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Treatment of drug-resistant pulmonary tuberculosis in adults

Treatment of drug-resistant pulmonary tuberculosis in adults
Authors:
Neil W Schluger, MD
Scott K Heysell, MD, MPH
Gerald Friedland, MD
Section Editor:
John Bernardo, MD
Deputy Editor:
Elinor L Baron, MD, DTMH
Literature review current through: Dec 2022. | This topic last updated: Dec 01, 2022.

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".)

Treatment 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 that includes patient-centered case management [1-5]. Favorable outcomes depend on rapid and accurate diagnosis together with administration of proper therapy with close monitoring to assure adherence to the treatment regimen and patient safety. (See "Diagnosis of pulmonary tuberculosis in adults".)

The treatment of drug-resistant TB is a rapidly evolving field of investigation. Precise treatment regimens should be informed by regional guidelines as well as drug availability, local disease burden, and local TB program resources.

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 individuals with human immunodeficiency virus (HIV). (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)

TERMINOLOGY — TB terminology is inconsistent in the literature [6]. Relevant terms are defined in the table (table 1).

DEFINITIONS

Types of drug-resistant TB — Definitions for drug-resistant TB are summarized in the table (table 2).

Drug categories — Definitions to describe the categories of antituberculous drugs include the following:

First-line drugs – First-line drugs include isoniazid, rifampin, pyrazinamide, and ethambutol; these drugs constitute the initial treatment regimen for drug-susceptible TB (table 3).

Second-line drugs – Second-line drugs are drugs used when resistance to first-line drugs is encountered (or suspected), or in cases of first-line drug intolerance or toxicity (table 4).

CLINICAL PRESENTATION — The clinical manifestations and radiographic features of drug-resistant TB are comparable with those of drug-susceptible TB. (See "Clinical manifestations and complications of pulmonary tuberculosis" and "Diagnosis of pulmonary tuberculosis in adults".)

The most important predictors of drug-resistant TB are [5,7]:

A previous episode of TB treatment

Persistent or progressive clinical and/or radiographic findings while on first-line 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 5) 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

When to pursue empiric treatment for drug-resistant TB – Design of an optimal treatment regimen strongly depends on understanding drug susceptibility of the patient's isolate; efforts should be directed at obtaining that information as quickly as possible.

The decision to treat empirically for drug-resistant TB (ie, a regimen including second-line drugs) pending conventional, culture-based drug susceptibility data depends on the severity of clinical illness (smear positivity, presence of cavitary disease, extrapulmonary disease) and the degree of suspicion for drug-resistant TB (given epidemiologic factors or rifampin resistance on Xpert MTB/RIF test).

Patients for whom an empiric treatment regimen for drug-resistant disease may be warranted include:

Patients with treatment failure (acid-fast bacilli sputum culture positive after four months of therapy, assuming drug sensitivity testing is not available)

Patients with relapse (recurrent TB after apparent cure)

Patients with exposure to an individual with infectious drug-resistant pulmonary TB

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

Timing – 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. In such cases, rapid molecular testing for drug susceptibility should be obtained, if available.

Regimen selection  

Clinical approach – Options for empiric treatment for drug-resistant disease include an expanded regimen (six or more drugs) or bedaquiline, pretomanid, and linezolid (BPaL). Some clinicians may choose to start with an expanded regimen, with de-escalation once susceptibility data are available. In settings where drug susceptibility patterns are well understood, empiric use of BPaL may also be a reasonable approach; this should be done with caution given increasing use of the agents in this regimen and associated risk for resistance. In addition, BPaL may be a useful alternative regimen for patients who are failing or intolerant of an expanded empiric regimen.

Available regimens – Regimens for empiric treatment include:

-Expanded regimen – 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 second-line drugs. These additional drugs might include a fluoroquinolone (levofloxacin or moxifloxacin), bedaquiline, an injectable agent, and/or another core second-line agent (table 6). 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. The regimen should be chosen in consultation with an individual who has expertise with treatment of drug-resistant TB and should be administered in a context of patient-centered case management with directly observed therapy. (See "Adherence to tuberculosis treatment".)

-BPaL – This regimen is discussed below. (See 'Bedaquiline, pretomanid, and linezolid' below.)

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

Regimen adjustment – The regimen should be adjusted accordingly once drug susceptibility results are available, as discussed in the following sections. Design of an optimal treatment regimen is strongly dependent on understanding drug susceptibility of the patient's isolate and efforts should be directed at obtaining that information as quickly as possible.

Nitrosamine impurities in rifampin − In August 2020, the US Food and Drug Administration announced detection of nitrosamine impurities in samples of rifampin [8]. Some such compounds have been implicated as possible carcinogens in long-term animal studies, with toxicity largely related to cumulative exposure. For treatment of TB disease, we favor continued use of rifampin if acceptable to the patient, as the risk of not taking rifampin likely outweighs any potential risk from nitrosamine impurities.

TREATMENT OF MONORESISTANT TB — The clinical approach to treatment of monoresistant TB varies depending on the agent to which the isolate is resistant. In general, the approach to selection of antituberculous therapy is similar for people with and without HIV, although many favor extending the duration of therapy for patients with HIV 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 [5,9]:

Option 1 – Daily rifampin, ethambutol, pyrazinamide, and levofloxacin for six months (or four months after culture conversion) [1,9-11]. In patients with HIV, it is reasonable to prolong therapy for an additional three months [12-14]. We are in agreement with the American Thoracic Society 2019 guidelines, which indicate the duration of pyrazinamide may be shortened to two months in select circumstances (noncavitary disease, relatively low burden of disease, pyrazinamide toxicity) [1].

This approach is supported by a meta-analysis including more than 3900 patients with INH-resistant TB in 23 studies, adding a fluoroquinolone to the treatment regimen was associated with greater treatment success (adjusted odds ratio 2.8, 95% CI 1.1-7.3), but there was no effect on mortality or acquired rifampin resistance. Among those who received a shortened duration of pyrazinamide (one to three months) the treatment success rate was 99 percent [15].

