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Treatment of drug-resistant pulmonary tuberculosis in adults

Authors: Neil W Schluger, MD, Scott K Heysell, MD, MPH, Gerald Friedland, MD
Section Editor: C Fordham von Reyn, MD
Deputy Editor: Elinor L Baron, MD, DTMH

All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Nov 2017. | This topic last updated: Nov 30, 2017.

INTRODUCTION — Tuberculosis (TB) is a leading cause of morbidity and mortality worldwide. Diagnosis, treatment,
and prevention of TB has become more complex because of resistance to commonly used antituberculous drugs. (See
"Epidemiology and molecular mechanisms of drug-resistant tuberculosis".)

Management of drug-resistant TB can be difficult and may necessitate use of second-line drugs and/or surgical
resection. Management of such patients should be undertaken by individuals with expertise in this area or in very close
consultation with such individuals, in the context of a supportive public health infrastructure [1-3]. Good patient outcomes
depend upon rapid and accurate diagnosis together with administration of proper therapy with close monitoring to assure
adherence to the treatment regimen and patient safety.

Issues related to treatment of drug-resistant TB are reviewed here. Issues related to treatment of drug-susceptible TB
are discussed separately, as are issues related to interactions between second-line TB drugs and antiretroviral therapy
in HIV-infected individuals. (See "Treatment of drug-susceptible pulmonary tuberculosis in HIV-uninfected adults" and
"Treatment of pulmonary tuberculosis in HIV-infected adults: Initiation of therapy".)

DEFINITIONS — Definitions to describe the different types of drug-resistant tuberculosis include the following:

● The term "drug-resistant tuberculosis" refers to TB caused by an isolate of Mycobacterium tuberculosis that is
resistant to one or more antituberculous drugs.

● The term "monoresistant TB" refers to TB caused by an isolate of M. tuberculosis that is resistant to a single
antituberculous agent.

● The term "poly-resistant TB" refers to TB caused by an isolate of M. tuberculosis that is resistant to more than one
antituberculous agent; the isolate may be resistant to either isoniazid or rifampin but not both.

● The term "multidrug-resistant TB" (MDR-TB) refers to TB caused by an isolate of M. tuberculosis that is resistant to
both isoniazid and rifampin and possibly additional agents [4].

● The term "extensively drug-resistant TB" (XDR-TB) refers to TB caused by an isolate of M. tuberculosis that is
resistant to at least isoniazid, rifampin, and fluoroquinolones as well as either aminoglycosides (amikacin,
kanamycin) or capreomycin or both [5]. (See "Epidemiology of extensively drug-resistant tuberculosis", section on
'Definitions'.)

● The term "totally drug-resistant TB" (TDR-TB) refers to an isolate of M. tuberculosis resistant to all locally tested
medications [6,7]. However, the published studies initially describing TDR-TB did not include susceptibility testing for
less frequently used agents with activity against TB (including cycloserine, terizidone, clofazimine, linezolid, or
carbapenems) or more recently introduced agents (including bedaquiline and delamanid). (See "Epidemiology of
extensively drug-resistant tuberculosis", section on 'Definitions'.)

● Primary drug resistance refers to infection caused by a drug-resistant strain of M. tuberculosis contracted in the
 ● Primary drug resistance refers to infection caused by a drug-resistant strain of M. tuberculosis contracted in the
absence of previous antituberculous therapy.

● Secondary drug resistance refers to the development of drug resistance during or following antituberculous therapy
in patients who had previously had drug-susceptible TB and have not been reinfected by a different drug-resistant
organism.

CLINICAL PRESENTATION — The clinical manifestations and radiographic features of drug-resistant tuberculosis (TB)
are comparable with those of drug-susceptible TB. (See "Epidemiology, clinical manifestations, and diagnosis of
tuberculosis in HIV-infected patients" and "Diagnosis of pulmonary tuberculosis in HIV-uninfected adults".)

The most important predictors of drug-resistant TB are [2,8]:

● A previous episode of TB treatment

● Persistent or progressive clinical and/or radiographic findings while on TB therapy

● Residence in or travel to a region with high prevalence of drug-resistant TB

● Exposure to an individual with known or suspected infectious drug-resistant TB

Additional risk factors associated with development of drug-resistant TB are summarized in the table (table 1) and are
discussed further separately. (See "Epidemiology and molecular mechanisms of drug-resistant tuberculosis", section on
'Risk factors for development of drug resistance'.)

EMPIRIC TREATMENT — The decision to start an expanded empiric treatment regimen for drug-resistant tuberculosis
(TB; a regimen including second-line drugs) pending conventional, culture-based drug susceptibility data depends on the
severity of clinical illness and the degree of suspicion for drug-resistant tuberculosis (given epidemiologic factors and/or
results of acid-fast bacilli [AFB] smear and nucleic acid amplification [NAA] testing).

Patients for whom an expanded empiric treatment regimen may be warranted include:

● Patients with treatment failure (AFB sputum culture positive after four months of therapy)

● Patients with relapse (recurrent TB after prior completion of treatment with apparent cure)

● Patients with exposure to an individual with drug-resistant TB

● Patients with residence in or travel to a region with high prevalence of drug-resistant tuberculosis

It may be reasonable to defer treatment until drug susceptibility results are available for patients who are not severely ill
and can be isolated if potentially infectious, particularly for circumstances in which few remaining treatment options are
available.

An expanded empiric regimen usually consists of first-line drugs (isoniazid, rifampin, and pyrazinamide) plus two or more
additional drugs. Severe systemic infection (such as meningitis or miliary disease) should prompt addition of at least
three additional drugs. These additional drugs include a fluoroquinolone, an injectable agent, and/or another core
second-line agent (table 2). A single drug should never be added to a failing regimen, as this may lead to acquired
resistance to the new drug.

The choice of second-line drugs should reflect the prior treatment history, the drug resistance pattern of the source case
(if available), the likely patterns of resistance in the patient's region of origin, and, if available, results of molecular testing
of the isolate for drug resistance. The regimen should be chosen in consultation with an individual who has expertise
with treatment of drug-resistant tuberculosis and should be administered with directly observed therapy.

The regimen should be adjusted accordingly once drug susceptibility results are available, as discussed in the following
sections.

Drug dosing is summarized in the tables (table 3 and table 4).

TREATMENT OF MONORESISTANT TB — The clinical approach to treatment of monoresistant tuberculosis (TB) varies
depending on the agent to which the isolate is resistant. In general, the approach to selection of antituberculous therapy
is similar for HIV-uninfected and HIV-infected patients, although many favor extending the duration of therapy for HIV-
infected patients by approximately three months.

Drug dosing is summarized in the tables (table 3 and table 4).

Isoniazid monoresistance — The approach to treatment of patients with isoniazid (INH)-monoresistant TB is generally
based on expert opinion informed by retrospective or single-arm studies.

Options for treatment of patients with known INH-monoresistant TB include [2]:

● Option 1: Daily rifampin, ethambutol, and pyrazinamide (with or without a fluoroquinolone) for six to nine months (or
four months after culture conversion) [9]; in HIV-infected patients, it is reasonable to prolong therapy for an
additional three months [10-12].

This approach is based on trials conducted by the Hong Kong Chest Service/British Medical Research Council,
which demonstrated success rates of 95 to 98 percent among 107 patients with INH-resistant disease [13]. It is also
supported by a retrospective study of patients with INH-monoresistant TB treated for six months; rates of treatment
failure or relapse were comparable with patients with drug-susceptible TB [12], although for many patients the
duration of therapy was extended because pyrazinamide was not administered for the entire six months initially.

● Option 2: If the patient does not tolerate pyrazinamide, a regimen consisting of rifampin, ethambutol, and a
fluoroquinolone for 9 to 12 months may be used; fluoroquinolone susceptibility should be confirmed [14].

