a drug(s) for which important revised regulatory and/or
warning information has been released.

-   [July 08, 2008, Fluoroquinolones (ciprofloxacin, norfloxacin,
    ofloxacin, levofloxacin, moxifloxacin,
    gemifloxacin)](http://www.fda.gov/medwatch/safety/2008/safety08.htm#Fluoroquinolone):
    A BOXED WARNING and Medication Guide are to be added to the
    prescribing information to strengthen existing warnings about the
    increased risk of developing tendinitis and tendon rupture in
    patients taking fluoroquinolones for systemic use.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Tuberculosis

#### GUIDELINE CATEGORY

Treatment

#### CLINICAL SPECIALTY

Family Practice\
Infectious Diseases\
Internal Medicine\
Pediatrics\
Preventive Medicine\
Pulmonary Medicine

#### INTENDED USERS

Advanced Practice Nurses\
Physician Assistants\
Physicians\
Public Health Departments

#### GUIDELINE OBJECTIVE(S)

To guide the treatment of tuberculosis in settings where mycobacterial
cultures, drug susceptibility testing, radiographic facilities, and
second-line drugs are routinely available

#### TARGET POPULATION

Adults and children of all ages with tuberculosis who live in geographic
settings where mycobacterial cultures, drug susceptibility testing,
radiographic facilities, and second-line drugs are routinely available

#### INTERVENTIONS AND PRACTICES CONSIDERED

1.  Patient-centered case-management with an adherence plan that
    emphasizes directly observed therapy (DOT)

2.  Decision to initiate treatment based on: an evaluation of
    epidemiologic information; clinical, pathological, and radiographic
    findings; results of microscopic examination of acid-fast bacilli
    \[AFB\]) -- stained sputum (smears) and cultures for mycobacteria,
    purified protein derivative (PPD)-tuberculin skin test

3.  Treatment with first-line antituberculosis drugs (isoniazid \[INH\];
    rifampin \[RIF\], rifabutin, rifapentine, pyrazinamide \[PZA\],
    ethambutol \[EMB\])

4.  Treatment with second-line antituberculosis drugs (cycloserine,
    ethionamide, streptomycin, amikacin/kanamycin, capreomycin,
    p-aminosalicylic acid \[PAS\], levofloxacin, moxifloxacin,
    gatifloxacin)

5.  Treatment with combination antituberculosis drug therapy (INH and
    RIF \[Rifamate®\]; INH, RIF, and PZA \[Rifater®\])

6.  Identification and management of patients at increased risk of
    treatment failure and relapse

7.  Microbiological evaluation (sputum cultures) of response to
    treatment

8.  Monitoring for and management of drug interactions and adverse
    effects of drug therapy

9.  Treatment considerations in special situations (HIV infection;
    children; extrapulmonary tuberculosis; culture-negative pulmonary
    tuberculosis and radiographic evidence of prior pulmonary
    tuberculosis; renal insufficiency and end-stage renal disease; liver
    disease; pregnancy; and breastfeeding) and in low-income countries

10. Management of relapse, treatment failure, and drug resistance

#### MAJOR OUTCOMES CONSIDERED

-   Effectiveness of treatment measures in rendering the patient
    noninfectious, preventing drug resistance, minimizing the risk of
    disability and death, and preventing relapse

-   Safety, tolerability, and adverse effects of drugs

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

For this revision of the recommendations essentially all clinical trials
of antituberculosis treatment in the English language were reviewed.

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

Infectious Diseases Society of America/United States Public Health
Service Rating System

**Quality of Evidence**

I.  At least one properly randomized trial with clinical end points

II. Clinical trials that either are not randomized or were conducted in
    other populations

III. Expert opinion

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

Not stated

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

The process by which this revision of the recommendations for treatment
was developed was modified substantially from the previous versions. For
the first time the Infectious Diseases Society of America (IDSA) has
become a cosponsor of the statement, together with the American Thoracic
Society (ATS) and the Centers for Disease Control and Prevention (CDC).
The IDSA has had representation on prior statement committees but has
not previously been a cosponsor of the document. Practice guidelines
that serve to complement the current statement have been developed by
the IDSA. In addition to the IDSA, representatives of the American
Academy of Pediatrics (AAP), the (United States) National Tuberculosis
Controllers Association (NTCA), the Canadian Thoracic Society (CTS), the
International Union against Tuberculosis and Lung Disease (IUATLD), and
the World Health Organization (WHO) participated in the revision. By
virtue of their different perspectives these committee members served to
provide broader input and to help ensure that the guidelines are placed
in an appropriate context.

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

Infectious Diseases Society of America/United States Public Health
Service Rating System

A.  Preferred; should generally be offered

B.  Alternative; acceptable to offer

C.  Offer when preferred or alternative regimens cannot be given

D.  Should generally not be offered

E.  Should never be offered

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

Comparison with Guidelines from Other Groups\
External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

These recommendations were compared with those of the World Health
Organization (WHO) International Union Against Tuberculosis and Lung
Disease (IUATLD).

This guideline was approved by the American Thoracic Society (ATS) Board
of Directors, by the Centers for Disease Control and Prevention (CDC),
and by the Council of the Infectious Disease Society of America (IDSA)
in October 2002.

This guideline appeared in the American Journal of Respiratory and
Critical Care Medicine (2003;167:603-62).

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

Definitions for the ratings for the strength of the recommendations
(A-E) and the quality of the evidence (I-III) are provided at the end of
the \"Major Recommendations.\"

**Responsibility for Successful Treatment**

The overall goals for treatment of tuberculosis are 1) to cure the
individual patient, and 2) to minimize the transmission of
*Mycobacterium tuberculosis* to other persons. Thus, successful
treatment of tuberculosis has benefits both for the individual patient
and the community in which the patient resides. For this reason the
prescribing physician, be he/she in the public or private sector, is
carrying out a public health function with responsibility not only for
prescribing an appropriate regimen but also for successful completion of
therapy. Prescribing physician responsibility for treatment completion
is a fundamental principle in tuberculosis control. However, given a
clear understanding of roles and responsibilities, oversight of
treatment may be shared between a public health program and a private
physician.

**Organization and Supervision of Treatment**

Treatment of patients with tuberculosis is most successful within a
comprehensive framework that addresses both clinical and social issues
of relevance to the patient. It is essential that treatment be tailored
and supervision be based on each patient\'s clinical and social
circumstances (patient-centered care). Patients may be managed in the
private sector, by public health departments, or jointly, but in all
cases the health department is ultimately responsible for ensuring that
adequate, appropriate diagnostic and treatment services are available,
and for monitoring the results of therapy.

It is strongly recommended that patient-centered care be the initial
management strategy, regardless of the source of supervision. This
strategy should always include an adherence plan that emphasizes
directly observed therapy (DOT), in which patients are observed to
ingest each dose of antituberculosis medications, to maximize the
likelihood of completion of therapy. Programs utilizing DOT as the
central element in a comprehensive, patient-centered approach to case
management (enhanced DOT) have higher rates of treatment completion than
less intensive strategies. Each patient\'s management plan should be
individualized to incorporate measures that facilitate adherence to the
drug regimen. Such measures may include, for example, social service
support, treatment incentives and enablers, housing assistance, referral
for treatment of substance abuse, and coordination of tuberculosis
services with those of other providers.

**Recommended Treatment Regimens**

There are four recommended regimens for treating patients with
tuberculosis caused by drug-susceptible organisms. Although these
regimens are broadly applicable, there are modifications that should be
made under specified circumstances, described subsequently. Each regimen
has an initial phase of 2 months followed by a choice of several options
for the continuation phase of either 4 or 7 months. The recommended
regimens together with the number of doses specified by the regimen are
described in the table below titled \"*Drug regimens for
culture-positive pulmonary tuberculosis caused by drug-susceptible
organisms*.\" The initial phases are denoted by a number (1, 2, 3, or 4)
and the continuation phases that relate to the initial phase are denoted
by the number plus a letter designation (a, b, or c). Drug doses are
shown in Tables 3, 4 and 5 of the original guideline document.