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 [16].

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, INH, rifampin, pyrazinamide, and ethambutol), followed by continuation phase consisting of INH and rifampin with addition of ethambutol (rather than INH and rifampin alone) [17,18]. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection".)

Effective therapy for INH-monoresistant TB is associated with very high bacteriologic and clinical response rates (>95 percent) and low relapse rates (<5 percent) [14,19]. As an example, even regimens for INH-monoresistant TB excluding a fluoroquinolone and delivered in low-TB burden settings for longer durations may be comparable with the regimens outlined above [20].

Monoresistance to other agents

Rifampin – Patients with rifampin monoresistance should be treated as for multidrug-resistant TB (MDR-TB), in accordance with World Health Organization guidelines [2-4]. Rifampin resistance is considered a surrogate for MDR-TB because rifampin monoresistance is rare [21,22]. (See 'Treatment of MDR-TB or XDR-TB' below.)

Pyrazinamide – Patients with pyrazinamide monoresistance should be treated with INH and rifampin for nine months. This combination has a success rate >96 percent in large trials [23-25]. Many isolates with pyrazinamide monoresistance reflect Mycobacterium 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: INH, rifampin, pyrazinamide, and ethambutol [if not resistant] for two months; followed by continuation phase: INH and rifampin for four months). (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection".)

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

For treatment purposes, the distinction of polyresistant TB refers to INH resistance plus resistance to another first-line agent besides rifampin. Rifampin-resistant TB (considered a surrogate for multidrug-resistant TB [MDR-TB]) is treated as MDR-TB. (See 'Treatment of MDR-TB or XDR-TB' below.)

Treatment of polyresistant TB depends on the pattern of drug resistance; in general, the treatment regimen should include as many first-line agents as possible, plus a fluoroquinolone and/or another core second-line drug [26]:

Patients with TB resistant to INH and ethambutol should be treated with rifampin, pyrazinamide, and a fluoroquinolone (levofloxacin or moxifloxacin) for six to nine months.

Patients with TB resistant to INH and pyrazinamide should be treated with rifampin, ethambutol, and a fluoroquinolone (levofloxacin or moxifloxacin) for 9 to 12 months.

Patients with TB resistant to INH, ethambutol, and pyrazinamide should be treated with rifampin, a fluoroquinolone, and one or two additional oral agents to which the isolate is susceptible (possible additional agents include ethambutol, linezolid, or clofazimine; use of bedaquiline with a rifamycin is contraindicated) for 9 to 12 months.

For all polyresistant TB, treatment duration should be individualized to the rapidity of culture conversion to negative and consideration given to a longer duration for patients with extensive disease.

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

TREATMENT OF MDR-TB OR XDR-TB — Definitions for "multidrug-resistant TB (MDR-TB)" and "extensively drug-resistant TB (XDR-TB)" are summarized in the table (table 2).

The treatment approach discussed below is warranted for patients with rifampin-monoresistant TB, MDR-TB, or XDR-TB. Regimens should be chosen in consultation with an individual who has expertise with treatment of MDR-TB and in collaboration with a public health TB treatment program that can provide the infrastructure for safe completion of treatment.

In addition, consideration of surgery is warranted under specific circumstances. (See 'Role of surgery' below.)

General principles

Clinical considerations – Design of the treatment regimen should be guided by a number of factors, including [5]:

Drug susceptibility test results.

Cross-resistance (which occurs among fluoroquinolones, among injectable agents, between isoniazid [INH] 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.

Availability and cost of drugs and drug monitoring.

Experience and results with current drug regimens for MDR.

Availability of case management, including directly observed therapy (DOT), to ensure that drugs are taken appropriately and adverse events can be identified as they develop.

Guidelines – Treatment guidelines include those issued by the World Health Organization (WHO) and by the American Thoracic Society (ATS), United States Centers for Disease Control and Prevention (CDC), European Respiratory Society (ERS), and Infectious Disease Society of America (IDSA):

The WHO issued a Rapid Communication in May 2022 reflecting priority for use of abbreviated bedaquiline-containing all-oral regimens in most patients with rifampin-resistant TB, MDR-TB, and pre-XDR-TB in regions where these drugs are available [27].

This follows the WHO 2020 guidelines for treatment of rifampin-resistant and MDR-TB that prioritized use of all-oral regimens of shorter duration (9 to 12 months) in select patients [2-4]. In addition, the 2020 guidelines continued to include guidance for use of a longer, individualized regimen (up to 20 months) comprised entirely of oral agents for patients with more extensive disease, complex resistance patterns, or intolerance to drugs in shorter course regimens.

The ATS/CDC/ERS/IDSA issued guidelines for treatment of drug-resistant TB in November 2019 [1]. These guidelines prioritize use of an all-oral regimen and make no recommendation for or against use of a short-course regimen.

Some differences between these guidelines are described below. (See 'Longer, individualized regimen' below.)

Tailoring treatment to susceptibility data – Treatment regimens should be tailored when drug susceptibility data are available. If full drug susceptibility is documented, the patient does not have drug-resistant TB; in such cases, the additional drugs may be discontinued and treatment may be completed with a standard regimen. If MDR-TB or XDR-TB is documented, drugs to which the isolate is resistant should be discontinued, and new drugs should be added such that at least five drugs active against the isolate are included in the regimen. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults without HIV infection" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)

Patients currently receiving an appropriate regimen who are doing well should continue that regimen unless the patient or provider has substantive objections to continued use, or the patient has experienced injectable agent related toxicity. In some settings, the feasibility of transitioning to a newer regimen may be limited by side effects, monitoring issues, drug availability, and cost.