For treatment of patients for whom drug susceptibility testing is not available but who are known to reside in a region with
a background level of INH resistance >7 percent, an acceptable approach consists of a standard intensive phase (eg,
isoniazid, rifampin, pyrazinamide, and ethambutol), followed by continuation phase consisting of isoniazid and rifampin
with addition of ethambutol (rather than isoniazid and rifampin alone) [15,16]. (See "Treatment of drug-susceptible
pulmonary tuberculosis in HIV-uninfected adults".)

Effective therapy for INH-monoresistant TB is associated with very high bacteriologic and clinical response rates (>95
percent) and low relapse rates (<5 percent) [12,17].

Monoresistance to other agents

● Rifampin – Patients with rifampin monoresistance should be treated as for multidrug-resistant TB, in accordance
with World Health Organization guidelines issued in 2016 [1]. (See 'Treatment of multidrug-resistant TB' below.)

● Pyrazinamide – Patients with pyrazinamide monoresistance should be treated with isoniazid and rifampin for nine
months. This combination has a success rate >96 percent in large trials [18-20]. Many isolates with pyrazinamide
monoresistance reflect M. bovis disease. (See "Mycobacterium bovis".)

● Other agents – Monoresistance to ethambutol, streptomycin, or second-line agents is of little clinical significance;
patients with disease caused by these isolates may be treated as for drug-susceptible TB (intensive phase:
isoniazid, rifampin, pyrazinamide, and ethambutol [if not resistant] for two months; followed by continuation phase:
isoniazid and rifampin for four months). (See "Treatment of drug-susceptible pulmonary tuberculosis in HIV-
uninfected adults".)

TREATMENT OF POLY-RESISTANT TB — The term "poly-resistant tuberculosis (TB)" refers to TB caused by an isolate
of M. tuberculosis that is resistant to more than one antituberculous agent; the isolate may be resistant to either isoniazid
or rifampin but not both. (See 'Definitions' above.)

Treatment of poly-resistant TB depends on the pattern of drug resistance; in general, it should include as many first-line
agents as possible plus a fluoroquinolone and, in some cases, an injectable drug. Suggested regimens are summarized
in the table (table 5).

Drug dosing is summarized in the tables (table 3 and table 4).

Drug dosing is summarized in the tables (table 3 and table 4).

TREATMENT OF MULTIDRUG-RESISTANT TB — The term "multidrug-resistant tuberculosis (MDR-TB)" refers to an

isolate of M. tuberculosis that is resistant to both isoniazid and rifampin and possibly additional agents. (See 'Definitions'
above.)

The treatment approach discussed below is warranted for patients with MDR-TB or rifampin-monoresistant TB.
Regimens should be chosen in consultation with an individual who has expertise with treatment of MDR-TB whenever
possible.

In addition, consideration of surgery is warranted under specific circumstances. (See 'Role of surgery for MDR- or XDR-
TB' below.)

Clinical approach

Nonpregnant adults

General principles — The approach to treatment of MDR-TB depends on results of drug susceptibility testing
(DST) and availability of antituberculous agents. Management of MDR-TB cases should be supervised by medical
personnel with expertise and experience in administering complicated antituberculous regimens, in conjunction with
appropriate laboratory facilities to document drug susceptibility and to monitor patient safety and response to therapy
[21].

Antituberculous drugs that may be used for treatment of MDR-TB are summarized in the table (table 2). Dosing for
antituberculous drug agents is summarized in the tables (table 3 and table 4). Issues related to individual antituberculous
agents are discussed separately. (See "Antituberculous drugs: An overview".)

In general, the optimal number of drugs, combination of drugs, and duration of therapy for treatment of MDR-TB are
uncertain. Options for treatment of MDR-TB include the conventional MDR treatment regimen (total duration of therapy
generally 20 to 26 months) or a shortened regimen (total duration of therapy 9 to 12 months).

● Conventional regimen – The conventional regimen (total duration 20 to 26 months) for treatment of MDR-TB
consists of an intensive phase (administration of at least five effective drugs including an injectable drug) for at least
6 months after sputum culture conversion, followed by a continuation phase (administration of at least four effective
drugs in the absence of an injectable drug) for an additional 12 months, providing at least 18 months of treatment
beyond sputum culture conversion [1]. A single drug should never be added to a failing regimen, as this may lead to
acquired resistance to the new drug.

Support for this approach comes from a retrospective cohort study including 668 Peruvian patients who started an
individualized MDR-TB regimen. Regimens of four likely effective drugs were associated with higher mortality rates
than regimens with five likely effective drugs (adjusted hazard ratio [HR] 2.87, 95% CI 1.35-6.09, versus adjusted
HR 2.76, 95% CI 0.92-8.27) [22]. In addition, the mortality rate for regimens of five likely effective drugs with likely
effective pyrazinamide (PZA) was similar to that for the regimen of five likely effective drugs without PZA (HR 1.00,
95% CI 0.12-8.00).

The conventional regimen is discussed in greater detail below. (See 'Conventional regimen' below.)

● Shortened regimen – The shortened regimen (total duration 9 to 12 months) is appropriate for nonpregnant patients
with MDR-TB (in the absence of extrapulmonary disease), with an isolate known to be susceptible to
fluoroquinolones and injectable antituberculous agents and with no prior exposure to second-line agents for more
than one month [1]. Patients with known or suspected MDR-TB who do not meet criteria for the shortened MDR-TB
regimen should be treated with the conventional regimen.

The shortened regimen is discussed in greater detail below. (See 'Shortened regimen' below.)

Design of the treatment regimen can be difficult and must take into account several factors [2]:

● Drug susceptibility test results.

 ● Cross-resistance (which occurs among fluoroquinolones, among injectable agents, between isoniazid and
ethionamide, and between bedaquiline and clofazimine).

● Prior use of antituberculous agents; patients who have taken a drug for longer than one month have less effect from
that drug, even if in vitro testing demonstrates susceptibility. Nonetheless, most favor inclusion of first-line drugs with
documented susceptibility in the regimen, though some may choose not to count previously used drugs as one of
the target effective drugs.

● Adverse effects and drug toxicity.

All patients with drug-resistant TB should be assigned to a clinical case manager who oversees all aspects of the
patient's care (medical and social) and provides supervised treatment (directly observed therapy [DOT]) [23,24].
Adherence to MDR-TB therapy is particularly difficult because regimens are prolonged and employ drugs with
considerable adverse effects. (See "Adherence to tuberculosis treatment".)

Repeat sputum should be obtained for acid-fast bacilli (AFB) microscopy and culture two months after initiation of
therapy [1,2]. If positive, the sputum evaluation should be repeated monthly until negative and the duration of the
intensive phase should continue until at least six months after sputum culture conversion.

Treatment regimens should be tailored once drug susceptibility data are available. If full drug susceptibility is
documented, the patient does not have drug-resistant TB; the additional drugs may be discontinued and treatment may
be completed with a standard regimen. If MDR-TB is documented, drugs to which the isolate is resistant should be
discontinued, and new drugs should be added such that at least four drugs active against the most prevalent drug-
resistant strains are included in the regimen based on the sequence outlined above. (See "Treatment of drug-susceptible
pulmonary tuberculosis in HIV-uninfected adults" and "Treatment of pulmonary tuberculosis in HIV-infected adults:
Initiation of therapy".)

Regimens — Conventional and shortened regimens for treatment of MDR-TB are described in the following
sections.

Conventional regimen — In general, patients with known or suspected MDR-TB (infection acquired in area
with high prevalence of MDR-TB or infection following contact with an individual known to have MDR-TB) should be
treated with the conventional regimen (total duration of therapy 20 to 26 months).