**Table: Drug Regimens for Culture-positive Pulmonary Tuberculosis
Caused by Drug-susceptible Organisms**

**[Regimen 1 (Initial Phase)]{.underline}**

*Drugs*: Isoniazid (INH); Rifampin (RIF); Pyrazinamid (PZA); Ethambutol
(EMB)

*Interval and doses ^@^ (minimal duration)*: Seven days per week (wk)
for 56 doses (8 wk) or 5 days/week (d/wk) for 40 doses (8 wk) ^&^

**Regimen 1a (Continuation Phase)**

*Drugs*: INH/RIF

*Interval and doses ^@\$^ (minimal duration)*: Seven days per week for
126 doses (18 wk) or 5 d/wk for 90 doses (18 wk) ^&^

*Ranges of total doses (minimal duration)*: 182-130 (26 wk)

*Rating (evidence)*: HIV-: A (I); HIV+: A (II)

**Regimen 1b (Continuation Phase)**

*Drugs*: INH/RIF

*Interval and doses ^@\$^ (minimal duration)*: Twice weekly for 36 doses
(18 wk)

*Ranges of total doses (minimal duration)*: 92-76 (26 wk)

*Rating (evidence)*: HIV-: A (I); HIV+: A (II) ^\#^

**Regimen 1c \*\* (Continuation Phase)**

*Drugs*: INH/RPT

*Interval and doses ^@\$^ (minimal duration)*: Once weekly for 18 doses
(18 wk)

*Ranges of total doses (minimal duration)*: 74-58 (26 wk)

*Rating (evidence)*: HIV-: B (I); HIV+: E (I)

**[Regimen 2 (Initial Phase)]{.underline}**

*Drugs*: INH, RIF, PZA, EMB

*Interval and doses ^@^ (minimal duration)*: Seven days per week for 14
doses (2 wk), then twice weekly for 12 doses (6 wk) or 5 d/wk for 10
doses (2 wk), ^&^ then twice weekly for 12 doses (6 wk)

**Regimen 2a (Continuation Phase)**

*Drugs*: INH/RIF

*Interval and doses ^@\$^ (minimal duration)*) Twice weekly for 36 doses
(18 wk)

*Ranges of total doses (minimal duration)*: 62-58 (26 wk)

*Rating (evidence)*: HIV-: A (II); HIV+: B (II) ^\#^

**Regimen 2b\*\* (Continuation Phase)**

*Drugs*: INH/RPT

*Interval and doses ^@\$^ (minimal duration)*: Once weekly for 18 doses
(18 wk)

*Ranges of total doses (minimal duration)*: 44-40 (26 wk)

*Rating (evidence)*:HIV-: B (I); HIV+: E (I)

**[Regimen 3 (Initial Phase)]{.underline}**

*Drugs*: INH, RIF, PZA, EMB

*Interval and doses ^@^ (minimal duration)*: Three times weekly for 24
doses (8 wk)

**Regimen 3a (Continuation Phase)**

*Drugs*: INH/RIF

*Interval and doses ^@\$^ (minimal duration)*: Three times weekly for 54
doses (18 wk)

*Ranges of total doses (minimal duration)*: 78 (26 wk)

*Rating (evidence)*: HIV-: B (I); HIV+: B (II)

**[Regimen 4 (Initial Phase)]{.underline}**

*Drugs*: INH, RIF, EMB

*Interval and doses^@^ (minimal duration)*: Seven days per week for 56
doses (8 wk) or 5 d/wk for 40 doses (8 wk) ^&^

**Regimen 4a (Continuation Phase)**

*Drugs*: INH/RIF

*Interval and doses ^@\$^ (minimal duration)*: Seven days per week for
217 doses (31 wk) or 5 d/wk for 155 doses (31 wk) ^&^

*Ranges of total doses (minimal duration*): 273-195 (39 wk)

*Rating (evidence)*: HIV-: C (I); HIV+: C (II)

**Regimen 4b (Continuation Phase)**

*Drugs*: INH/RIF

*Interval and doses ^@\$^ (minimal duration*): Twice weekly for 62 doses
(31 wk)

*Ranges of total doses (minimal duration)*: 118-102 (39 wk)

*Rating (evidence)*: HIV-: C (I); HIV+: C (II)

@ When direct observation of therapy (DOT) is used, drugs may be given 5
days/week and the necessary number of doses adjusted accordingly.
Although there are no studies that compare five with seven daily doses,
extensive experience indicates this would be an effective practice.

\$ Patients with cavitation on initial chest radiograph and positive
cultures at completion of 2 months of therapy should receive a 7-month
(31 week; either 217 doses \[daily\] or 62 doses \[twice weekly\])
continuation phase.

& Five-day-a-week administration is always given by DOT. Rating for 5
day/week regimens is AIII.

\# Not recommended for HIV-infected patients with CD4+ cell counts \<100
cells/microliter

\*\* Options 1c and 2b should be used only in HIV-negative patients who
have negative sputum smears at the time of completion of 2 months of
therapy and who do not have cavitation on initial chest radiograph (see
text). For patients started on this regimen and found to have a positive
culture from the 2-month specimen, treatment should be extended an extra
3 months.

The general approach to treatment is summarized in Figure 1 of the
original guideline document. Because of the relatively high proportion
of adult patients with tuberculosis caused by organisms that are
resistant to isoniazid, four drugs are necessary in the initial phase
for the 6-month regimen to be maximally effective. Thus, in most
circumstances, the treatment regimen for all adults with previously
untreated tuberculosis should consist of a 2-month initial phase of
isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol
(EMB) (see Table above titled \"Drug regimens for culture-positive
pulmonary tuberculosis caused by drug-susceptible organisms,\" Regimens
1\--3). If (when) drug susceptibility test results are known and the
organisms are fully susceptible, EMB need not be included. For children
whose visual acuity cannot be monitored, EMB is usually not recommended
except when there is an increased likelihood of the disease being caused
by INH-resistant organisms (see Table below titled \"Epidemiological
circumstances in which an exposed person is at increased risk of
infection with drug-resistant Mycobacterium tuberculosis) or when the
child has \"adult-type\" (upper lobe infiltration, cavity formation)
tuberculosis. If PZA cannot be included in the initial phase of
treatment, or if the isolate is resistant to PZA alone (an unusual
circumstance), the initial phase should consist of INH, RIF, and EMB
given daily for 2 months (Regimen 4). Examples of circumstances in which
PZA may be withheld include severe liver disease, gout, and, perhaps,
pregnancy. EMB should be included in the initial phase of Regimen 4
until drug susceptibility is determined.

**Table: Epidemiological Circumstances in which an Exposed Person is at
Increased Risk of Infection with Drug-resistant *Mycobacterium
tuberculosis*\***

-   Exposure to a person who has known drug-resistant tuberculosis

-   Exposure to a person with active tuberculosis who has had prior
    treatment for tuberculosis (treatment failure or relapse) and whose
    susceptibility test results are not known

-   Exposure to persons with active tuberculosis from areas in which
    there is a high prevalence of drug resistance

-   Exposure to persons who continue to have positive sputum smears
    after 2 months of combination chemotherapy

-   Travel in an area of high prevalence of drug resistance

**\*Note**: This information is to be used in deciding whether or not to
add a fourth drug (usually EMB) for children with active tuberculosis,
not to infer the empiric need for a second-line regimen.