Patient-centered case management – Management should be supervised by clinicians with expertise and experience in administering complicated antituberculous regimens using patient-centered case management, in conjunction with appropriate laboratory facilities to document drug susceptibility and to monitor patient safety and response to therapy [28]. Discussion with the local or state health department and/or National Jewish Hospital may be useful [29].  

All patients with drug-resistant TB should be assigned to a clinical case manager (usually a nurse with specialty training in TB case management), who oversees the medical and social aspects of care and provides supervised treatment (DOT) [30,31]. (See "Adherence to tuberculosis treatment".)

Drug susceptibility testing — Access to drug-susceptibility testing for all drugs in the treatment regimen is an important component of TB management [32]. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Microbiologic testing'.)

Patients who are candidates for treatment with a bedaquiline-containing regimen may have options further tailored by use of the MTBDRsl assay (not generally available in the United States); 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 [33]. 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 [34].

Regimen selection

Clinical approach — Options for treatment of MDR-TB or XDR-TB include an abbreviated regimen (6 to 12 months) or a longer individualized regimen (all-oral regimen for at least 18 months) [1-4]. In most cases, an abbreviated regimen is preferred if the drugs are available. Indications for which there is insufficient evidence for use of an abbreviated regimen are summarized below; in such cases, treatment with a longer individualized regimen is warranted.

Abbreviated regimens – In general, an abbreviated regimen (6 to 9 months) may be used for treatment of nonpregnant adults with uncomplicated pulmonary MDR-TB or XDR-TB, if susceptibility testing permits (see 'Drug susceptibility testing' above), in the absence of an indication for treatment with a longer regimen (as outlined below).

Options include:

BPaL – The bedaquiline, pretomanid, and linezolid (BPaL) regimen (administered orally for 6 months) may be used for treatment of MDR-TB, fluoroquinolone-resistant MDR-TB, XDR-TB, or patients with other drug contraindications [2]. This regimen is emerging as a preferred regimen in several United States TB programs, even in the absence of fluoroquinolone resistance.

Patients treated with BPaL who fail to respond should be managed with expert consultation. While addition of moxifloxacin to the BPaL regimen (BPaLM) has also been endorsed by the WHO [27], we await publication of clinical data for this regimen.

Additional details including administration logistics and supporting evidence are discussed below. (See 'Bedaquiline, pretomanid, and linezolid' below.)

Other bedaquiline-containing regimens – An all-oral regimen containing bedaquiline and other antituberculous drugs may be used if BPaL is not feasible (eg, pretomanid and/or linezolid cannot be used due to resistance or resource constraints).

Additional details including administration logistics and supporting evidence are discussed below. (See 'Other bedaquiline-based regimens' below.)

Delamanid, linezolid, levofloxacin, and pyrazinamide – If a bedaquiline-based abbreviated regimen is not feasible, a 9-month regimen of delamanid, linezolid, levofloxacin, and pyrazinamide is an acceptable alternative [35]. (See 'Delamanid, linezolid, levofloxacin, and pyrazinamide' below.)

Indications for use of a longer, individualized regimen − Indications for use of a longer, individualized regimen include [1,2,4,36]:

Disseminated, meningeal, or central nervous system disease.

In patients with advanced HIV infection (CD4 <50 cells/microL) and extrapulmonary disease, some experts would use a longer, individualized regimen; patients with advanced HIV infection and no extrapulmonary disease may be treated with BPaL. (See 'Bedaquiline, pretomanid, and linezolid' below and 'Patients with HIV infection' below.)

Pregnancy. (See 'Pregnant patients' below.)

Extensive (or advanced) TB disease, such as bilateral cavitary disease or extensive parenchymal damage on chest radiography.

Contraindication to one or more drugs in the shorter course regimens; these include:

-Prior exposure to one or more agents in the regimen for more than one month (unless susceptibility to these drugs is confirmed).

-Confirmed resistance or suspected ineffectiveness to a drug in the regimen (except INH resistance).

-Intolerance to a drug in the regimen or risk of toxicity due to drug-drug interactions.

-One or more drugs in the regimen are unavailable.

Additional details including administration logistics and supporting evidence are discussed below. (See 'Longer, individualized regimen' below.)

Abbreviated regimens — Abbreviated bedaquiline-containing regimens include BPaL (a 6-month, all-oral regimen of bedaquiline, pretomanid, and linezolid), BPaLM (a 6-month, all-oral regimen of BPaL plus moxifloxacin), or an alternative bedaquiline-containing all-oral regimen.

While addition of moxifloxacin to the BPaL regimen (BPaLM) has been endorsed by the WHO [27], we await publication of clinical data for this regimen.

Bedaquiline, pretomanid, and linezolid — Considerations for selection of BPaL are described above. (See 'Empiric treatment' above and 'Regimen selection' above.)

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

Drug dosing − Drug dosing is summarized in the table (table 4).

Linezolid − The optimal linezolid dosing is uncertain; we favor 600 mg daily, given similar efficacy and lower rate of adverse events with this regimen (as observed in the ZeNix study), relative to 1200 mg daily (as used in the Nix-TB study) [37,38]:

-In the Nix-TB study, a prospective study including 109 patients in South Africa with XDR-TB or MDR-TB, linezolid dosing consisted of 1200 mg daily for up to 26 weeks (with dose adjustment depending on adverse effects; peripheral neuropathy and myelosuppression were observed in 81 and 48 percent of patients, respectively) [37].

-In the subsequent ZeNix study, a trial including 181 participants with highly resistant TB, patients were treated with bedaquiline, pretomanid, and linezolid, with random assignment to receive variable linezolid dosing (1200 mg for 6 months, 1200 mg for 2 months, 600 mg for 6 months, or 600 mg for 2 months) [38]. High rates of treatment success were observed in all arms (93, 89, 91, and 84 percent, respectively). Peripheral neuropathy occurred in 38, 24, 24, and 13 percent, respectively; myelosuppression occurred in 22, 15, 2, and 7 percent, respectively. The linezolid dose was modified (interrupted, reduced, or discontinued) in 51, 30, 13, and 13 percent, respectively. In this small study, the risk-benefit ratio favored the group that received a linezolid at a dose of 600 mg daily for 26 weeks, with a lower incidence of adverse events reported and fewer linezolid dose modifications.