An empiric conventional regimen consists of the following [1,2,25,26]:

● An intensive phase consisting of at least five drugs – Susceptible first-line drugs if any (pyrazinamide and/or
ethambutol), a fluoroquinolone, an injectable agent, and one or more additional oral second-line agents
(ethionamide, cycloserine, linezolid, or para-aminosalicylic acid) given for at least six months beyond sputum
culture conversion (performed after two months of treatment). If there are not at least five active drugs available in
these categories, add-on agents include high-dose isoniazid, clofazimine, bedaquiline, delamanid, and a
carbapenem (meropenem or imipenem) plus clavulanate (table 6 and figure 1). (See "Antituberculous drugs: An
overview", section on 'Second-line agents'.)

● A continuation phase consisting of the drugs used during the intensive phase with the exception of the injectable
agent, given for 18 to 24 months beyond sputum culture conversion (performed after two months of treatment).
Patients with extensive disease or cavitary disease may warrant a longer duration for the injectable drug and/or use
of an additional oral second-line drug. Patients who have received prior treatment with pyrazinamide or ethambutol
may also warrant an additional oral second-line drug.

The World Health Organization (WHO) favors empiric addition of high-dose isoniazid (15 to 20 mg/kg/day) to the above
regimens [1].

Regimens should be tailored to the drug susceptibility results when available and to drug side effects and toxicities.

General principles related to directly observed therapy, follow-up sputum examination, and tailoring treatment regimens
are discussed above. (See 'General principles' above.)
are discussed above. (See 'General principles' above.)

Shortened regimen — The shortened MDR-TB regimen for pulmonary tuberculosis (total duration of therapy 9
to 11 months) was described by the WHO in 2016 [1]; it is appropriate for nonpregnant patients with MDR-TB who meet
the following criteria:

● Absence of extrapulmonary disease

● Access to all component antituberculous drugs in the regimen: moxifloxacin, kanamycin, prothionamide,
clofazimine, high-dose isoniazid, pyrazinamide, and ethambutol

● No resistance to the drugs in the regimen (except isoniazid resistance)

● No previous exposure to drugs in the regimen for more than one month

Patients with MDR-TB who are candidates for treatment with a shortened treatment regimen may be identified using the
MTBDRsl assay; the WHO has advocated use of this assay as the initial test for detection of resistance to
fluoroquinolones and second-line injectable drugs. The MTBDRsl assay does not test for resistance to clofazimine and
pyrazinamide, predicts most but not all resistance to kanamycin and the fluoroquinolones (compared with phenotypic
culture-based testing), and predicts ethambutol resistance less reliably [27]. The MTBDRsl assay is not approved by the
US Food and Drug Administration and is not routinely available in the United States unless validated by the testing
laboratory [28]. (See "Diagnosis of pulmonary tuberculosis in HIV-uninfected adults", section on 'Probe-based (NAA)
tests'.)

The implementation of the shortened regimen is challenging in the absence of access to rigorous drug-susceptibility
testing for all drugs in the regimen [29]. Accordingly, drug-susceptibility should be scaled up to meet local needs in
conjunction with introduction of any novel antibiotic regimen. In addition, the shortened regimen may not be applicable in
certain regions of the world (such as countries of the former Soviet Union), where there are many patients with previous
treatment for TB and MDR-TB is common [30,31].

In the United States, some experts favor use of the shortened regimen for patients with MDR-TB and minimal
radiographic disease or low bacillary burden [2].

The shortened regimen consists of the following components:

● Intensive phase – Four months (daily) of seven drugs: high-dose isoniazid (15 to 20 mg/kg/day), ethambutol,
pyrazinamide, moxifloxacin, kanamycin, prothionamide, and clofazimine. The duration of the intensive phase is
extended to six months for patients with positive sputum AFB microscopy and culture performed two months after
initiation of therapy. (See 'General principles' above.)

● Continuation phase – Five months (daily) of four drugs: ethambutol, pyrazinamide, moxifloxacin, and clofazimine.

General principles related to directly observed therapy, follow-up sputum examination, and tailoring treatment regimens
are discussed above. (See 'General principles' above.)

The shorter MDR-TB regimen advocated by the WHO is based in part on reported success with a "nine-month
Bangladesh regimen" consisting of nine months of treatment with gatifloxacin, ethambutol, pyrazinamide, and
clofazimine, supplemented in the first four months by kanamycin, prothionamide, and high-dose isoniazid [32]. If sputum
smears were still positive at four months, the intensive phase was continued until smears were negative, and the
continuation phase was fixed at an additional five months. DOT was used throughout. Among 515 patients,
bacteriologically favorable outcomes were achieved in 84 percent of cases. The strongest predictor of failure was the
presence of high-level fluoroquinolone resistance. Because of slow response to therapy, only half of the patients could
complete treatment within 9 months, but 95 percent completed within 12 months, a significantly shorter time than
required for most other recommended regimens.

Monitoring — Patient education regarding symptoms of hepatitis and other possible drug toxicities should be
reviewed with the patient at each DOT visit and reinforced at each clinic visit. Patients should be instructed to report
signs or symptoms of toxicity to their provider immediately and stop medications until advised to resume treatment.
signs or symptoms of toxicity to their provider immediately and stop medications until advised to resume treatment.
Issues related to laboratory monitoring for patients on antituberculous drugs are discussed separately. (See
"Antituberculous drugs: An overview", section on 'Clinical and laboratory monitoring for adverse effects'.)

During treatment, sputum should be obtained for AFB smear and culture and drug susceptibility testing at monthly
intervals until two consecutive cultures are negative [10]. Following two successive months of negative sputum cultures,
repeat culture and drug susceptibility testing are usually reserved only for persistent or worsening symptoms despite
adequate adherence to therapy.

In patients with extensive pulmonary disease, monthly or biweekly chest radiographs may also be monitored to gauge for
radiographic signs of further treatment failure and/or to prompt consideration of adjunctive surgery.

Children — Management of children with MDR-TB is discussed further separately. (See "Tuberculosis disease in
children", section on 'Drug-resistant TB'.)

Pregnant women — The optimal approach to treatment of pregnant women with MDR-TB is uncertain. In general,
the approach to selection of antituberculous agents is similar to the conventional MDR-TB regimen for nonpregnant
adults. Data are insufficient for use of the shortened MDR-TB regimen in pregnant women. (See 'Regimens' above.)

Pyrazinamide is usually excluded from treatment of drug-susceptible TB during pregnancy in the United States, although
it is used elsewhere. There are no controlled data on the use of pyrazinamide in pregnancy, and its use in pregnant
women with drug-resistant disease is justifiable for circumstances in which drug choice is limited and benefit outweighs
risk [1].

Antituberculous agents that are not considered safe in pregnancy include injectable agents, ethionamide, and
prothionamide. In one case series describing the long-term follow-up of six children with intrauterine exposure to second-
line agents during treatment of MDR-TB during pregnancy, there was no evidence of significant toxicity among the
children (average age at follow-up 3.7 years); one child was diagnosed with MDR-TB [33].

The experience with treatment of MDR-TB in pregnancy is limited; data from Peru have demonstrated that birth
outcomes among pregnant women treated for MDR-TB are comparable with outcomes among nonpregnant individuals
[34].

Treatment failure — Treatment failure refers to positive cultures after four months of antituberculous therapy.
Treatment failure should raise concern for resistance to drugs in the regimen being administered at the time when failure
is diagnosed. Treatment failure in the setting of drug-resistant TB likely reflects relatively weak potency of second-line
antituberculous drugs.

A new treatment regimen should be developed based on drug susceptibility testing results, together with careful review
of previous medications and adherence [10]. Any agent taken for more than one month is likely to have decreased
efficacy. Patients with treatment failure should receive highest priority for directly observed therapy.

An empiric retreatment regimen should include at least four drugs likely to be effective. This usually entails use of a
regimen with greater toxicity than the prior regimen.