The initial phase may be given daily throughout (Regimens 1 and 4),
daily for 2 weeks and then twice weekly for 6 weeks (Regimen 2), or
three times weekly throughout (Regimen 3). For patients receiving daily
therapy, EMB can be discontinued as soon as the results of drug
susceptibility studies demonstrate that the isolate is susceptible to
INH and RIF. When the patient is receiving less than daily drug
administration, expert opinion suggests that EMB can be discontinued
safely in less than 2 months (i.e., when susceptibility test results are
known), but there is no evidence to support this approach.

Although clinical trials have shown that the efficacy of streptomycin
(SM) is approximately equal to that of EMB in the initial phase of
treatment, the increasing frequency of resistance to SM globally has
made the drug less useful. Thus, SM is not recommended as being
interchangeable with EMB unless the organism is known to be susceptible
to the drug or the patient is from a population in which SM resistance
is unlikely.

The continuation phase (see Table above titled \"Drug regimens for
culture-positive pulmonary tuberculosis caused by drug-susceptible
organisms\") of treatment is given for either 4 or 7 months. The 4-month
continuation phase should be used in the large majority of patients. The
7-month continuation phase is recommended only for three groups:
patients with cavitary pulmonary tuberculosis caused by drug-susceptible
organisms and whose sputum culture obtained at the time of completion of
2 months of treatment is positive; patients whose initial phase of
treatment did not include PZA; and patients being treated with once
weekly INH and rifapentine and whose sputum culture obtained at the time
of completion of the initial phase is positive. The continuation phase
may be given daily (Regimens 1a and 4a), two times weekly by direct
observation of therapy (DOT) (Regimens 1b, 2a, and 4b), or three times
weekly by DOT (Regimen 3a). For human immunodeficiency virus
(HIV)-seronegative patients with noncavitary pulmonary tuberculosis (as
determined by standard chest radiography), and negative sputum smears at
completion of 2 months of treatment, the continuation phase may consist
of rifapentine and INH given once weekly for 4 months by DOT (Regimens
1c and 2b) (See Figure 1 titled \"Treatment algorithm for tuberculosis\"
in the original guideline document\"). If the culture at completion of
the initial phase of treatment is positive, the once weekly INH and
rifapentine continuation phase should be extended to 7 months. All of
the 6-month regimens, except the INH\--rifapentine once weekly
continuation phase for persons with HIV infection (**Rating EI**), are
rated as **AI** or **AII**, or **BI** or **BII**, in both HIV-infected
and uninfected patients. The once-weekly continuation phase is
contraindicated (**Rating EI**) in patients with HIV infection because
of an unacceptable rate of failure/relapse, often with
rifamycin-resistant organisms. For the same reason twice weekly
treatment, either as part of the initial phase (Regimen 2) or
continuation phase (Regimens 1b and 2a), is not recommended for
HIV-infected patients with CD4^+^ cell counts \<100 cells/microliters.
These patients should receive either daily (initial phase) or three
times weekly (continuation phase) treatment. Regimen 4 (and 4a/4b), a
9-month regimen, is rated **CI** for patients without HIV infection and
**CII** for those with HIV infection.

**Deciding To Initiate Treatment**

The decision to initiate combination antituberculosis chemotherapy
should be based on epidemiologic information; clinical, pathological,
and radiographic findings; and the results of microscopic examination of
acid-fast bacilli (AFB)\--stained sputum (smears) (as well as other
appropriately collected diagnostic specimens) and cultures for
mycobacteria. A purified protein derivative (PPD)-tuberculin skin test
may be done at the time of initial evaluation, but a negative
PPD-tuberculin skin test does not exclude the diagnosis of active
tuberculosis. However, a positive PPD-tuberculin skin test supports the
diagnosis of culture-negative pulmonary tuberculosis, as well as latent
tuberculosis infection in persons with stable abnormal chest radiographs
consistent with inactive tuberculosis (see below).

If the suspicion of tuberculosis is high or the patient is seriously ill
with a disorder, either pulmonary or extrapulmonary, that is thought
possibly to be tuberculosis, combination chemotherapy using one of the
recommended regimens should be initiated promptly, often before AFB
smear results are known and usually before mycobacterial culture results
have been obtained. A positive AFB smear provides strong inferential
evidence for the diagnosis of tuberculosis. If the diagnosis is
confirmed by isolation of *M. tuberculosis* or a positive nucleic acid
amplification test, treatment can be continued to complete a standard
course of therapy (see Figure 1 titled \"Treatment algorithm for
tuberculosis\" in the original guideline document). When the initial AFB
smears and cultures are negative, a diagnosis other than tuberculosis
should be considered and appropriate evaluations undertaken. If no other
diagnosis is established and the PPD-tuberculin skin test is positive
(in this circumstance a reaction of 5 mm or greater induration is
considered positive), empirical combination chemotherapy should be
initiated. If there is a clinical or radiographic response within 2
months of initiation of therapy and no other diagnosis has been
established, a diagnosis of culture-negative pulmonary tuberculosis can
be made and treatment continued with an additional 2 months of INH and
RIF to complete a total of 4 months of treatment, an adequate regimen
for culture-negative pulmonary tuberculosis (see Figure 2 titled
\"Treatment algorithm for active, culture-negative pulmonary
tuberculosis and inactive tuberculosis\" in the original guideline
document). If there is no clinical or radiographic response by 2 months,
treatment can be stopped and other diagnoses including inactive
tuberculosis considered.

If AFB smears are negative and suspicion for active tuberculosis is low,
treatment can be deferred until the results of mycobacterial cultures
are known and a comparison chest radiograph is available (usually within
2 months) (see Figure 2 titled \"Treatment algorithm for active,
culture-negative pulmonary tuberculosis and inactive tuberculosis\" in
the original guideline document). In low-suspicion patients not
initially being treated, if cultures are negative, the PPD-tuberculin
skin test is positive (5 mm or greater induration), and the chest
radiograph is unchanged after 2 months, one of the three regimens
recommended for the treatment of latent tuberculosis infection could be
used. These include (*1*) INH for a total of 9 months, (*2*) RIF with or
without INH for a total of 4 months, or (*3*) RIF and PZA for a total of
2 months. Because of reports of an increased rate of hepatotoxicity with
the RIF\--PZA regimen, it should be reserved for patients who are not
likely to complete a longer course of treatment, can be monitored
closely, and do not have contraindications to the use of this regimen.

**Baseline and Follow-Up Evaluations**

Patients suspected of having tuberculosis should have appropriate
specimens collected for microscopic examination and mycobacterial
culture. When the lung is the site of disease, three sputum specimens
should be obtained. Sputum induction with hypertonic saline may be
necessary to obtain specimens and bronchoscopy (both performed under
appropriate infection control measures) may be considered for patients
who are unable to produce sputum, depending on the clinical
circumstances. Susceptibility testing for INH, RIF, and EMB should be
performed on a positive initial culture, regardless of the source of the
specimen. Second-line drug susceptibility testing should be done only in
reference laboratories and be limited to specimens from patients who
have had prior therapy, who are contacts of patients with drug-resistant
tuberculosis, who have demonstrated resistance to rifampin or to other
first-line drugs, or who have positive cultures after more than 3 months
of treatment.

It is recommended that all patients with tuberculosis have counseling
and testing for HIV infection, at least by the time treatment is
initiated, if not earlier. For patients with HIV infection, a CD4^+^
lymphocyte count should be obtained. Patients with risk factors for
hepatitis B or C viruses (e.g., injection drug use, foreign birth in
Asia or Africa, HIV infection) should have serologic tests for these
viruses. For all adult patients baseline measurements of serum amino
transferases (aspartate aminotransferase \[AST\], alanine
aminotransferase \[ALT\]), bilirubin, alkaline phosphatase, and serum
creatinine and a platelet count should be obtained. Testing of visual
acuity and red-green color discrimination should be obtained when EMB is
to be used.