Bedaquiline − There is no consensus on bedaquiline dosing; many early implementers of BPaL use the dose administered in the Nix-TB study (400 mg once daily for two weeks followed by 200 mg three times a week for 24 weeks) [37].

Supporting evidence − Use of BPaL regimen is supported by the following studies:

The Nix-TB study included 109 patients in South Africa with XDR-TB or MDR-TB (treatment intolerant or nonresponsive) treated with bedaquiline (400 mg once daily for two weeks followed by 200 mg three times a week for 24 weeks), pretomanid (200 mg daily for 26 weeks), and linezolid (1200 mg once daily for up to 26 weeks) [37]. At six months follow-up, successful treatment (defined as a culture-negative survival six months after the end of treatment) was achieved in 90 percent of patients. Approximately half of patients were HIV infected (patients with CD4 counts <50 cells/microL were excluded); results were similar for patients with and without HIV. Adverse events included peripheral neuropathy (81 percent) and myelosuppression (48 percent); these were managed with linezolid dose reductions or treatment interruptions.

The ZeNix study, using alternative linezolid regimens, is described in the preceding section [38].  

The TB-PRACTECAL study evaluated a six-month regimen of BPaLM in a randomized trial including patients ≥15 years with rifampicin-resistant pulmonary TB in Uzbekistan, South Africa, and Belarus [39]. The trial was stopped early for efficacy; publication of data collected up to the end of recruitment is forthcoming.

Patients treated with BPaL who fail to respond should be managed with expert consultation.

Other bedaquiline-based regimens — Considerations for selection of an all-oral, bedaquiline-containing regimen are discussed above. (See 'Regimen selection' above.)

9- to 12-month regimen

Regimen administration – The regimen consists of the following components [2,4]:

-Intensive phase – Four months (daily) of seven drugs: bedaquiline, high-dose INH (15 to 20 mg/kg/day), ethambutol, pyrazinamide, moxifloxacin or levofloxacin, prothionamide or ethionamide, and clofazimine. In the 2020 WHO guideline update, use of bedaquiline is recommended in place of an injectable agent [2].

The duration of the intensive phase is extended to six months for patients with positive sputum acid-fast bacilli (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 case management/directly observed therapy, follow-up sputum examination, and tailoring treatment regimens are discussed above. (See 'General principles' above.)

Patients who do not respond to the regimen or develop intolerance to a component drug should be treated with the longer regimen. (See 'Longer, individualized regimen' below.)

Supporting evidence – Use of an all-oral, bedaquiline-containing regimen of 9 to 12 months for treatment of MDR-TB is supported by a 2019 randomized trial (the STREAM stage 1 trial) including more than 380 patients with rifampin-resistant pulmonary TB disease (susceptible to fluoroquinolones and aminoglycosides) treated with a short regimen (high-dose moxifloxacin, clofazimine, ethambutol, and pyrazinamide administered for 40 weeks, together with kanamycin, prothionamide, and high-dose INH during the first 16 weeks) or a long regimen (total treatment duration of 20 months, including an eight-month intensive phase with use of injectable drugs, in accordance with 2011 WHO guidelines [40] (which were standard of care at the time the trial was begun) [41]. Approximately one-third of patients had HIV infection. The short regimen was noninferior to the long regimen; favorable status (negative cultures at 132 weeks and at a previous occasion, with no intervening positive culture) was observed in 78.8 versus 79.8 of participants, respectively, and safety outcomes were comparable between the groups.

In the 2020 WHO guideline update, use of bedaquiline is recommended in place of an injectable agent [2]. This approach is supported by data from South Africa’s Electronic Drug-Resistant Tuberculosis Registry (including more than 890 patients treated with an abbreviated bedaquiline-containing regimen and more than 980 treated with a regimen containing an injectable agent); among patients with MDR/RR-TB, higher treatment success rates were observed among those treated with an abbreviated bedaquiline-containing regimen than those treated with a regimen containing an injectable agent (73 versus 60 percent) [2,42].

In 2022, a randomized trial (the STREAM stage 2 trial) including more than 500 patients with rifampin-resistant pulmonary TB disease ≥15 years of age in 7 countries (Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda) noted superior efficacy of a 9-month bedaquiline and fluoroquinolone-based oral regimen over a 9-month injectable-containing regimen (favorable outcome 83 versus 71 percent at 76 weeks; adjusted risk difference 11 percent, 95% CI 3-19) [43]. Ototoxicity occurred less frequently among patients treated with the oral regimen (2 versus 9 percent); the frequency of grade 3 to 4 adverse events was similar in both groups (53 versus 50 percent). In addition, superior efficacy of a 6-month regimen including bedaquiline and 8 weeks of an injectable agent over the 9-month injectable-containing regimen was also observed (91 versus 69 percent; adjusted difference 22 percent, 95% CI 13-31).

6-month regimen – A six-month all-oral regimen (including levofloxacin, bedaquiline, and linezolid) was evaluated in a randomized trial including 93 patients in South Africa with MDR-TB (of whom 55 percent had HIV infection) who were randomly assigned to treatment with either a six-month all-oral regimen (including levofloxacin, bedaquiline, and linezolid) or a longer, >9-month injectable-based regimen [44]. Those in the intervention arm were 2.2 times more likely to experience a favorable 24-month outcome (>12-month relapse-free cure or treatment success) than those in the standard-of-care arm (51 versus 23 percent; relative risk 2.2 [95% CI 1.2-4.1]). Grade 3 adverse events occurred frequently in both arms but were more common in the intervention group (55 versus 32 percent); adverse events included anemia due to linezolid and hearing loss due to kanamycin.