Therapeutic drug-level monitoring may be useful in patients who do not respond to a seemingly appropriate regimen
administered with directly observed therapy and has been used routinely at the initiation of therapy in some centers
[35,36]. Low serum levels of anti-TB drugs have been reported in patients with malabsorption and in some individuals
with HIV infection (even in the absence of clinical malabsorption) [37,38]. (See "Antituberculous drugs: An overview",
section on 'Serum drug concentration monitoring'.)

Outcomes — Treatment success rates for MDR-TB range from 30 to 80 percent; factors associated with treatment
success include [4,39-46]:

● Duration of therapy at least 18 months

● Directly observed therapy throughout treatment

 ● Surgical resection

● Fluoroquinolone use

● No previous treatment

Factors associated with unfavorable outcomes include:

● Male gender

● Alcohol abuse

● Lack of weight gain

● Smear positivity at diagnosis

● Fluoroquinolone resistance

● HIV coinfection

TREATMENT OF EXTENSIVELY DRUG-RESISTANT TB — The term "extensively drug-resistant tuberculosis (XDR-

TB)" refers to TB caused by an isolate of M. tuberculosis that is resistant to at least isoniazid, rifampin, and
fluoroquinolones as well as either aminoglycosides (amikacin, kanamycin) or capreomycin or both. (See 'Definitions'
above.)

Regimens should be chosen in consultation with an individual who has expertise with treatment of multidrug-resistant
tuberculosis (MDR-TB) whenever possible and in collaboration with the jurisdictional public health program. (See
'Resources for expert guidance' below.)

In addition, consideration of surgery is warranted under specific circumstances. (See 'Role of surgery for MDR- or XDR-
TB' below.)

Clinical approach — The approach to treatment of XDR-TB depends on results of drug susceptibility testing (DST) and
availability of antituberculous agents. Management of XDR-TB cases should be supervised by medical personnel with
expertise and experience in administering complicated antituberculous regimens, in conjunction with appropriate
laboratory facilities to document drug susceptibility and to monitor patient safety and response to therapy.

Antituberculous drugs that may be used for treatment of XDR-TB are summarized in the table (table 2). Dosing for
antituberculous drug agents is summarized in the tables (table 3 and table 4). Issues related to individual antituberculous
agents are discussed separately. (See "Antituberculous drugs: An overview".)

The approach to selecting antituberculous drugs for treatment of XDR-TB is as follows (table 6) [2,3,47-50]:

● An intensive phase consisting of at least six drugs – Susceptible first-line drugs if any (pyrazinamide and/or
ethambutol), a fluoroquinolone (preferably high-dose moxifloxacin), an injectable agent (preferably capreomycin),
and one or more additional oral agents (preferably linezolid and either bedaquiline or delamanid; additional options
include ethionamide, cycloserine, para-aminosalicylic acid, high-dose isoniazid, clofazimine, or a carbapenem
[meropenem or imipenem] plus clavulanate) given for at least six months beyond sputum culture conversion
(performed after two months of treatment). (See "Antituberculous drugs: An overview", section on 'Second-line
agents'.)

● A continuation phase consisting of the drugs used during the intensive phase with the exception of the injectable
agent, given for 18 to 24 months beyond culture conversion (performed after two months of treatment). Patients with
extensive disease or cavitary disease may warrant a longer duration for the injectable drug and/or use of an
additional oral second-line drug. Patients who have received prior treatment with pyrazinamide or ethambutol may
also warrant an additional oral second-line drug.

● If susceptibility to the injectable agent is confirmed and the drug is tolerated, the intensive phase (six drugs including
the injectable agent) should be extended from 6 months to 12 months, and the continuation phase may be reduced
 the injectable agent) should be extended from 6 months to 12 months, and the continuation phase may be reduced
accordingly to 12 to 18 months (from 18 to 24 months).

Outcomes — The overall prognosis for adults with XDR-TB is poor with high mortality; delays in diagnosis, malnutrition,
and level of immunosuppression contribute to an increased risk of death [51,52].

Among HIV-uninfected patients, survival rates for XDR-TB range from 48 to 60 percent in cohorts from South Korea,
Russia, and Peru [47,53,54].

Most studies suggest that HIV status correlates with poorer outcomes:

● In XDR-TB cases reported from the United States, there was an overall 35 percent mortality, but mortality was 81
percent in the subset of HIV-infected patients [55]. However, many of these occurred before the availability of potent
antiretroviral therapy.

● In the original case series from Tugela Ferry, South Africa, the mortality rate among those identified with both HIV
and XDR-TB infection was 98 percent [56]. In subsequent analysis of 139 patients with XDR-TB, 80 percent died.
Factors significantly associated with mortality included CD4 count ≤50 cells/mm3 and resistance to all six anti-TB
drugs tested; use of antiretroviral therapy (ART) was protective [57].

● In a retrospective study of 227 patients with XDR-TB in South Africa (82 of whom were HIV infected), the number of
deaths did not differ significantly between HIV-infected and HIV-uninfected patients (41 percent versus 30 percent);
ART use (mostly zidovudine, lamivudine, and efavirenz) was protective [52].

● In a cohort including 107 patients with XDR-TB in South Africa (41 percent of whom were HIV infected), at 60
months of follow-up, 73 percent had died, 4 percent defaulted, 10 percent failed treatment, and only 11 percent had
a favorable outcome; use of antiretroviral therapy was an independent predictor of survival [58].

HIV-INFECTED PATIENTS — General issues related to treatment of tuberculosis (TB) in HIV-infected patients are
discussed separately. (See "Treatment of pulmonary tuberculosis in HIV-infected adults: Initiation of therapy".)

The approach to selection of antituberculous drugs for HIV-infected patients with monoresistant or polyresistant TB is as
described above. (See 'Treatment of monoresistant TB' above and 'Treatment of poly-resistant TB' above.)

The approach to selection of antituberculous drugs for HIV-infected patients with multidrug-resistant tuberculosis (MDR-
TB) or extensively drug-resistant tuberculosis (XDR-TB) is as described above for treatment of XDR-TB [3]. If the patient
is able to tolerate medication, treatment should be administered for 24 months beyond sputum culture conversion. After
the cessation of therapy, patients should be examined every four months for an additional 24 months to monitor for
evidence of relapse. (See 'Treatment of extensively drug-resistant TB' above.)

For patients not yet on antiretroviral therapy (ART), diagnosis of TB warrants initiation of ART; the approach to timing
depends on the patient's immune status. Early initiation of ART and integration of HIV and TB care are important
management issues; failure to administer ART in patients with drug-resistant TB has been associated with higher
mortality rates [52,59]. Issues related to timing of ART are discussed separately. (See "Treatment of pulmonary
tuberculosis in HIV-infected adults: Initiation of therapy".)

Studies are needed to clarify the pharmacokinetic and pharmacodynamic interactions between antiretroviral agents and
second-line agents for drug-resistant TB [60]. Notable toxicities and potential drug interactions include (table 7):

● Neuropsychiatric effects associated with cycloserine and efavirenz use

● Peripheral neuropathy associated with both linezolid and aminoglycosides and the rarely used nucleoside reverse
transcriptase inhibitors, stavudine and didanosine

● Gastrointestinal side effects, which are common with many protease inhibitors and many of the second-line agents
for TB (eg, fluoroquinolones, ethionamide, and para-aminosalicylic acid) [61]

● Nephrotoxicity associated with tenofovir and aminoglycosides

The integrase strand inhibitor class of antiretrovirals may be most compatible with second-line anti-TB drugs.

The importance of early institution of ART in coinfected patients was demonstrated in a substudy of the SAPiT trial, in
which ART delay (associated with mortality rate of 56 per 100 person-years) was reduced to 11 per 100 person-years
(an 86 percent reduction) when ART was introduced early [59].