During treatment of patients with pulmonary tuberculosis, a sputum
specimen for microscopic examination and culture should be obtained at a
minimum of monthly intervals until two consecutive specimens are
negative on culture. More frequent AFB smears may be useful to assess
the early response to treatment and to provide an indication of
infectiousness. For patients with extrapulmonary tuberculosis the
frequency and kinds of evaluations will depend on the site involved. In
addition, it is critical that patients have clinical evaluations at
least monthly to identify possible adverse effects of the
antituberculosis medications and to assess adherence. Generally,
patients do not require follow-up after completion of therapy but should
be instructed to seek care promptly if signs or symptoms recur.

Routine measurements of hepatic and renal function and platelet count
are not necessary during treatment unless patients have baseline
abnormalities or are at increased risk of hepatotoxicity (e.g.,
hepatitis B or C virus infection, alcohol abuse). At each monthly visit
patients taking EMB should be questioned regarding possible visual
disturbances including blurred vision or scotomata; monthly testing of
visual acuity and color discrimination is recommended for patients
taking doses that on a milligram per kilogram basis are greater than
those listed in the original guideline document (see Table 5 titled
\"Suggested ethambutol doses, using whole tablets, for adults weighing
40-90 kilograms\" in the original guideline document) and for patients
receiving the drug for longer than 2 months.

**Identification and Management of Patients at Increased Risk of
Treatment Failure and Relapse**

The presence of cavitation on the initial chest radiograph combined with
having a positive sputum culture at the time the initial phase of
treatment is completed has been shown in clinical trials to identify
patients at high risk for adverse outcomes (treatment failure, usually
defined by positive cultures after 4 months of treatment, or relapse,
defined by recurrent tuberculosis at any time after completion of
treatment and apparent cure). For this reason it is particularly
important to conduct a microbiological evaluation 2 months after
initiation of treatment (See Figure 1 titled \"Treatment algorithm for
tuberculosis\" in the original guideline document). Approximately 80% of
patients with pulmonary tuberculosis caused by drug-susceptible
organisms who are started on standard four-drug therapy will have
negative sputum cultures at this time. Patients with positive cultures
after 2 months of treatment should undergo careful evaluation to
determine the cause. For patients who have positive cultures after 2
months of treatment and have not been receiving DOT, the most common
reason is nonadherence to the regimen. Other possibilities, especially
for patients receiving DOT, include extensive cavitary disease at the
time of diagnosis, drug resistance, malabsorption of drugs, laboratory
error, and biological variation in response.

In the United States Public Health Service (USPHS) Study 22, nearly 21%
of patients in the control arm of the study (a continuation phase of
twice weekly INH and RIF) who had both cavitation on the initial chest
radiograph and a positive culture at the 2-month juncture relapsed.
Patients who had only one of these factors (either cavitation or a
positive 2-month culture) had relapse rates of 5\--6% compared with 2%
for patients who had neither risk factor. In view of this evidence, it
is recommended that, for patients who have cavitation on the initial
chest radiograph and whose 2-month culture is positive, the minimum
duration of treatment should be 9 months (a total of 84\--273 doses
depending on whether the drugs are given daily or intermittently) (see
Figure 1 titled \"Treatment algorithm for tuberculosis\" in the original
guideline document and Table above titled \"Drug regimes for
culture-positive pulmonary tuberculosis caused by drug-susceptible
organisms\"). The recommendation to lengthen the continuation phase of
treatment is based on expert opinion and on the results of a study of
the optimal treatment duration for patients with silicotuberculosis
showing that extending treatment from 6 to 8 months greatly reduced the
rate of relapse (**Rating AIII**). The recommendation is also supported
by the results of a trial in which the once weekly INH\--rifapentine
continuation phase was extended to 7 months for patients at high risk of
relapse. The rate of relapse was reduced significantly compared with
historical control subjects from another trial in which the continuation
phase was 4 months.

For patients who have either cavitation on the initial film or a
positive culture after completing the initial phase of treatment (i.e.,
at 2 months), the rates of relapse were 5\--6%. In this group decisions
to prolong the continuation phase should be made on an individual basis.

**Completion of Treatment**

A full course of therapy (completion of treatment) is determined more
accurately by the total number of doses taken, not solely by the
duration of therapy. For example, the \"6-month\" daily regimen (given 7
days/week; see below) should consist of at least 182 doses of INH and
RIF, and 56 doses of PZA. Thus, 6 months is the minimum duration of
treatment and accurately indicates the amount of time the drugs are
given only if there are no interruptions in drug administration. In some
cases, either because of drug toxicity or nonadherence to the treatment
regimen, the specified number of doses cannot be administered within the
targeted period. In such cases the goal is to deliver the specified
number of doses within a recommended maximum time. For example, for a
6-month daily regimen the 182 doses should be administered within 9
months of beginning treatment. If treatment is not completed within this
period, the patient should be assessed to determine the appropriate
action to take\-\--continuing treatment for a longer duration or
restarting treatment from the beginning, either of which may require
more restrictive measures to be used to ensure completion.

Clinical experience suggests that patients being managed by DOT
administered 5 days/week have a rate of successful therapy equivalent to
those being given drugs 7 days/week. Thus, \"daily therapy\" may be
interpreted to mean DOT given 5 days/week and the required number of
doses adjusted accordingly. For example, for the 6-month \"daily\"
regimen given 5 days/week the planned total number of doses is 130.
(Direct observation of treatment given 5 days/week has been used in a
number of clinical trials, including USPHS Study 22, but has not been
evaluated in a controlled trial; thus, this modification should be rated
AIII.) As an option, patients might be given the medications to take
without DOT on weekends.

Interruptions in treatment may have a significant effect on the duration
of therapy. Reinstitution of treatment must take into account the
bacillary load of the patient, the point in time when the interruption
occurred, and the duration of the interruption. In general, the earlier
in treatment and the longer the duration of the interruption, the more
serious the effect and the greater the need to restart therapy from the
beginning.

**Practical Aspects of Patient Management During Treatment**

The first-line antituberculosis medications should be administered
together; split dosing should be avoided. Fixed-dose combination
preparations may be administered more easily than single drug tablets
and may decrease the risk of acquired drug resistance and medication
errors. Fixed-dose combinations may be used when DOT is given daily and
are especially useful when DOT is not possible, but they are not
formulated for use with intermittent dosing. It should be noted that for
patients weighing more than 90 kg the dose of PZA in the three-drug
combination is insufficient and additional PZA tablets are necessary.
There are two combination formulations approved for use in the United
States: INH and RIF (Rifamate®) and INH, RIF, and PZA (Rifater®).

Providers treating patients with tuberculosis must be especially
vigilant for drug interactions. Given the frequency of comorbid
conditions, it is quite common for patients with tuberculosis to be
taking a variety of other medications, the effects of which may be
altered by the antituberculosis medications, especially the rifamycins.
These interactions are described in Section 7 of the original guideline
document, titled \"Drug Interactions.\"

Adverse effects, especially gastrointestinal upset, are relatively
common in the first few weeks of antituberculosis therapy; however,
first-line antituberculosis drugs, particularly RIF, must not be
discontinued because of minor side effects. Although ingestion with food
delays or moderately decreases the absorption of antituberculosis drugs,
the effects of food are of little clinical significance. Thus, if
patients have epigastric distress or nausea with the first-line drugs,
dosing with meals or changing the hour of dosing is recommended.
Administration with food is preferable to splitting a dose or changing
to a second-line drug.