Delamanid, linezolid, levofloxacin, and pyrazinamide — A nine-month all-oral regimen of delamanid, linezolid, levofloxacin, and pyrazinamide was evaluated in a randomized trial (MDR-END) including 168 adults in South Korea with MDR-TB (resistant to isoniazid and rifampin but not to fluoroquinolones) who were randomly assigned to treatment with the study regimen or a >20-month injectable based-regimen [35]. Rates of treatment success at 24 months were similar between the study and control groups (75.0 versus 70.6 percent), and the study met its predefined noninferiority margin of less than 10 percent; the between-group difference was 4.4 percent (97.5% one-sided CI –9.5 percent to ∞). Serious adverse events occurred more frequently among patients with delamanid or linezolid exposure (24.8 versus 17.1 percent). Study limitations included exclusion of children and patients with HIV infection. Thus far, there are no data directly comparing this regimen with a bedaquiline-containing regimen.

Longer, individualized regimen — Indications for use of a longer, individualized regimen are discussed above. (See 'Regimen selection' above.)

WHO versus ATS/CDC/ERS/IDSA – The longer, individualized regimen consists of an intensive phase followed by a continuation phase. Guidelines issued by the WHO and the ATS/CDC/ERS/IDSA differ with regard to the following [1-4]:

Intensive phase  

-Number of drugs – The ATS/CDC/ERS/IDSA favors at least five drugs; the WHO favors at least four drugs.

-Duration – The ATS/CDC/ERS/IDSA favors five to seven months following sputum culture conversion; the WHO favors at least six months.

Continuation phase

-Number of drugs – The ATS/CDC/ERS/IDSA favors four drugs; the WHO favors three drugs.

Total duration of therapy – The ATS/CDC/ERS/IDSA favors 15 to 21 months beyond culture conversion; the WHO favors 15 to 17 months beyond culture conversion.

We favor the approach recommended by the ATS/CDC/ERS/IDSA, given uncertainty regarding the likely efficacy of second-line drugs and the variability in clinical response to therapy [45-47].

Regimen administration – A longer regimen consists of the following [1-4]:

Intensive phase – Administration of at least five drugs (if possible), given for five to seven months following sputum culture conversion (performed after two months of treatment). The regimen should be created as outlined in the table (table 6) to include use of a fluoroquinolone (levofloxacin or moxifloxacin), bedaquiline, linezolid, clofazimine, and cycloserine, unless there are contraindications such as toxicity or lack of efficacy.

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 above approach is in alignment with that of the 2019 ATS/CDC/ERS/IDSA guidelines; the 2019-2020 WHO guidelines differ in that they favor use of at least four drugs [1-4]. Both guidelines prioritize use of bedaquiline and linezolid, and both favor use of oral agents over injectable agents.

If an all-oral regimen cannot be assembled, an injectable agent (amikacin or streptomycin) may be used. In such cases, an intensive phase of six to seven months is suggested for most patients; the duration may be modified according to the patient’s response to therapy [10]. (See "Antituberculous drugs: An overview", section on 'Second-line agents'.)

The injectable agent capreomycin may retain susceptibility against some strains that are resistant to amikacin and kanamycin; however, this agent is no longer recommended given association with treatment failure in individual patient data meta-analysis [15].

Clofazimine is not commercially available in the United States. In order to obtain the drug, clinicians should contact the US Food and Drug Administration (301-796-0797) to apply for a single-patient Investigational New Drug.

Continuation phase – Administration of the drugs used during the intensive phase (excluding bedaquiline or injectable agent), given for 15 to 24 months beyond sputum culture conversion [1]. Patients with extensive disease or cavitary disease may warrant a longer duration 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 cannot be confirmed.

Patients with HIV infection treated with an individualized regimen, antituberculous treatment should be administered for at least 18 months; after the cessation of therapy, they should be monitored every four months for an additional 24 months to evaluate for evidence of relapse.

The above approach to drug selection in the intensive phase is supported by a retrospective review of treatment of MDR and XDR-TB in South Africa; use of bedaquiline was associated with a reduction in the risk of all-cause mortality for patients with rifampicin-resistant or MDR-TB (hazard ratio [HR] 0·35, 95% CI 0.28-0.46) and XDR-TB (HR 0·26, 95% CI 0.18-0.38) compared with standard regimens [48]. (See "Antituberculous drugs: An overview", section on 'Second-line agents'.)

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, social support, follow-up sputum examination, and tailoring treatment regimens are discussed above. (See 'General principles' above.)

Supporting evidence – The prioritization of oral agents is supported in large part from findings of a meta-analysis including more than 12,000 adults with MDR-TB in 50 incongruent studies followed by the EndTB observational study a total of 1094 patients from 13 countries [15,49,50] and the more widespread rollout of bedaquiline-containing regimens in South Africa. According to the meta-analysis, treatment completion or cure was observed in 61 percent of cases and was positively associated with use of linezolid, levofloxacin, carbapenems, moxifloxacin, bedaquiline, and clofazimine [15]. Associations were observed between reduced mortality and use of linezolid (adjusted risk difference -0.20, 95% CI -0.23 to -0.16), levofloxacin (-0.06, 95% CI -0.09 to -0.04), moxifloxacin (-0.07, 95% CI -0.10 to -0.04), or bedaquiline (-0.14, 95% CI -0.19 to -0.10).

Monitoring

General approach — High-quality, patient-centered clinical case management, usually involving public health nurses and/or community health workers, is critical for successful TB treatment.

Patient education – Patient education regarding medications, details of administration, and 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 also instructed to report 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'.)

