Management of Drug-Resistant Tuberculosis
Drug-resistant TB requires an all-oral regimen of at least 5 effective drugs guided by drug susceptibility testing, with bedaquiline, a later-generation fluoroquinolone, linezolid, and clofazimine forming the core of treatment for 15-24 months after culture conversion. 1, 2
Core Principles of DR-TB Management
Only include drugs to which the patient's M. tuberculosis isolate has documented or high likelihood of susceptibility - drugs known to be ineffective based on in vitro resistance or molecular testing must never be used, even when resistance exists in only 1% of the organism population. 1
Never add a single drug to a failing regimen - this invariably leads to amplification of resistance, including acquired resistance to the newly added drug. When treatment failure occurs, add at least 2-3 new drugs to which susceptibility can be logically inferred. 1, 2, 3
Essential Diagnostic Steps
Perform drug susceptibility testing (DST) on the first isolate from all patients to guide appropriate treatment selection. 2, 3 Both molecular and phenotypic DST should be utilized, as molecular methods can provide rapid results while phenotypic testing confirms resistance patterns. 4
Consult a DR-TB expert immediately when drug resistance is suspected or confirmed - experts can be found through CDC-supported TB Centers of Excellence, local health department TB Control Programs, or international MDR-TB expert groups. 1
Building the Treatment Regimen for MDR-TB
Core Drugs (Strongly Recommended)
Later-generation fluoroquinolone (levofloxacin or moxifloxacin) - this is the cornerstone of any MDR-TB regimen. Levofloxacin is preferred over moxifloxacin due to fewer adverse events and less QTc prolongation. 2, 5
Bedaquiline - strongly recommended as a core component of the regimen. 1, 2, 5
Additional Effective Drugs (Conditionally Recommended)
Linezolid - conditionally recommended as an effective component, though requires monitoring for hematologic and neurologic toxicity. 2, 5
Clofazimine - conditionally recommended for inclusion. 2, 5
Cycloserine or terizidone - conditionally recommended, though neuropsychiatric side effects require careful monitoring. 2, 5
Drugs to Include Selectively
Pyrazinamide - include only when the isolate has not been found resistant to it. 2
Ethambutol - include only when other more effective drugs cannot be assembled to achieve a total of five drugs in the regimen. 2
Injectable agents - if needed to compose an effective regimen, amikacin or streptomycin may be included when susceptibility is confirmed, but kanamycin and capreomycin should NOT be used due to poor outcomes. 2, 5
Carbapenems (always used with amoxicillin-clavulanic acid) - may be included if needed to compose an effective regimen. 2
Treatment Duration and Phases
Intensive phase: 5-7 months after culture conversion - this phase includes all drugs in the regimen. 2, 5
Total treatment duration for MDR-TB: 15-21 months after culture conversion. 2
Total treatment duration for XDR-TB: 15-24 months after culture conversion - the longer duration reflects the more resistant nature of XDR-TB. 2, 5
Culture conversion is defined as two consecutive negative cultures taken at least 30 days apart. 1
Monitoring and Follow-Up
Obtain monthly sputum cultures until conversion, then less frequently to identify early evidence of treatment failure. 1
If sputum cultures remain positive after 3 months of treatment, or if bacteriological reversion occurs, repeat DST immediately. 1
Monitor clinically at each visit - assess for decrease in cough and systemic symptoms, increase in weight (record monthly), and adverse effects. 1
Educate patients about adverse effects and investigate all adverse effects diligently. Some adverse effects like nausea and vomiting can be managed by changing dosing schedule, giving medications with a small snack, or premedicating with antiemetics (noting QTc prolongation risk). 1
Role of Surgery
Elective partial lung resection (lobectomy or wedge resection) may be considered for adults with MDR-TB or XDR-TB receiving antimicrobial therapy, but only after several months of intensive chemotherapy and only by experienced surgeons. 2, 5
Treatment Adherence
Directly observed therapy (DOT) is strongly recommended for all DR-TB patients - patient nonadherence is a major cause of treatment failure and development of further drug resistance, which can be life-threatening. 1, 6
Case management should be patient-centered, addressing physical, psychological, social, material, and informational needs throughout the prolonged treatment course. 1
Special Populations
HIV co-infected patients require careful attention to drug-drug interactions, particularly between bedaquiline and antiretrovirals, and may have malabsorption requiring therapeutic drug monitoring. 6, 7
Contacts of MDR-TB patients should receive treatment for latent TB infection with a 6-12 month regimen of a later-generation fluoroquinolone alone or with a second drug, based on the source case's drug susceptibility pattern. 2
Critical Pitfalls to Avoid
Using fewer than 5 effective drugs in the intensive phase leads to poorer outcomes and risk of further resistance amplification. 5
Treating for less than 15 months after culture conversion is associated with higher relapse rates. 5
Including drugs based on regional surveillance data alone without considering the patient's individual treatment history and the source case's resistance pattern can lead to ineffective regimens. 1
Failing to monitor for QTc prolongation when using multiple drugs that prolong the QT interval (bedaquiline, fluoroquinolones, clofazimine) can result in serious cardiac events. 1, 7