Drug-induced hepatitis, the most serious common adverse effect, is
defined as a serum AST level more than three times the upper limit of
normal in the presence of symptoms, or more than five times the upper
limit of normal in the absence of symptoms. If hepatitis occurs INH,
RIF, and PZA, all potential causes of hepatic injury, should be stopped
immediately. Serologic testing for hepatitis viruses A, B, and C (if not
done at baseline) should be performed and the patient questioned
carefully regarding exposure to other possible hepatotoxins, especially
alcohol. Two or more antituberculosis medications without
hepatotoxicity, such as EMB, SM, amikacin/kanamycin, capreomycin, or a
fluoroquinolone (levofloxacin, moxifloxacin, or gatifloxacin), may be
used until the cause of the hepatitis is identified. Once the AST level
decreases to less than two times the upper limit of normal and symptoms
have significantly improved, the first-line medications should be
restarted in sequential fashion. Close monitoring, with repeat
measurements of serum AST and bilirubin and symptom review, is essential
in managing these patients.

**Treatment in Special Situations**

*HIV Infection*

Recommendations for the treatment of tuberculosis in HIV-infected adults
are, with a few exceptions, the same as those for HIV-uninfected adults
(see table above titled \"Drug regimes for culture-positive pulmonary
tuberculosis caused by drug-susceptible organisms\"). The
INH\--rifapentine once weekly continuation phase (Regimens 1c and 2b) is
contraindicated in HIV-infected patients because of an unacceptably high
rate of relapse, frequently with organisms that have acquired resistance
to rifamycins. The development of acquired rifampin resistance has also
been noted among HIV-infected patients with advanced immunosuppression
treated with twice weekly rifampin- or rifabutin-based regimens.
Consequently, patients with CD4^+^ cell counts \<100/microliters should
receive daily or three times weekly treatment (Regimen 1/1a or Regimen
3/3a). DOT and other adherence-promoting strategies are especially
important for patients with HIV-related tuberculosis.

Management of HIV-related tuberculosis is complex and requires expertise
in the management of both HIV disease and tuberculosis. Because
HIV-infected patients are often taking numerous medications, some of
which interact with antituberculosis medications, it is strongly
encouraged that experts in the treatment of HIV-related tuberculosis be
consulted. A particular concern is the interaction of rifamycins with
antiretroviral agents and other antiinfective drugs. Rifampin can be
used for the treatment of tuberculosis with certain combinations of
antiretroviral agents. Rifabutin, which has fewer problematic drug
interactions, may also be used in place of rifampin and appears to be
equally effective although the doses of rifabutin and antiretroviral
agents may require adjustment. As new antiretroviral agents and more
pharmacokinetic data become available, these recommendations are likely
to be modified.

On occasion, patients with HIV-related tuberculosis may experience a
temporary exacerbation of symptoms, signs, or radiographic
manifestations of tuberculosis while receiving antituberculosis
treatment. This clinical or radiographic worsening (paradoxical
reaction) occurs in HIV-infected patients with active tuberculosis and
is thought to be the result of immune reconstitution as a consequence of
effective antiretroviral therapy. Symptoms and signs may include high
fevers, lymphadenopathy, expanding central nervous system lesions, and
worsening of chest radiographic findings. The diagnosis of a paradoxical
reaction should be made only after a thorough evaluation has excluded
other etiologies, particularly tuberculosis treatment failure.
Nonsteroidal antiinflammatory agents may be useful for symptomatic
relief. For severe paradoxical reactions, prednisone (1\--2 mg/kg per
day for 1\--2 weeks, then in gradually decreasing doses) may be used,
although there are no data from controlled trials to support this
approach (**Rating CIII**).

*Children*

Because of the high risk of disseminated tuberculosis in infants and
children younger than 4 years of age, treatment should be started as
soon as the diagnosis of tuberculosis is suspected. In general, the
regimens recommended for adults are also the regimens of choice for
infants, children, and adolescents with tuberculosis, with the exception
that ethambutol is not used routinely in children. Because there is a
lower bacillary burden in childhood-type tuberculosis there is less
concern with the development of acquired drug resistance. However,
children and adolescents may develop \"adult-type\" tuberculosis with
upper lobe infiltration, cavitation, and sputum production. In such
situations an initial phase of four drugs should be given until
susceptibility is proven. When clinical or epidemiologic circumstances
(see Table above titled \"Epidemiological circumstances in which an
exposed person is at increased risk of infection with drug-resistant
Mycobacterium tuberculosis\") suggest an increased probability of INH
resistance, EMB can be used safely at a dose of 15\--20 mg/kg per day,
even in children too young for routine eye testing. Streptomycin,
kanamycin, or amikacin also can be used as the fourth drug, when
necessary.

Most studies of treatment in children have used 6 months of INH and RIF
supplemented during the first 2 months with PZA. This three-drug
combination has a success rate of greater than 95% and an adverse drug
reaction rate of less than 2%. Most treatment studies of intermittent
dosing in children have used daily drug administration for the first 2
weeks to 2 months. DOT should always be used in treating children.

Because it is difficult to isolate *M. tuberculosis* from a child with
pulmonary tuberculosis, it is frequently necessary to rely on the
results of drug susceptibility tests of the organisms isolated from the
presumed source case to guide the choice of drugs for the child. In
cases of suspected drug-resistant tuberculosis in a child or when a
source case isolate is not available, specimens for microbiological
evaluation should be obtained via early morning gastric aspiration,
bronchoalveolar lavage, or biopsy.

In general, extrapulmonary tuberculosis in children can be treated with
the same regimens as pulmonary disease. Exceptions are disseminated
tuberculosis and tuberculous meningitis, for which there are inadequate
data to support 6-month therapy; thus 9\--12 months of treatment is
recommended.

The optimal treatment of pulmonary tuberculosis in children and
adolescents with HIV infection is unknown. The American Academy of
Pediatrics recommends that initial therapy should always include at
least three drugs, and the total duration of therapy should be at least
9 months, although there are no data to support this recommendation.

*Extrapulmonary Tuberculosis*

The basic principles that underlie the treatment of pulmonary
tuberculosis also apply to extrapulmonary forms of the disease. Although
relatively few studies have examined treatment of extrapulmonary
tuberculosis, increasing evidence suggests that 6- to 9-month regimens
that include INH and RIF are effective. Thus, a 6-month course of
therapy is recommended for treating tuberculosis involving any site with
the exception of the meninges, for which a 9- 12-month regimen is
recommended. Prolongation of therapy also should be considered for
patients with tuberculosis in any site that is slow to respond. The
addition of corticosteroids is recommended for patients with tuberculous
pericarditis and tuberculous meningitis.

*Culture-negative Pulmonary Tuberculosis and Radiographic Evidence of
Prior Pulmonary Tuberculosis*

Failure to isolate *M. tuberculosis* from persons suspected of having
pulmonary tuberculosis on the basis of clinical features and chest
radiographic examination does not exclude a diagnosis of active
tuberculosis. Alternative diagnoses should be considered carefully and
further appropriate diagnostic studies undertaken in persons with
apparent culture-negative tuberculosis. The general approach to
management is shown in Figure 2, titled \"Treatment algorithm for
active, culture-negative pulmonary tuberculosis and inactive
tuberculosis\" in the original guideline. A diagnosis of tuberculosis
can be strongly inferred by the clinical and radiographic response to
antituberculosis treatment. Careful reevaluation should be performed
after 2 months of therapy to determine whether there has been a response
attributable to antituberculosis treatment. If either clinical or
radiographic improvement is noted and no other etiology is identified,
treatment should be continued for active tuberculosis. Treatment
regimens in this circumstance include one of the standard 6-month
chemotherapy regimens or INH, RIF, PZA, and EMB for 2 months followed by
INH and RIF for an additional 2 months (4 months total). However,
HIV-infected patients with culture-negative pulmonary tuberculosis
should be treated for a minimum of 6 months.