Cardiac monitoring – Several antituberculous drugs may be associated with significant cardiac toxicity; bedaquiline, clofazimine, delamanid, and fluoroquinolones (especially moxifloxacin) have been associated with QTc prolongation. For patients on one or more of these drugs, baseline electrolytes (including potassium, calcium, and magnesium) should be checked and corrected if abnormal. In addition, electrocardiograms should be obtained at baseline, two weeks, and monthly thereafter. If QTc >500 ms, the suspected drug(s) should be stopped, electrolytes should be checked and corrected if needed, and electrocardiograms should be monitored until normalized; these interventions are particularly important in patients with underlying cardiac considerations and/or on other drugs associated with QTc prolongation.

Sputum monitoring – Repeat sputum should be obtained for AFB microscopy and culture two months after initiation of therapy [5,10,36,51]. If culture 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 [12]. 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.

A positive sputum culture ≥3 months after initiation of treatment should prompt a search for an explanation (eg, nonadherence to treatment, inappropriate/incorrect medications, malabsorption or suboptimal pharmacokinetics, or emergence of secondary drug resistance). [1]. (See "Diagnosis of pulmonary tuberculosis in adults", section on 'Drug susceptibility testing'.)

Medication adherence – It is critical that challenges with medication adherence are identified and addressed so that patients are able take medications as directed. Sputum and clinical progress should be monitored at least monthly, in order to minimize the risk of treatment failure and emerging drug resistance, as treatment challenges continue for many patients through the entire course of therapy [52].

For patients in whom a change in therapy may be indicated (because of medication intolerance or persistently positive sputum cultures), considerations include use of novel drugs and/or an individualized regimen. (See 'Regimen selection' above.)

Chest radiography – 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.

Social support – Patients should be supported through treatment including social support, transportation, food, attention to alcohol and other substance use, and safe housing with attention to infection control measures. (See "Adherence to tuberculosis treatment" and "Tuberculosis transmission and control in health care settings".)

Detecting emergence of resistance — For patients with MDR-TB treated with a longer, individualized regimen including at least five drugs (table 6) who demonstrate continued culture positivity, it may be useful to pursue phenotypic (culture-based) drug susceptibility testing and molecular drug susceptibility testing of all administered drugs at least every two months [53].

Such an approach may be warranted because several studies have documented increased minimum inhibitory concentrations to bedaquiline, associated with cross-resistance to clofazimine, during treatment [53,54]. In one study including 200 sputum isolates from 124 patients with pulmonary MDR-TB, resistance to bedaquiline and clofazimine (by culture-based testing) was observed in 5.6 percent of cases [53]. In four cases, selection for drug-resistant isolates was observed despite optimized treatment regimens based on phenotypic drug susceptibility patterns and whole genome sequencing results. In three patients, the first available isolates were resistant to both bedaquiline and clofazimine on initial cultures.

Role of surgery — In general, surgery for treatment of pulmonary MDR-TB or XDR-TB is most beneficial for patients with poor clinical response or intolerance to supervised medical therapy who have pulmonary disease that is amenable to resection (for example, lobectomy or wedge resection) as well as adequate pulmonary reserve to tolerate resection [1,55].

Consideration of surgery for management of MDR-TB and XDR-TB is warranted in the following circumstances [5,55-64]:

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

XDR-TB 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 TB. 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.

The above approach is supported by a meta-analysis of 26 studies including more than 6000 patients with MDR-TB [55]. Partial lung resection surgery was associated with improved treatment success (defined as no treatment failure and no relapse; adjusted odds ratio [aOR] 3.0, 95% CI 1.5-5.9) but pneumonectomy was not (aOR 1.1, 95% CI 0.6-2.3). Treatment success was more likely when surgery was performed after culture conversion than before (aOR 2.6, 95% CI 0.9-7.1).

Approach to treatment failure

Definition and clinical considerations – 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, at least in part, the relatively weak potency of second-line antituberculous drugs.

Developing a new treatment regimen – A new treatment regimen should be developed based on drug susceptibility testing results, together with careful review of previous medications and adherence [12]. Any agent previously taken for more than one month is likely to have decreased efficacy. Patients with treatment failure should receive highest priority for intensive case management and 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.

Drug level monitoring – 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 [65,66]. 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) [67,68]. (See "Antituberculous drugs: An overview", section on 'Serum drug concentration monitoring'.)

Special populations

Pregnant patients

Clinical approach – The optimal approach to treatment of pregnant patients with MDR-TB is uncertain. In general, the approach to selection of antituberculous agents is similar to the longer, individualized regimen MDR-TB regimen for nonpregnant adults. Data are insufficient for use of the bedaquiline-containing regimens in pregnancy. (See 'Regimen selection' above.)

Role of pyrazinamide – 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 is presumed to outweigh risk [51].

Agents to avoid in pregnancy – Antituberculous agents that are not considered safe in pregnancy include injectable agents, fluoroquinolones, 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 [69]. Fluoroquinolones should be avoided in pregnancy [70].

Outcomes – In a 2022 systematic review and meta-analysis of 10 studies including 275 pregnant patients with MDR-TB, the pooled proportions of treatment success and favorable pregnancy outcomes were 73 percent [71]. Adverse events (including impairment in liver and/or kidney function, hearing loss, and hypokalemia) occurred in more than half of the patients.

Issues related to treatment of TB in pregnancy are discussed further separately. (See "Tuberculosis disease (active tuberculosis) in pregnancy".)

Children — Management of children with MDR-TB is discussed further separately. (See "Tuberculosis disease in children".)

Outcomes

MDR-TB – Treatment success rates for MDR-TB range from 30 percent (historically) to approximately 80 percent in contemporary trials and settings with adequate programmatic support; factors associated with treatment success in previous studies include [72-80]:

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 sex

Alcohol abuse

Poor adherence

Lack of weight gain

Smear positivity at diagnosis

Fluoroquinolone resistance

Late appearance for care

Advanced HIV coinfection (See 'Patients with HIV infection' below.)