ROLE OF SURGERY FOR MDR- OR XDR-TB — In general, surgery for treatment of tuberculosis is most effective for
patients with poor clinical response or intolerance to supervised medical therapy who have pulmonary disease that is
amenable to complete resection (lobectomy, wedge resection, or pneumonectomy) [62]. Consideration of surgery for
management of multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR-TB) is
warranted in the following circumstances [2,47,62-70]:

● Persistently positive sputum cultures beyond four to six months of antituberculous therapy

● Presence of extensive drug resistance that is unlikely to be cured with antituberculous therapy alone

● Presence of complications such as massive hemoptysis or persistent bronchopleural fistula

In general, surgery should be performed only after several months of antituberculous therapy have been administered,
after smear conversion (if possible), and ideally after culture conversion. Ideally, the surgical team should have extensive
experience in surgical treatment of tuberculosis. A full course of antituberculous therapy should be administered
following surgical resection; the date of surgery may be considered the date of culture conversion if there are no
subsequent positive sputum cultures.

RESOURCES FOR EXPERT GUIDANCE — In the United States, expert guidance can be obtained through the Centers
for Disease Control and Prevention's network of Regional Training and Medical Consultation Centers. These centers
provide timely expert consultation on management of drug-resistant tuberculosis (TB).

The European Respiratory Society and the World Health Organization support a TB Consilium, a confidential and online
consultation service for physicians caring for patients with complex multidrug-resistant or extensively drug-resistant
tuberculosis or HIV coinfection [71]. The TB Consilium provides access to experts with answers delivered within a week
in English or Russian language [72].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and
regions around the world are provided separately. (See "Society guideline links: Diagnosis and treatment of
tuberculosis".)

SUMMARY AND RECOMMENDATIONS

● The term "drug-resistant tuberculosis (TB)" refers to TB caused by an isolate of Mycobacterium tuberculosis that is
resistant to one or more antituberculous drugs. Risk factors for drug-resistant TB are summarized in the table (table
1). (See 'Definitions' above.)

● The decision to start an empiric treatment regimen (including second-line drugs) for drug-resistant TB (pending drug
susceptibility data) depends on the severity of clinical illness and the degree of suspicion for drug-resistant
tuberculosis. Patient categories for whom an expanded empiric treatment regimen may be warranted are
summarized above. An expanded empiric regimen usually consists of first-line drugs (isoniazid, rifampin, and
pyrazinamide) plus two or more additional drugs. Additional drugs include a fluoroquinolone, an injectable agent,
and/or another core second-line agent (table 2). Drug dosing is summarized in the tables (table 3 and table 4). (See
'Empiric treatment' above.)

● The term "monoresistant TB" refers to TB caused by an isolate of M. tuberculosis that is resistant to a single
antituberculous agent. The term "poly-resistant TB" refers to TB caused by an isolate of M. tuberculosis that is
resistant to more than one antituberculous agent; the isolate may be resistant to either isoniazid or rifampin but not
both (table 5). The clinical approach to treatment of monoresistant TB or poly-resistant TB varies depending on the
pattern of drug resistance. Treatment options are discussed above. (See 'Definitions' above and 'Treatment of
monoresistant TB' above and 'Treatment of poly-resistant TB' above.)
 monoresistant TB' above and 'Treatment of poly-resistant TB' above.)

● The term "multidrug-resistant TB (MDR-TB)" refers to TB caused by an isolate of M. tuberculosis that is resistant to
both isoniazid and rifampin and possibly additional agents. Options for treatment of MDR-TB include the
conventional MDR treatment regimen (total duration of therapy generally 20 to 26 months) or a shortened regimen
(total duration of therapy 9 to 12 months). (See 'Definitions' above and 'Treatment of multidrug-resistant TB' above.)

• For nonpregnant patients with MDR-TB (in the absence of extrapulmonary disease), with isolate known to be
susceptible to fluoroquinolones and injectable antituberculous agents and no prior exposure to second-line
agents for more than one month, we suggest treatment with a shortened MDR-TB regimen (Grade 2C). The
shortened regimen consists of an intensive phase including daily administration of seven drugs for four months,
followed by a continuation phase including daily administration of four drugs for five months. (See 'Shortened
regimen' above.)

• Patients who do not meet criteria for the shortened MDR-TB regimen should be treated with the conventional
regimen (figure 1 and table 6). The conventional regimen consists of an intensive phase including at least five
drugs given for at least six months beyond sputum culture conversion (performed after two months of
treatment), followed by a continuation phase including the drugs used during the intensive phase with the
exception of the injectable agent, given for 18 to 24 months beyond sputum culture conversion. (See
'Conventional regimen' above.)

● The term "extensively drug-resistant TB (XDR-TB)" refers to TB caused by an isolate of M. tuberculosis that is
resistant to at least isoniazid, rifampin, and fluoroquinolones as well as either aminoglycosides (amikacin,
kanamycin) or capreomycin or both. Treatment of XDR-TB consists of an intensive phase including at least six
drugs given for at least six months beyond sputum culture conversion, followed by a continuation phase including
the drugs used during the intensive phase with the exception of the injectable agent, given for 18 to 24 months
beyond culture conversion. (See 'Treatment of extensively drug-resistant TB' above.)

● In general, surgery for treatment of tuberculosis is most effective for patients with poor clinical response or
intolerance to supervised medical therapy who have pulmonary disease that is amenable to complete resection.
Consideration of surgery is warranted for management of MDR-TB in the setting of persistently positive cultures
beyond four to six months of antituberculous therapy, presence of extensive patterns of drug resistance that are
unlikely to be cured with antituberculous therapy alone, or presence of complications such as massive hemoptysis
or persistent bronchopleural fistula. (See 'Role of surgery for MDR- or XDR-TB' above.)

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

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Consilium. Eur Respir J 2013; 41:491.

Topic 8028 Version 62.0

GRAPHICS
Risk factors for drug-resistant tuberculosis

Patients with history of tuberculosis

Persistent or progressive clinical and/or radiographic findings while on antituberculous therapy

Lack of conversion of cultures to negative during first three months of antituberculous therapy

Incomplete adherence to prescribed antituberculous therapy

Lack of directly observed therapy or poorly supervised antituberculous therapy

Documented treatment failure or relapse

History of an inappropriate treatment regimen, including too few effective drugs or inadequate drug dosing

Patients without prior history of tuberculosis

Exposure to an individual with known or suspected drug-resistant TB

Residence in or travel to a region with high prevalence of drug-resistant tuberculosis

Residence in or work in an institution or setting with documented drug-resistant tuberculosis

Among foreign-born individuals: Emigration within the previous two years

TB: tuberculosis.

Data from: Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant
Tuberculosis: A Survival Guide for Clinicians, Third Edition.

Graphic 108729 Version 1.0

Antituberculous agents for treatment of drug-resistant tuberculosis

A. Fluoroquinolones* Levofloxacin
Moxifloxacin
Gatifloxacin ¶

B. Second-line injectable agents Amikacin

Capreomycin
Kanamycin Δ
Streptomycin ◊

C. Other core second-line agents* Ethionamide/prothionamide

Cycloserine/terizidone
Linezolid
Clofazimine §

D. Add-on agents (not part of the D1 Pyrazinamide

core MDR-TB regimen) Ethambutol
High-dose isoniazid

D2 Bedaquiline
Delamanid

D3 Para-aminosalicyclic acid
Imipenem-cilastatin ¥
Meropenem ¥
Amoxicillin-clavulanate ¥
(Thioacetazone) ‡

The approach to selecting an antituberculous regimen is discussed in the UpToDate text on diagnosis, treatment, and
prevention of drug-resistant tuberculosis. If a minimum number of core second-line TB medicines cannot be reached
by using agents from groups A, B, and C alone, drugs from group D2 or, if not possible, from group D3 are added.
by using agents from groups A, B, and C alone, drugs from group D2 or, if not possible, from group D3 are added.
Agents from group D1 may be used if they are considered to add benefit (eg, high-dose isoniazid in patients without
high-level isoniazid resistance).