Persons with a positive tuberculin skin test who have radiographic
evidence of prior tuberculosis (e.g., upper lobe fibronodular
infiltrations) but who have not received adequate therapy are at
increased risk for the subsequent development of tuberculosis. Unless
previous radiographs are available showing that the abnormality is
stable, it is recommended that sputum examination (using sputum
induction if necessary) be performed to assess the possibility of active
tuberculosis being present. Also, if the patient has symptoms of
tuberculosis related to an extrapulmonary site, an appropriate
evaluation should be undertaken. Once active tuberculosis has been
excluded (i.e., by negative cultures and a stable chest radiograph), the
treatment regimens are those used for latent tuberculosis infection: INH
for 9 months, RIF (with or without INH) for 4 months, or RIF and PZA for
2 months (for patients who are unlikely to complete a longer course and
who can be monitored closely) see Figure 2 titled \"Treatment algorithm
for active, culture-negative pulmonary tuberculosis and inactive
tuberculosis\" in the original guideline document).

*Renal Insufficiency and End-stage Renal Disease*

Specific dosing guidelines for patients with renal insufficiency and
end-stage renal disease are provided in Table 15 titled \"Dosing
recommendatioins for adult patients with reduced renal function and for
adult patients receiving hemodialysis\" in the original guideline
document. For patients undergoing hemodialysis, administration of all
drugs after dialysis is preferred to facilitate DOT and to avoid
premature removal of drugs such as PZA and cycloserine. To avoid
toxicity it is important to monitor serum drug concentrations in persons
with renal failure who are taking cycloserine or EMB. There is little
information concerning the effects of peritoneal dialysis on clearance
of antituberculosis drugs.

*Liver Disease*

INH, RIF, and PZA all can cause hepatitis that may result in additional
liver damage in patients with preexisting liver disease. However,
because of the effectiveness of these drugs (particularly INH and RIF),
they should be used if at all possible, even in the presence of
preexisting liver disease. If serum AST is more than three times normal
before the initiation of treatment (and the abnormalities are not
thought to be caused by tuberculosis), several treatment options exist.
One option is to treat with RIF, EMB, and PZA for 6 months, avoiding
INH. A second option is to treat with INH and RIF for 9 months,
supplemented by EMB until INH and RIF susceptibility are demonstrated,
thereby avoiding PZA. For patients with severe liver disease a regimen
with only one hepatotoxic agent, generally RIF plus EMB, could be given
for 12 months, preferably with another agent, such as a fluoroquinolone,
for the first 2 months; however, there are no data to support this
recommendation.

In all patients with preexisting liver disease, frequent clinical and
laboratory monitoring should be performed to detect drug-induced hepatic
injury.

*Pregnancy and Breastfeeding*

Because of the risk of tuberculosis to the fetus, treatment of
tuberculosis in pregnant women should be initiated whenever the
probability of maternal disease is moderate to high. The initial
treatment regimen should consist of INH, RIF, and EMB. Although all of
these drugs cross the placenta, they do not appear to have teratogenic
effects. Streptomycin is the only antituberculosis drug documented to
have harmful effects on the human fetus (congenital deafness) and should
not be used. Although detailed teratogenicity data are not available,
PZA can probably be used safely during pregnancy and is recommended by
the World Health Organization (WHO) and the International Union against
Tuberculosis and Lung Disease (IUATLD). If PZA is not included in the
initial treatment regimen, the minimum duration of therapy is 9 months.

Breastfeeding should not be discouraged for women being treated with the
first-line antituberculosis agents because the small concentrations of
these drugs in breast milk do not produce toxicity in the nursing
newborn. Conversely, drugs in breast milk should not be considered to
serve as effective treatment for tuberculosis or for latent tuberculosis
infection in a nursing infant. Pyridoxine supplementation (25 mg/day) is
recommended for all women taking INH who are either pregnant or
breastfeeding. The amount of pyridoxine in multivitamins is variable but
generally less than the needed amount.

**Management of Relapse, Treatment Failure, and Drug Resistance**

Relapse refers to the circumstance in which a patient becomes and
remains culture negative while receiving therapy but, at some point
after completion of therapy, either becomes culture positive again or
has clinical or radiographic deterioration that is consistent with
active tuberculosis. In the latter situation rigorous efforts should be
made to establish a diagnosis and to obtain microbiological confirmation
of the relapse to enable testing for drug resistance. Most relapses
occur within the first 6\--12 months after completion of therapy. In
nearly all patients with tuberculosis caused by drug-susceptible
organisms and who were treated with rifamycin-containing regimens using
DOT, relapses occur with susceptible organisms. However, in patients who
received self-administered therapy or a nonrifamycin regimen and who
have a relapse, the risk of acquired drug resistance is substantial. In
addition, if initial drug susceptibility testing was not performed and
the patient fails or relapses with a rifamycin-containing regimen given
by DOT, there is a high likelihood that the organisms were resistant
from the outset.

The selection of empirical treatment for patients with relapse should be
based on the prior treatment scheme and severity of disease. For
patients with tuberculosis that was caused by drug-susceptible organisms
and who were treated under DOT, initiation of the standard four-drug
regimen is appropriate until the results of drug susceptibility tests
are available. However, for patients who have life-threatening forms of
tuberculosis, at least three additional agents to which the organisms
are likely to be susceptible should be included.

For patients with relapse who did not receive DOT, who were not treated
with a rifamycin-based regimen, or who are known or presumed to have had
irregular treatment, it is prudent to infer that drug resistance is
present and to begin an expanded regimen with INH, RIF, and PZA plus an
additional two or three agents based on the probability of in vitro
susceptibility. Usual agents to be employed would include a
fluoroquinolone (levofloxacin, moxifloxacin, or gatifloxacin), an
injectable agent such as SM (if not used previously and susceptibility
to SM had been established), amikacin, kanamycin, or capreomycin, with
or without an additional oral drug.

Treatment failure is defined as continued or recurrently positive
cultures during the course of antituberculosis therapy. After 3 months
of multidrug therapy for pulmonary tuberculosis caused by
drug-susceptible organisms, 90\--95% of patients will have negative
cultures and show clinical improvement. Thus, patients with positive
cultures after 3 months of what should be effective treatment must be
evaluated carefully to identify the cause of the delayed conversion.
Patients whose sputum cultures remain positive after 4 months of
treatment should be deemed treatment failures.

Possible reasons for treatment failure in patients receiving appropriate
regimens include nonadherence to the drug regimen (the most common
reason), drug resistance, malabsorption of drugs, laboratory error, and
extreme biological variation in response. If treatment failure occurs,
early consultation with a specialty center is strongly advised. If
failure is likely due to drug resistance and the patient is not
seriously ill, an empirical retreatment regimen could be started or
administration of an altered regimen could be deferred until results of
drug susceptibility testing from a recent isolate are available. If the
patient is seriously ill or sputum AFB smears are positive, an empirical
regimen should be started immediately and continued until susceptibility
tests are available. For patients who have treatment failure, *M.
tuberculosis* isolates should be sent promptly to a reference laboratory
for drug susceptibility testing to both first- and second-line agents.

A fundamental principle in managing patients with treatment failure is
never to add a single drug to a failing regimen; so doing leads to
acquired resistance to the new drug. Instead, at least two, and
preferably three, new drugs to which susceptibility could logically be
inferred should be added to lessen the probability of further acquired
resistance. Empirical retreatment regimens might include a
fluoroquinolone, an injectable agent such as SM (if not used previously
and the patient is not from an area of the world having high rates of SM
resistance), amikacin, kanamycin, or capreomycin, and an additional oral
agent such as *p*-aminosalicylic acid (PAS), cycloserine, or
ethionamide. Once drug-susceptibility test results are available, the
regimen should be adjusted according to the results.

Patients having tuberculosis caused by strains of *M. tuberculosis*
resistant to at least INH and RIF (multidrug-resistant \[MDR\]) are at
high risk for treatment failure and further acquired drug resistance.
Such patients should be referred to or consultation obtained from
specialized treatment centers as identified by the local or state health
departments or CDC. Although patients with strains resistant to RIF
alone have a better prognosis than patients with MDR strains, they are
also at increased risk for treatment failure and additional resistance
and should be managed in consultation with an expert.