XDR-TB – Prior to trial data demonstrating efficacy of the BPaL regimen (see 'Bedaquiline, pretomanid, and linezolid' above), the overall prognosis for adults with XDR-TB has been poor with high mortality; delays in diagnosis, malnutrition, and level of immunosuppression contribute to an increased risk of death [81,82].

Among patients without HIV infection, survival rates for XDR-TB range from 48 to 60 percent in cohorts from South Korea, Russia, and Peru [56,83,84].

Most studies suggest that advanced HIV status correlates with poorer outcomes, which are improved with antiretroviral therapy (ART):

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 patients with HIV [85]. However, most of these occurred before the availability of potent ART.

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 [86]. 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 ART was protective [87]. In another study, advanced disease, multiorgan dysfunction and absence of ART were associated with mortality [81].

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 patient with HIV and patients without HIV (41 percent versus 30 percent); ART use (mostly zidovudine, lamivudine, and efavirenz) was protective [82].

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 ART was an independent predictor of survival [88].

PATIENTS WITH HIV INFECTION — General issues related to treatment of TB in patients with HIV are discussed separately. Treatment regimens for TB and HIV should be integrated; management in conjunction with an HIV expert is essential to ensure proper antiretroviral adherence and monitoring. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)

Antituberculous therapy — The approach to selection of antituberculous drugs for patients with HIV and monoresistant or polyresistant TB is as described above. (See 'Treatment of monoresistant TB' above and 'Treatment of polyresistant TB' above.)

The approach to selection of antituberculous drugs for patients with HIV and multidrug-resistant TB (MDR-TB) or extensively drug-resistant TB (XDR-TB) is as described above for patients without HIV infection [89]. (See 'Treatment of MDR-TB or XDR-TB' above.)

Abbreviated bedaquiline-containing regimen – The World Health Organization (WHO) 2020 guidelines support the use of a an abbreviated bedaquiline-containing regimen in patients with HIV infection [4]; however, further study of this approach in this population is needed.

In a randomized trial including more than 400 patients with MDR-TB in Africa and Asia treated with a shortened or conventional regimen (the STREAM stage 1 trial), the composite outcome of treatment success did not differ among people with HIV who received the conventional or the shortened regimen; however, mortality was higher in the subgroup treated with the shortened regimen (17.5 versus 8 percent) [41,90].

In a randomized trial (the STREAM stage 2 trial) including more than 500 patients with rifampin-resistant pulmonary TB disease ≥15 years of age, 73 patients had HIV infection (mostly from South Africa and Uganda). Within this group, favorable outcomes were observed more frequently among patients treated with a 9-month bedaquiline- and fluoroquinolone-based oral regimen than among patients treated with a 9-month injectable-containing regimen (96 versus 36 percent) [43].

Individualized regimen – For patients treated with an individualized regimen, antituberculous treatment should be administered for at least 18 months; after the cessation of therapy, patients should be monitored every four months for an additional 24 months to evaluate for evidence of relapse. (See 'Treatment of MDR-TB or XDR-TB' above.)

Antiretroviral therapy

Timing — For patients with HIV 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 critically important management issues; failure to initiate and administer ART in patients with drug-resistant TB has been associated with higher mortality rates [82,91]. In a substudy of the SAPiT trial, mortality associated with ART delay was reduced from 56 to 11 per 100 person-years when ART was introduced early [91]. Issues related to timing of ART are discussed separately. (See "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)

Regimen selection — The integrase strand transfer inhibitor class of antiretrovirals may be most compatible with second-line antituberculous drugs. For patients with HIV initiating ART and TB treatment with second-line agents (eg, excluding rifampin), the preferred regimen is dolutegravir in combination with a nucleoside reverse-transcriptase inhibitor backbone. Compared with efavirenz, dolutegravir has been associated with lower potential for drug-drug interactions, more rapid viral suppression, and a higher genetic barrier to developing HIV drug resistance. In addition, dolutegravir, as opposed to efavirenz, putatively does not interact with bedaquiline. Dolutegravir is formulated as a single-tablet fixed-dose combination (tenofovir-lamivudine-dolutegravir), which may facilitate adherence. (See "Selecting antiretroviral regimens for treatment-naive persons with HIV-1: Patients with comorbid conditions" and "Treatment of drug-susceptible pulmonary tuberculosis in nonpregnant adults with HIV infection: Initiation of therapy".)

Given the benefits of ART along with the complexities of coadministration of medications for drug-resistant TB, patients with HIV should be managed in partnership with providers with expertise in HIV.

Studies are needed to clarify the pharmacokinetic and pharmacodynamic interactions between antiretroviral agents and second-line agents for drug-resistant TB [92]. Notable toxicities and potential drug interactions include (table 7):

Bedaquiline:

Decreased bedaquiline serum exposure with efavirenz; this interaction prompted the WHO to recommend substitution of efavirenz with nevirapine, which has less effect on bedaquiline levels; however, twice-daily dosing of nevirapine is required [93-95].

Bedaquiline should be used with caution if coadministered with boosted protease inhibitors, as bedaquiline concentrations may be increased (leading to exposure-related toxicities) [96].

Bedaquiline is compatible with the integrase strand inhibitor class of antiretrovirals; availability of once daily dolutegravir has facilitated coadministration of bedaquiline.

Neuropsychiatric effects associated with cycloserine and efavirenz use.

Concomitant administration of pretomanid with CYP3A4 inducers such as efavirenz have resulted in decreased plasma concentrations of pretomanid.

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) [97].

Nephrotoxicity associated with tenofovir and aminoglycosides.

Outcomes — Early initiation of ART in patients with HIV with drug-susceptible TB (especially those with low CD4+ T cell counts) is strongly supported by randomized trials [91,98-102]. Accumulating evidence suggests lower mortality among patients with HIV with MDR-TB who are treated for both conditions concurrently [91]. Further, a report from a cohort in rural South Africa suggested that the mortality benefits can extend to patients with HIV with MDR-TB in an integrated decentralized programmatic setting [103].