MDR-TB: multidrug-resistant tuberculosis.

* Medicines in groups A and C are shown by decreasing order of usual preference for use (subject to other considerations; refer
to the UpToDate topic on diagnosis, treatment, and prevention of drug-resistant tuberculosis).
¶ Gatifloxacin is associated with dysglycemia and is no longer commercially available.
Δ Kanamycin is not available in the United States.
◊ In general, use of streptomycin should be avoided, given widespread resistance; its use should be restricted to the setting of
known in vitro susceptibility, no history of prior use, and contraindication to amikacin (which is the preferred injectable agent).
§ In the United States, use of clofazimine for treatment of drug-resistant TB requires submission of an investigational new drug
(IND) application to the US Food and Drug Administration (FDA).
¥ Carbapenems and clavulanate are meant to be used together; clavulanate is only available in formulations combined with
amoxicillin.
‡ HIV status must be tested and confirmed to be negative before thioacetazone is started.

Adapted from WHO Treatment guidelines for drug-resistant tuberculosis – 2016 update. World Health Organization 2016
(http://www.who.int/tb/areas-of-work/drug-resistant-tb/treatment/resources/en/, accessed 2 June 2016). Copyright © 2016.

Graphic 83653 Version 19.0

Dosing of first-line antituberculosis drugs in adults*

 Doses
Drug Preparations
Daily 1x/week 2x/week 3x/week

First-line drugs

Isoniazid ¶ Tablets (50 mg, 5 mg/kg (usual 15 mg/kg (usual 15 mg/kg (usual 15 mg/kg (usual
100 mg, 300 maximum dose maximum dose maximum dose maximum dose
mg); elixir (50 300 mg) 900 mg) 900 mg) 900 mg)
mg/5 mL);
aqueous solution
(100 mg/mL) for
intravenous or
intramuscular
injection

Rifampin Capsules (150 10 mg/kg (usual – 10 mg/kg (usual 10 mg/kg (usual

(rifampicin) Δ mg, 300 mg); maximum dose maximum dose maximum dose
capsule contents 600 mg) 600 mg) 600 mg)
may be
suspended for
oral
administration;
aqueous solution
for intravenous
injection

Rifabutin Δ Capsule (150 mg) 5 mg/kg (usual – Not recommended Not recommended
maximum dose
300 mg)

Rifapentine Δ Tablet (150 mg, – 10 to 20 mg/kg – –

film coated) once weekly
during
continuation
phase of
treatment ◊

Pyrazinamide Tablet (500 mg, Dosing – Dosing Dosing

scored) summarized in summarized in summarized in
separate table separate table separate table

Ethambutol Tablets (100 mg, Dosing – Dosing Dosing

400 mg) summarized in summarized in summarized in
separate table separate table separate table

Adult dosing listed in this table is used in patients ≥15 years old or weighing >40 kg.
Antituberculous agents are used in multidrug combination regimens of varying duration, which are described in
detail in a separate table (refer to the UpToDate table on regimens for treatment of drug-susceptible tuberculosis)
and in the accompanying text.

* Dosing based on actual weight is acceptable in patients who are not obese. For obese patients (>20% above ideal body weight
[IBW]), dosing based on IBW may be preferred for initial doses. Some clinicians prefer a modified IBW (IBW + [0.40 × (actual
weight – IBW)]) as is done for initial aminoglycoside doses. Because tuberculosis drug dosing for obese patients has not been
established, therapeutic drug monitoring may be considered for such patients.
¶ Pyridoxine (vitamin B6; 25 to 50 mg/day) is given with isoniazid to individuals at risk for neuropathy (eg, pregnant women,
breastfeeding infants, and individuals with HIV infection, diabetes, alcoholism, malnutrition, chronic renal failure, or advanced
age). For patients with peripheral neuropathy, experts recommend increasing pyridoxine dose to 100 mg/day.
Δ Rifabutin dose may need to be adjusted when there is concomitant use of protease inhibitors or nonnucleoside reverse
transcriptase inhibitors. Refer to the UpToDate topic on treatment of pulmonary tuberculosis in HIV-infected adults for specific
dose adjustments.
◊ Rarely used in practice; it may be an alternative in the continuation phase of treatment in a once-weekly regimen to facilitate
directly observed therapy. For further details, refer to the UpToDate topic on rifamycins.

Data adapted from:

1. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and
Prevention/Infectious Diseases Society of American clinical practice guidelines: Treatment of drug-susceptible
 Prevention/Infectious Diseases Society of American clinical practice guidelines: Treatment of drug-susceptible
tuberculosis. Clin Infect Dis 2016. Epub ahead of print
2. Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A
Survival Guide for Clinicians, Third Edition.

Graphic 55978 Version 8.0

Dosing of second-line antituberculosis drugs in adults

Adult dose:
Patients with
creatinine
Adult dose* Main and rare
clearance <30
​Drug (normal renal but serious Pregnancy
mL/min or
function) adverse effects
patients on
intermittent
hemodialysis
Levofloxacin 750 to 1000 mg orally 750 to 1000 mg orally GI toxicity, CNS Potential choice when
or IV once daily ¶ or IV three times effects, rash, there are no suitable
weekly dysglycemia, alternatives
tendonitis, tendon
rupture, QT
prolongation

Moxifloxacin 400 mg orally or IV No change GI toxicity, CNS Potential choice when

once daily (doses up effects, rash, there are no suitable
to 800 mg once daily dysglycemia, alternatives
have been used) tendonitis, tendon
rupture, QT
prolongation,
hepatotoxicity

Amikacin Δ ◊ § ¥ 15 mg/kg IM or IV 12 to 15 mg/kg/dose Ototoxicity, vestibular Avoid

once daily (usual IM or IV two to three toxicity,
maximum 1 g) times weekly ‡ nephrotoxicity,
adjusted according to adjusted according to electrolyte
serum concentrations serum concentrations disturbances, local
pain with IM injection

Kanamycin Δ ◊ § ¥ 15 mg/kg IM or IV 12 to 15 mg/kg/dose Ototoxicity, vestibular Avoid

once daily (usual IM or IV two to three toxicity,
maximum 1 g) times weekly ‡ nephrotoxicity,
adjusted according to adjusted according to electrolyte
serum concentrations serum concentrations disturbances

Capreomycin Δ § ¥ 15 mg/kg IM or IV 12 to 15 mg/kg/dose Ototoxicity, vestibular Avoid

once daily (usual IM or IV two to three toxicity,
maximum 1 g) times weekly ‡ nephrotoxicity,
adjusted according to adjusted according to electrolyte
serum concentrations serum concentrations disturbances, local
pain with IM injections

Streptomycin Δ § ¥ 15 mg/kg IM or IV 12 to 15 mg/kg/dose Ototoxicity, vestibular Avoid

once daily (usual IM or IV two to three toxicity,
maximum 1 g) times weekly ‡ nephrotoxicity,
adjusted according to electrolyte
serum concentrations disturbances, local
pain with IM injections

Ethionamide †,** , ¶¶ 15 to 20 mg/kg orally No change; some GI toxicity (antiemetic Potential choice when
(usually 500 to 750 suggest 250 to 500 premedication is often there are no suitable
mg per day) as a mg/day helpful), hepatic alternatives
single daily dose or toxicity, metallic taste,
two divided doses neurotoxicity including
(maximum 1 g per optic neuritis
 (maximum 1 g per optic neuritis
day) (administer with
pyridoxine 100 mg per
day), endocrine
effects including
hypothyroidism (treat
with thyroid
replacement)

Cycloserine †,** , ΔΔ 10 to 15 mg/kg orally 250 mg orally once CNS toxicity Potential choice when
in two divided doses daily or 500 mg orally (psychiatric there are no suitable
(usually 250 mg twice three times weekly symptoms, seizures alternatives
daily, maximum 500 adjusted according to usually occur at peak
mg twice daily) serum concentrations concentrations >35
adjusted according to mcg/mL but may
serum concentrations occur in the normal
therapeutic range),
peripheral neuropathy,
dermatologic effects
include serious
cutaneous
hypersensitivity
reactions.
Administration of
pyridoxine 50 mg (oral
once per day) for
every 250 mg of
cycloserine may be
useful in preventing or
reducing
neurotoxicity.