Definitive randomized or controlled studies have not been performed to
establish optimum regimens for treating patients with the various
patterns of drug-resistant tuberculosis; thus, treatment recommendations
are based on expert opinion, guided by a set of general principles
specified in Section 9, titled \"Management of Relapse, Treatment
Failure, and Drug Resistance\" in the original guideline document. Table
16 titled \"Potential regimens for the management of patients with
drug-resistant pulmonary tuberculosis\" in the original guideline
document contains treatment regimens suggested for use in patients with
various patterns of drug-resistant tuberculosis (all are rated
**AIII**).

The role of resectional surgery in the management of patients with
extensive pulmonary MDR tuberculosis has not been established in
randomized studies and results have been mixed. Surgery should be
performed by surgeons with experience in these situations and only after
the patient has received several months of intensive chemotherapy.
Expert opinion suggests that chemotherapy should be continued for 1\--2
years postoperatively to prevent relapse.

**Treatment of Tuberculosis in Low-Income Countries: Recommendations of
the WHO and Guidelines from the IUATLD**

A summary of the important differences between the recommendations in
this document and those of the IUATLD and the WHO is found in Section
10, titled \"Treatment of Tuberculosis in Low-Income Countries:
Recommendations of the WHO and the IUTLD\" of the original guideline
document.

**[Definitions]{.underline}**:

Infectious Diseases Society of America/United States Public Health
Service Rating System for Strength of Recommendations:

A.  Preferred; should generally be offered

B.  Alternative; acceptable to offer

C.  Offer when preferred or alternative regimens cannot be given

D.  Should generally not be offered

E.  Should never be offered

Infectious Diseases Society of America/United States Public Health
Service Rating System for Quality of Evidence:

I.  At least one properly randomized trial with clinical end points

II. Clinical trials that either are not randomized or were conducted in
    other populations

III. Expert opinion

#### CLINICAL ALGORITHM(S)

Algorithms are provided in the original guideline document for:

-   The Treatment for Tuberculosis

-   The Treatment for Active, Culture-negative Pulmonary Tuberculosis
    and Inactive Tuberculosis

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for selected
recommendations (see Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   The overall goals for treatment of tuberculosis are 1) to cure the
    individual patient, and 2) to minimize the transmission of
    *Mycobacterium tuberculosis* to other persons. Thus, successful
    treatment of tuberculosis has benefits both for the individual
    patient and the community in which the patient resides.

-   It is well established that appropriate treatment of tuberculosis
    rapidly renders the patient noninfectious, prevents drug resistance,
    minimizes the risk of disability or death from tuberculosis, and
    nearly eliminates the possibility of relapse.

#### POTENTIAL HARMS

**[Overall Potential Harms]{.underline}**

-   Adverse effects of medications

-   Drug interactions

**Specific Adverse Effects of First-Line Drugs**

-   *Isoniazid*. Asymptomatic elevation of aminotransferases; clinical
    hepatitis; fatal hepatitis; peripheral neurotoxicity; central
    nervous system effects; lupus-like syndrome; hypersensitivity
    reactions; monoamine (histamine/tyramine) poisoning; diarrhea

-   *Rifampin*. Cutaneous reactions; gastrointestinal reactions (nausea,
    anorexia, abdominal pain); flulike syndrome; hepatotoxicity; severe
    immunologic reactions; orange discoloration of bodily fluids
    (sputum, urine, sweat, tears); drug interactions due to induction of
    hepatic microsomal enzymes

-   *Rifabutin*. Hematologic toxicity; uveitis; gastrointestinal
    symptoms; polyarthralgias; hepatotoxity; pseudojaundice (skin
    discoloration with normal bilirubin); rash; flulike syndrome; orange
    discoloration of bodily fluids (sputum, urine, sweat, tears)

-   *Rifapentine*. Similar to those associated with RIF; may increase
    metabolism of coadministered drugs that are metabolized by these
    enzymes

-   *Pyrazinamide*. Hepatotoxicity; gastrointestinal symptoms (nausea,
    vomiting); nongouty polyarthralgia; asymptomatic hyperuricemia;
    acute gouty arthritis; transient morbilliform rash; dermatitis

-   *Ethambutol*: Retrobulbar neuritis; peripheral neuritis; cutaneous
    reactions

**Specific Adverse Effects of Second-Line Drugs**

-   *Cycloserine*. Central nervous system effects

-   *Ethionamide*. Gastrointestinal effects; hepatotoxicity;
    neurotoxicity; endocrine effects

-   *Streptomycin*. Ototoxicity; neurotoxicity; nephrotoxicity

-   *Amikacin and kanamycin*. Ototoxicity; nephrotoxicity

-   *Capreomycin*. Nephrotoxicity; ototoxicity

-   *p-Aminosalicylic acid*. Hepatotoxicity; gastrointestinal distress;
    malabsorption syndrome; hypothyroidism; coagulopathy

-   *Levofloxacin*. Gastrointestinal disturbance; neurologic effects;
    cutaneous reactions

**Note**: Refer to the original guideline document for details about the
adverse effects listed above.

**Drug Interactions**

-   *Drug interactions due to rifamycins*. The drugs used to treat
    tuberculosis affect the metabolism of many other drugs, and can
    result in a lack of efficacy (interactions with the rifamycins) or
    toxicity (interactions with isoniazid and the fluoroquinolones).
    Most of the clinically relevant drug\--drug interactions involving
    the antituberculosis drugs are due to the effect of the rifamycins
    (rifampin, rifabutin, and rifapentine) on the metabolism of other
    drugs. All of the rifamycins are inducers of a variety of metabolic
    pathways, particularly those involving the various isozymes of the
    cytochrome P450 system. By inducing the activity of metabolic
    enzymes, rifamycin therapy results in a decrease in the serum
    concentrations of many drugs, sometimes to levels that are
    subtherapeutic. The rifamycins differ substantially in their potency
    as enzyme inducers; rifampin is the most potent, rifapentine is
    intermediate, and rifabutin is the least potent enzyme inducer. The
    well-described, clinically relevant drug-drug interactions involving
    the rifamycins are presented in Table 12 of the original guideline
    document.

-   *Drug interactions due to isoniazid*. Isoniazid is a relatively
    potent inhibitor of several cytochrome P450 isozymes (CYP2C9,
    CYP2C19, and CYP2E1), but has minimal effect on CYP3A. As an
    inhibitor, isoniazid can increase concentrations of some drugs to
    the point of toxicity. The clearest examples of toxicity due to the
    inhibitory activity of isoniazid are the anticonvulsants, phenytoin
    and carbamazepine. Isoniazid also increases concentrations of
    benzodiazepines metabolized by oxidation, such as diazepam and
    triazolam, but not those metabolized by conjugation, such as
    oxazepam. It is worth noting that rifampin has the opposite effect
    on the serum concentrations of many of these drugs. The available
    data demonstrate that the inductive effect of rifampin outweighs the
    inhibitory effect of isoniazid, so that the overall effect of
    combined therapy with rifampin and isoniazid is a decrease in the
    concentrations of drugs such as phenytoin and diazepam. Isoniazid
    may increase toxicity of other drugs\-\--acetaminophen, valproate,
    serotonergic antidepressants, disulfiram, warfarin, and
    theophylline\-\--but these potential interactions have not been well
    studied.

-   *Drug interactions due to fluoroquinolones*. Ciprofloxacin inhibits
    the metabolism of theophylline and can cause clinical theophylline
    toxicity. However, levofloxacin, gatifloxacin, and moxifloxacin do
    not affect theophylline metabolism.