Among adults with MDR-TB, coinfection with HIV is associated with increased mortality; use of ART has been shown to mitigate this risk. In a meta-analysis including more than 11,000 adults with MDR-TB from 52 studies, 33 percent were patients with HIV and, of those, 77 percent were on ART [104]. The mortality rate was higher among patients with HIV than among those without HIV (adjusted odds ratio [aOR] 2.4, 95% CI 2.0-2.9); importantly, the mortality rate was higher among patients with HIV who were not on ART (aOR 4.2, 95% CI 3.0-5.9), and lower among on those with ART (aOR 1.8, 95% CI 1.5-2.2). These findings indicate that ART and high-quality anti-TB drugs reduce deaths due to MDR-TB in adults with HIV.

Access to prioritized drugs (ie, bedaquiline, linezolid, and fluoroquinolones) as well as ART are both especially important for treatment of patients with HIV and MDR-TB. In the above meta-analysis, a lower mortality rate was observed among patients on ART treated with bedaquiline and linezolid than among patients on ART who were not treated with these two drugs (aOR 0.34, 95% CI 0.25-0.46) [104]. Using patients without HIV infection as a reference, the aOR of death was 2.4 (95% CI 2.0-2.9) for all patients with HIV infection, 1.8 (95% CI 1.5-2.2) for patients with HIV on ART, and 4.2 (95% CI 3.0-5.9) for patients with HIV and with no ART or unknown ART. Among patients with HIV, use of at least one World Health Organization Group A drug and specific use of moxifloxacin, levofloxacin, bedaquiline, or linezolid were associated with significantly decreased odds of death. This improved even further with use of two or more of these agents together.

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 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 TB or HIV coinfection [105]. The TB Consilium provides access to experts with answers delivered within a week in English or Russian language [106].

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

General principles - Treatment of drug-resistant tuberculosis (TB) is a rapidly evolving field that often calls for an individualized, multidisciplinary approach to patient management. Treatment of patients with known or suspected drug resistance 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 and clinical infrastructure that includes appropriate laboratory services and patient-centered case management. (See 'Introduction' above.)

Definitions – Definitions for drug-resistant TB are summarized in the table (table 2). Risk factors for drug-resistant TB are summarized in the table (table 5). (See 'Definitions' above.)

Empiric treatment − The decision to start an empiric treatment regimen for drug-resistant TB (pending drug susceptibility data) depends on the severity of illness and the degree of clinical suspicion for drug-resistant TB. 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 [INH], rifampin, and pyrazinamide) plus two or more additional drugs, including a fluoroquinolone and/or another core second-line agents (table 6). In settings where drug susceptibility patterns are well understood, empiric use of a six-month all-oral regimen of bedaquiline, pretomanid, and linezolid (BPaL) may also be a reasonable approach. Drug dosing is summarized in the tables (table 3 and table 4). (See 'Empiric treatment' above.)

Monoresistant and polyresistant TB − The clinical approach to treatment of monoresistant TB or polyresistant TB varies depending on the pattern of drug resistance. Treatment options are discussed above. (See 'Treatment of monoresistant TB' above and 'Treatment of polyresistant TB' above.)

Multidrug-resistant and extensively drug-resistant TB (MDR-TB and XDR-TB) − Regimen selection depends on a number of factors; these include disease severity, drug availability, administrative logistics, provider expertise, and patient preference.

For most nonpregnant patients with uncomplicated pulmonary MDR-TB or XDR-TB, we suggest treatment with an abbreviated regimen (6 to 12 months) (Grade 2C). A longer, individualized regimen is warranted for patient groups without sufficient data for use of an abbreviated regimen and in settings with limited drug availability. (See 'Regimen selection' above.)

Abbreviated regimens − BPaL has become a preferred regimen in many United States TB programs as well as globally. Alternative approaches consist of an alternative bedaquiline-containing regimen (total duration 9 to 12 months) or a 9-month regimen of delamanid, linezolid, levofloxacin, and pyrazinamide. (See 'Abbreviated regimens' above.)

Longer regimen: Indications − Indications for use of a longer, individualized regimen include (see 'Regimen selection' above):

-Disseminated, meningeal, or central nervous system disease

-Patients with advanced HIV infection (CD4<50 cells/microL) and extrapulmonary disease

-Pregnancy

-Extensive (or advanced) TB disease, such as bilateral cavitary disease or extensive parenchymal damage on chest radiography

-Contraindication to one or more drugs in the shorter course regimens

For patients with MDR-TB or XDR-TB in the setting of the above indications, we suggest a longer regimen rather than an abbreviated regimen (Grade 2C).

Longer regimen: Approach − The approach to creation of a longer, individualized regimen is outlined in the table (table 6). It consists of an intensive phase (administration of at least five effective drugs) for at least five to seven months after sputum culture conversion, followed by a continuation phase (administration of at least four effective drugs) for 15 to 24 months beyond sputum culture conversion. This approach reflects that of the American Thoracic Society, United States Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Disease Society of America; the number of drugs and months of therapy differ slightly from those outlined by the World Health Organization. (See 'Longer, individualized regimen' above.)

Role of surgery for MDR-TB or XDR-TB – In general, surgery for treatment of TB is most effective for patients with poor clinical response or intolerance to supervised medical therapy who have pulmonary disease that is amenable to resection (for example, lobectomy or wedge resection) as well as adequate pulmonary reserve. 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' above.)

Patients with HIV infection – For patients with HIV, treatment for HIV and TB should be integrated. 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. Management in conjunction with an HIV expert is essential to ensure proper antiretroviral adherence and monitoring. Issues related to ART selection are discussed above. (See 'Patients with HIV infection' above.)

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