Linezolid** 600 mg orally or IV No change (toxic Myelosuppression, GI Avoid (limited data)

once daily metabolites may toxicity, neuropathy
accumulate) (optic and peripheral);
pyridoxine 50 to 100
mg per day may be
useful in preventing or
reducing peripheral
neuropathy

Clofazimine (not 100 to 200 mg orally No change Red discoloration of Avoid

commercially available once daily skin, eyes, body
in the United fluids; GI toxicity,
States) ◊◊ photosensitivity,
others

High-dose isoniazid** 900 to 1500 mg 900 mg orally or IV Hepatitis, peripheral May be used
orally, IM, or IV twice three times weekly neuropathy
or three times weekly (administer with
pyridoxine),
hypersensitivity,
others

Bedaquiline 400 mg orally once No change for mild- QT prolongation, May be used
daily for two weeks, moderate renal hepatitis, GI toxicity,
followed by 200 mg dysfunction; use with others
three times weekly caution in severe renal
(maximum duration disease
studied 24 weeks)

Delamanid 100 mg orally twice No change; not GI toxicity, QT Avoid

daily with food recommended in prolongation
(maximum duration severe renal disease
studied 26 weeks) (data lacking)

Para-aminosalicylic 8 to 12 g orally in two No change; some GI toxicity, Potential choice when

acid † or three divided doses suggest 4 g/dose hepatotoxicity, there are no suitable
 acid † or three divided doses suggest 4 g/dose hepatotoxicity, there are no suitable
twice daily hypothyroidism (treat alternatives
with thyroid
replacement)

Imipenem-cilastatin 1000 mg IV every 12 500 mg IV every 12 GI toxicity, seizures Potential choice when
hours. Must be given hours (refer to there are no suitable
with clavulanate 125 Lexicomp monograph alternatives
mg orally every 8 to for detail)
12 hours (available as
amoxicillin-
clavulanate; see
below).

Meropenem 2000 mg IV every 8 to 500 mg IV every 12 GI toxicity, seizures Potential choice when
12 hours (based on hours (refer to there are no suitable
published study); Lexicomp monograph alternatives
1000 mg every 12 for detail)
hours may be
sufficient (based on
pharmacokinetic
data). Must be given
with clavulanate 125
mg orally every 8 to
12 hours (available as
amoxicillin-
clavulanate; see
below).

Amoxicillin- 2000 mg 1000 mg GI toxicity May be used

clavulanate amoxicillin/125 mg amoxicillin/125 mg
clavulanate orally clavulanate orally
every 8 to 12 hours every 12 hours

Thioacetazone (not 150 mg once daily Renally excreted; not GI toxicity, Potential choice when
available in the United recommended myelosuppression, there are no suitable
States) §§ hepatitis, peripheral alternatives
neuropathy, serious
cutaneous
hypersensitivity
reactions

Antituberculous agents are used in multidrug combination regimens of varying duration, which are described in detail
in a separate table (refer to the UpToDate table on regimens for treatment of drug-susceptible tuberculosis) and in
the accompanying text.

IV: intravenous; GI: gastrointestinal; CNS: central nervous system; IM: intramuscular; FDA: US Food and Drug Administration.
* Dose may need to be adjusted for renal impairment. Dosing of oral medications for treatment of multidrug-resistant
tuberculosis (MDR-TB) or extensively drug-resistant tuberculosis (XDR-TB) should be daily, not intermittent.
¶ Greater efficacy has been observed with administration of 1000 mg (compared with 500 mg) for treatment of multidrug-
resistant tuberculosis. For treatment of contacts to MDR-TB: 500 mg/day if ≤45.5 kg and 750 mg/day if >45.5 kg.
◊ For patients who are overweight or obese, dose is based on ideal body weight or dosing weight (a calculator is available in
UpToDate). Adjust dose based on serum concentration monitoring for target trough <1 mcg/mL and target peak of 56 to 64
mcg/mL for once-daily administration.
§ Injectable agents (ie, aminoglycosides and capreomycin) are typically given 5 days per week; injectable agents should be
administered 7 days per week for patients who are severely ill. The initial duration of therapy is at least two to three months
(and until culture conversion is documented). After documentation of culture conversion, three-days-per-week dosing can be
used for the remaining duration of injectable use (normally through at least six months beyond culture conversion).
¥ For patients over 59 years of age, some favor administering a lower dose (10 mg/kg), with standard target drug levels.
‡ For patients with creatinine clearance between 50 and 70 mL/min, 12 to 15 mg/kg/dose IM or IV three times weekly may be a
reasonable dose. For patients with creatinine clearance between 30 and 50 mL/min, 12 mg/kg/dose IM or IV twice weekly may
be a reasonable dose.
† Administration of cycloserine, para-aminosalicylic acid, and ethionamide should be via dose escalation (drug ramping) over a
two-week period. The initial dose of cycloserine should 250 mg orally once daily for 3 to 4 days, followed by 250 mg orally twice
daily for 3 to 4 days, followed by 250 mg orally in the morning and 500 mg orally in the evening; the goal peak serum
cycloserine level is <35 mcg/mL. The initial dose of para-aminosalicylic acid is 2 g orally twice daily for 3 to 4 days, followed by 2
cycloserine level is <35 mcg/mL. The initial dose of para-aminosalicylic acid is 2 g orally twice daily for 3 to 4 days, followed by 2
g orally in the morning and 4 g orally in the evening for 3 to 4 days, followed by 4 g orally twice daily. The initial dose of
ethionamide is 250 mg orally daily for 3 to 4 days, followed by 250 mg orally twice daily for 3 to 4 days, followed by 250 mg
orally in the morning and 500 mg orally in the evening.
** Patients on regimens including high-dose isoniazid, ethionamide, cycloserine, or linezolid should receive oral pyridoxine (100
mg daily) for prevention of neurotoxicity.
¶¶ Ethionamide can be given at bedtime or with a main meal in an attempt to reduce nausea. Clinicians experienced with using
ethionamide suggest starting with 250 mg once daily and gradually increasing as tolerated. Serum concentrations may be useful
in determining the appropriate dose for a given patient. Few patients tolerate 500 mg twice daily.
ΔΔ Clinicians experienced with using cycloserine suggest starting with 250 mg once daily and gradually increasing as tolerated.
Serum concentrations often are useful in determining the appropriate dose for a given patient. Few patients tolerate 500 mg
twice daily.
◊◊ Clofazimine is not commercially available in the United States; its use requires application to the US Food and Drug
Administration, Division of Special Pathogen and Immunologic Drug Products (telephone 301-796-1600 ).
§§ Thioacetazone should not be administered to patients with HIV infection.

References:

1. Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-Resistant Tuberculosis: A
Survival Guide for Clinicians, Third Edition.
2. Nahid P, Dorman SE, Alipanah N, et al. Official American Thoracic Society/Centers for Disease Control and
Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible
Tuberculosis. Clin Infect Dis 2016 Aug 10 [Epub ahead of print].
3. Treatment Guidelines from The Medical Letter, April 2012; Vol. 10 (116):29. www.medicalletter.org.
4. Centers for Disease Control and Prevention. Treatment of Tuberculosis. American Thoracic Society, CDC, and Infectious
Diseases Society of America. MMWR Recomm Rep 2003; 52:3.