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

-   The once-weekly continuation phase is contraindicated in patients
    with HIV infection because of an unacceptable rate of
    failure/relapse, often with rifamycin-resistant organisms.

-   Preexisting gout is generally a contraindication to the use of
    pyrazinamide.

-   Streptomycin is contraindicated in pregnancy.

-   Both amikacin and kanamycin are contraindicated in pregnant women
    because of risk of fetal nephrotoxicity and congenital hearing loss.

-   P-Aminosalicylic acid (PAS) is contraindicated in severe renal
    insufficiency because of the accumulation of the acetylated form.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

-   The recommendations in this statement are not applicable under all
    epidemiologic circumstances or across all levels of resources that
    are available to tuberculosis control programs worldwide. Although
    the basic principles of therapy described in this document apply
    regardless of conditions, the diagnostic approach, methods of
    patient supervision, and monitoring for response and for adverse
    drug effects, and in some instances the regimens recommended, are
    quite different in high-incidence, low-income areas compared with
    low-incidence, high-income areas of the world. A summary of the
    important differences between the recommendations in this document
    and those of the International Union Against Tuberculosis and Lung
    Disease (IUATLD) and the World Health Organization (WHO) is found in
    the original guideline document.

-   Many possible interactions involving the rifamycins have not been
    investigated fully and additional clinically relevant interactions
    undoubtedly will be described. Therefore, it is important to check
    all concomitant medications for possible, as well as confirmed,
    drug\--drug interactions with rifamycins.

-   The following drugs, which are suggested for use in selected cases,
    are not approved by the Food and Drug Administration for treatment
    of tuberculosis: rifabutin, amikacin, kanamycin, moxifloxacin,
    gatifloxacin, and levofloxacin.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

Successful treatment of tuberculosis depends on more than the science of
chemotherapy. To have the highest likelihood of success, chemotherapy
must be provided within a clinical and social framework based on an
individual patient´s circumstances. Optimal organization of treatment
programs requires an effective network of primary and referral services
and cooperation between clinicians and public health officials, between
health care facilities and community outreach programs, and between the
private and public sectors of medical care. Section 2 of the original
guideline describes the approaches to organization of treatment that
serve to ensure that treatment has a high likelihood of being
successful.

#### IMPLEMENTATION TOOLS

Clinical Algorithm\
Foreign Language Translations\
Personal Digital Assistant (PDA) Downloads\
Resources\
Staff Training/Competency Material\
Wall Poster

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

Getting Better

#### IOM DOMAIN

Effectiveness\
Patient-centeredness\
Safety

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Neff M. ATS, CDC, and IDSA update recommendations on the treatment of
tuberculosis. Am Fam Physician 2003 Nov 1;68(9):1854, 1857-8, 1861-2.
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=14620606)

Treatment of tuberculosis. MMWR Recomm Rep 2003 Jun 20;52(RR-11):1-77.
\[534 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=12836625)

#### ADAPTATION

Not applicable: Guideline was not adapted from another source.

#### DATE RELEASED

2003 Jun 20

#### GUIDELINE DEVELOPER(S)

American Thoracic Society - Medical Specialty Society\
Centers for Disease Control and Prevention - Federal Government Agency
\[U.S.\]\
Infectious Diseases Society of America - Medical Specialty Society

#### GUIDELINE DEVELOPER COMMENT

The current revision of this guideline was cosponsored by the American
Thoracic Society (ATS), the Centers for Disease Control and Prevention
(CDC), and the Infectious Diseases Society of America (IDSA).

Representatives of the American Academy of Pediatrics (AAP), the (United
States) National Tuberculosis Controllers Association (NTCA), the
Canadian Thoracic Society (CTS), the Union Against Tuberculosis and Lung
Disease (IUATLD), and the World Health Organization (WHO) also
participated in the revision.

#### SOURCE(S) OF FUNDING

American Thoracic Society\
Centers for Disease Control and Prevention (CDC)\
Infectious Diseases Society of America

#### GUIDELINE COMMITTEE

Joint Committee of the American Thoracic Society (ATS), the Infectious
Diseases Society of America (IDSA), and the Centers for Disease Control
and Prevention (CDC)

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Co-chairs*: Henry M. Blumberg, M.D., IDSA; Philip C. Hopewell, M.D.,
ATS; Richard J. O\'Brien, M.D., CDC

*Committee Members*: William J. Burman, M.D.; Richard E. Chaisson, M.D.;
Charles L. Daley, M.D.; Wafaa El Sadr, M.D., M.P.H.; Sue C. Etkind,
B.S.N., M.S.; Lloyd N. Friedman, M.D.; Paula Fujiwara, M.D., M.P.H.;
Malgosia Grzemska, M.D.; Michael D. Iseman, M.D.; Robert M. Jasmer,
M.D.; Venkatarama R. Koppaka, M.D., Ph.D.; Richard I. Menzies, M.D.;
Randall R. Reves, M.D.; Lee B. Reichman, M.D., M.P.H.; Patricia M.
Simone, M.D.; Jeffrey R. Starke, M.D.; Andrew A. Vernon, M.D., M.H.S.

\*Charles Peloquin, Pharm.D., also made substantial contributions to the
document.

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Michael Iseman, M.D., has indicated that he has a financial relationship
with Ortho-McNeil, which manufactures Levaquin®. The remaining preparers
have signed a conflict of interest disclosure form that verifies no
conflict of interest.

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the Centers for Disease Control and
Prevention (CDC) Web site:

-   [HTML Format](http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5211a1.htm)

-   [Portable Document Format
    (PDF)](http://www.cdc.gov/mmwr/PDF/rr/rr5211.pdf)

Print copies: Available from the Centers for Disease Control and
Prevention, MMWR, Atlanta, GA 30333. Additional copies can be purchased
from the Superintendent of Documents, U.S. Government Printing Office,
Washington, DC 20402-9325; (202) 783-3238.

The guideline is also available for Palm OS or Pocket PC download from
the [Centers for Disease Control and Prevention (CDC) Web
site](http://www.cdc.gov/tb/pubs/PDA_TBGuidelines/default.htm). and the
[AIDSinfo Web
site](http://www.aidsinfo.nih.gov/PDATools/guidelines.aspx).

#### AVAILABILITY OF COMPANION DOCUMENTS

Tools for implementation of the guideline are also available from the
[Centers for Disease Control and Prevention (CDC) Web
site](http://www.cdc.gov/tb/pubs/default.htm).

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on February 3, 2004. This summary
was updated on May 3, 2005 following the withdrawal of Bextra
(valdecoxib) from the market and the release of heightened warnings for
Celebrex (celecoxib) and other nonselective nonsteroidal
anti-inflammatory drugs (NSAIDs). This summary was updated by ECRI on
June 16, 2005, following the U.S. Food and Drug Administration advisory
on COX-2 selective and non-selective non-steroidal anti-inflammatory
drugs (NSAIDs). This summary was updated by ECRI on February 21, 2006
following the U.S. Food and Drug Administration (FDA) advisory on Tequin
(gatifloxacin). This summary was updated by ECRI Institute on July 28,
2008 following the U.S. Food and Drug Administration advisory on
fluoroquinolone antimicrobial drugs.

#### COPYRIGHT STATEMENT

No copyright restrictions apply.

### DISCLAIMER

#### NGC DISCLAIMER

The National Guideline Clearinghouse™ (NGC) does not develop, produce,
approve, or endorse the guidelines represented on this site.

All guidelines summarized by NGC and hosted on our site are produced
under the auspices of medical specialty societies, relevant professional
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Guidelines represented on the NGC Web site are submitted by guideline
developers, and are screened solely to determine that they meet the NGC
Inclusion Criteria which may be found at
<http://www.guideline.gov/about/inclusion.aspx> .

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concerning the content or clinical efficacy or effectiveness of the
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© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/3/2008