Graphic 66493 Version 13.0

Suggested regimens for treatment of poly-resistant tuberculosis

Minimum duration of
Pattern of drug resistance Suggested regimen
treatment
INH and EMB RIF, PZA, and fluoroquinolone 6 to 9 months*

INH and PZA RIF, EMB, and fluoroquinolone 9 to 12 months*

INH, EMB, PZA (+/– SM) RIF, fluoroquinolone, oral second-line 9 to 12 months
agent, plus an injectable agent for first
2 to 3 months ¶

RIF and EMB (+/– SM) INH, PZA, fluoroquinolone, plus an 12 to 18 months
injectable agent for first 2 to 3
months ¶

RIF and PZA (+/– SM) INH, EMB, fluoroquinolone, plus an 18 months
injectable agent for first 2 to 3
months ¶

The term "poly-resistant tuberculosis" refers to tuberculosis caused by an isolate of Mycobacterium tuberculosis that is
resistant to more than one antituberculous agent; the isolate may be resistant to either isoniazid or rifampin but not
both.

INH: isoniazid; EMB: ethambutol; PZA: pyrazinamide; SM: streptomycin; RIF: rifampin.
* A longer duration of therapy should be used for patients with extensive disease.
¶ A longer course of the injectable agent (6 months) may strengthen the regimen for patients with extensive disease.

Graphic 108731 Version 3.0

Conventional regimens for treatment of adults with drug-resistant tuberculosis

 Pattern of Minimum
drug Suggested regimen duration of Comments
resistance treatment
INH and RIF (± PZA, EMB, newer-generation 18 months In patients with extensive or cavitary
SM) fluoroquinolone (MFX or high-dose LFX), beyond culture disease, a longer duration for the
and injectable agent during the intensive conversion injectable agent may be considered, as
phase (for at least 6 months beyond well as an additional oral drug. Consider
culture conversion), and 1 additional oral using more than 1 additional oral drug if
agent (LZD, ETA, CS or PAS). there has been prior use of PZA or EMB.

INH, RIF (± EMB or PZA (if available), a newer- 18 months In patients with extensive or cavitary
SM), and EMB generation fluoroquinolone (MFX or high- beyond culture disease, a longer duration for the
or PZA dose LFX), injectable agent during the conversion injectable agent may be considered, as
intensive phase (for at least 6 months well as an additional oral drug.
beyond culture conversion), and 2
additional oral agents (LZD, ETA, CS, or
PAS).

INH, RIF, EMB, Injectable agent during the intensive 18 months In patients with extensive or cavitary
PZA (± SM) phase (for at least 6 months beyond beyond culture disease, a longer duration for the
culture conversion), and a newer- conversion injectable agent may be considered.
generation fluoroquinolone (MFX or high-
dose LFX), and 3 to 4 oral agents (LZD,
ETA, CS, PAS or additional second- or
third-line agents if needed).

INH, RIF, EMB, 4 to 5 second- or third-line drugs 24 months Duration of injectables should be at least
PZA, (include LZD, BDQ, or DLM) and an beyond culture 12 months if tolerated. Consider high-
fluoroquinolone injectable agent. conversion dose MFX. Consider surgery. TDM may
be useful.

INH, RIF, EMB, MFX (or high-dose LFX) plus at least 4 to 24 months Consider surgery. TDM may be useful.
PZA, injectables 5 second- or third-line oral drugs. beyond culture
Include LZD, BDQ, or DLM, if available. conversion
Include an injectable drug if there is 1
available to which the isolate is
susceptible.

INH, RIF, 5 to 6 second- and third-line agents. 24 months Consider high-dose INH treatment if low-
fluoroquinolone, LZD, BDQ, or DLM should be used; high- beyond culture level resistance is documented. Consider
injectable (XDR) dose MFX can be added (unless conversion surgery. TDM may be useful.
documented resistance). Use PZA and/or
EMB if remains susceptible. Include an
injectable drug if there is 1 available to
which the isolate is susceptible.

MDR: multidrug resistant; XDR: extensively drug resistant; TB: tuberculosis; INH: isoniazid; RIF: rifampin; SM: streptomycin;
PZA: pyrazinamide; EMB: ethambutol; MFX: moxifloxacin; LFX: levofloxacin; LZD: linezolid; ETA: ethionamide; CS: cycloserine;
PAS: para-aminosalicyclic acid; BDQ: bedaquiline; DLM: delamanid; TDM: therapeutic drug monitoring.

Modified with permission from: Curry International Tuberculosis Center and California Department of Public Health, 2016: Drug-
Resistant Tuberculosis: A Survival Guide for Clinicians, Third Edition, p. 260. Copyright © 2016 Curry International Tuberculosis
Center.

Graphic 113635 Version 1.0

Building a conventional regimen for treatment of adults with multidrug-resistant

tuberculosis
* Not available in the United States.
¶ Streptomycin: Use only if not previously used and if documented susceptibility.
Δ Awaiting approval by the US Food and Drug Administration.

Modified with permission from: Curry International Tuberculosis Center and California Department of Public Health, 2016:
Drug-Resistant Tuberculosis: A Survival Guide for Clinicians, Third Edition, p. 72. Copyright © 2016 Curry International
Tuberculosis Center.

Graphic 113634 Version 1.0

Common side effects shared by antiretrovirals and antituberculosis medications

 Antiretrovirals Antituberculosis medications
Hepatitis Nevirapine Isoniazid
Ritonavir-boosted protease Rifampin*
inhibitors Pyrazinamide

Gastrointestinal All antiretrovirals (less Fluoroquinolones

distress common with lamivudine and Ethionamide (associated with taste alteration)
emtricitabine)
Para-amniosalicylic acid

Nephrotoxicity Tenofovir (renal tubular Aminoglycosides (nephrotoxic TB agents carry particular risk of
disfunction) potentiating lactic acidosis common to the NRTIs used in antiretroviral
Idinavir-ritonavir rollout regimens)

Neuropsychiatric Efavirenz (insomnia, Cycloserine (headaches, tremor, seizure)

disorders drowsiness, vivid dreams) Terizidone (mainly headache and seizures)

Peripheral Stavudine Cycloserine

neuropathy Didanosine Streptomycin
Zidovudine Amnioglycosides
Isoniazid (overcome with pyridoxine administration)
Linezolid

Stavudine, didanosine, tenofovir, lamivudine, and emtricitabine are NRTIs. Nevirapine and efavirenz are NNRTIs.
Idinavir and ritonovir are protease inhibitors. Common global rollout antiretroviral regimens: (stavudine or zidovidine)
+ (lamivudine or emtricitabine) + (nevirapine or efavirenz) or (tenofovir or abacavir) + (lamivudine or emtricitabine)
+ (nevirapine or efavirenz).

MDR: multidrug resistant; NNRTIs: nonnuceloside reverse transcriptase inhibitors; NRTIs: nucleoside reverse transcriptase
inhibitors; TB: tuberculosis; XDR: extensively drug resistant.
* Rifampin induction of cytochrome P450 reduces serum levels of NNRTIs and protease inhibitors but is not therapeutically
relevant for MDR/XDR TB.

Modified with permission from: Shenoi S, Heysell SK, Moll AP, Friedland G. Multi-drug Resistant and Extensively Drug-Resistant
Tuberculosis: Consequences for the Global HIV Community. Curr Opin Infect Dis 2009; 22:11. Copyright © 2009 Lippincott
Williams & Wilkins.

Graphic 53563 Version 13.0

Contributor Disclosures
Neil W Schluger, MD Nothing to disclose Scott K Heysell, MD, MPH Nothing to disclose Gerald Friedland,
MD Nothing to disclose C Fordham von Reyn, MD Grant/Research/Clinical Trial Support: Oxford Immunotec
[Tuberculosis (vaccine)]. 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 a multi-level review process, and through requirements for references to be provided to support the
content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of
evidence.

Conflict of interest policy