What is the diagnosis, definition, and treatment of drug-resistant tuberculosis (TB)?

Drug-Resistant Tuberculosis: Definition, Diagnosis, and Treatment

Definition

Drug-resistant tuberculosis (DR-TB) is defined by resistance patterns to first-line anti-TB medications, with multidrug-resistant TB (MDR-TB) specifically referring to TB resistant to both isoniazid and rifampicin, the two most potent first-line agents. 1, 2

• Rifampicin-resistant TB (RR-TB): Resistance to rifampicin detected by phenotypic or molecular testing, with or without resistance to other drugs 1
• Extensively drug-resistant TB (XDR-TB): MDR-TB with additional resistance to any fluoroquinolone and at least one second-line injectable agent (amikacin, kanamycin, or capreomycin) 1
• Pre-XDR-TB: MDR-TB with additional resistance to either a fluoroquinolone or a second-line injectable, but not both 1

Globally, approximately 3.4% of new TB cases and 20% of previously treated cases have MDR-TB 2. Poverty remains a major driver of this epidemic 3.

Diagnosis

Rapid molecular drug susceptibility testing (DST) combined with conventional phenotypic culture-based DST should be performed immediately when DR-TB is suspected, as treatment delays of 28-30 days significantly increase transmission to contacts. 1

Molecular Diagnostics (Rapid)

• Targeted next-generation sequencing (tNGS) represents the newest class of molecular diagnostics, with two commercial workflows (GenoScreen Deeplex Myc-TB and Oxford Nanopore Technologies TB Drug Resistance Test) demonstrating >95% sensitivity and specificity for rifampicin and isoniazid, ≥94% sensitivity for fluoroquinolones, and 80% sensitivity for second-line injectables directly from clinical sediment samples 4
• tNGS can detect resistance mutations to bedaquiline and linezolid, which are not detectable by other WHO-recommended rapid diagnostics currently on the market 4
• Molecular DST is almost universally available in the United States, Europe, and low-incidence, high-resource countries 1
• Genome sequencing technologies based on targeted next-generation sequencing show early potential to mitigate diagnostic challenges 5

Phenotypic Drug Susceptibility Testing

• Conventional culture-based phenotypic DST remains essential for confirming resistance patterns and guiding treatment, though it requires weeks to complete 1, 6
• If sputum cultures remain positive after 3 months of treatment, or if bacteriological reversion from negative to positive occurs at any time, DST must be repeated 1

Clinical Evaluation

• Clinical diagnosis in endemic countries is limited to clinical evaluation combined with low-sensitivity microbiologic tests 1
• Extrapulmonary TB presents additional diagnostic challenges due to relative inaccessibility of disease sites, requiring response to treatment to be judged on clinical and radiographic findings 7

Special Populations

• HIV-infected patients may have malabsorption syndrome affecting drug levels; therapeutic drug monitoring should be considered in patients who adhere to therapy but fail to respond appropriately 8, 7
• Accurate diagnosis of TB in HIV-infected patients and pediatric populations remains challenging and requires specialized diagnostics 1

Treatment

Shorter All-Oral Bedaquiline-Containing Regimen (6-9 Months) - PREFERRED

For MDR/RR-TB patients meeting specific criteria, the WHO recommends a shorter 6-9 month all-oral bedaquiline-containing regimen as the preferred treatment option. 1

Eligibility Criteria (ALL must be met):

• No previous exposure to second-line TB drugs >1 month 1
• No fluoroquinolone resistance on DST 1
• No extensive pulmonary TB disease (cavities) or severe extrapulmonary TB (spinal/CNS/miliary) 1
• Not pregnant 1
• Age >6 years 1

Regimen Composition:

Intensive Phase (4-6 months):

• Bedaquiline (6 months total: daily for 2 weeks, then thrice weekly for 22 weeks) 1
• Levofloxacin OR moxifloxacin (levofloxacin preferred for fewer adverse events and less QTc prolongation) 1
• Clofazimine 1
• Pyrazinamide 1
• Ethambutol 1
• High-dose isoniazid 1
• Ethionamide 1

Continuation Phase (5 months):

• Levofloxacin/moxifloxacin 1
• Clofazimine 1
• Pyrazinamide 1
• Ethambutol 1

The intensive phase may be prolonged from 4 to 6 months pending sputum smear and culture conversion, but not longer than 6 months 1.

BPaL Regimen (6 Months) - Under Operational Research

The BPaL regimen (bedaquiline, pretomanid, linezolid) may be used under operational research conditions for MDR/RR-TB/pre-XDR-TB patients who have not had prior exposure to bedaquiline or linezolid (<2 weeks). 1

• This regimen requires active drug safety monitoring (aDSM) as further evidence on efficacy and safety is required 1
• If design of an effective regimen based on existing recommendations is not possible, BPaL may be considered as a last resort under programmatic conditions (outside operational research), with higher standards of monitoring for response and adverse events 1

Longer MDR-TB Regimen (18-20 Months)

For patients who do not meet criteria for shorter regimens, construct a longer regimen using at least 4 drugs to which the isolate has documented or high likelihood of susceptibility. 1

WHO Drug Classification for Building Long MDR-TB Regimens:

Group A (Include all three unless contraindicated):

• Levofloxacin OR moxifloxacin 1
• Bedaquiline 1
• Linezolid 1

Group B (Add one or both):

• Clofazimine 1
• Cycloserine/terizidone 1

Group C (Add to complete regimen if needed):

• Ethambutol 1
• Delamanid 1
• Pyrazinamide 1
• Imipenem-cilastatin or meropenem 1
• Amikacin (or streptomycin) 1
• Ethionamide or prothionamide 1
• p-aminosalicylic acid 1

Critical Treatment Principles

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 clinical/epidemiological information must not be used. 1

• If at least 1% of organisms in a solid media culture exhibit resistance to a drug, using that drug increases risk for poor outcomes and will eventually result in 100% resistance 1
• Consultation with a DR-TB expert is mandatory - experts can be found through CDC-supported TB Centers of Excellence, local health department TB Control Programs, British Thoracic Society MDR-TB Clinical Advisory Service, or Global TB Network 1
• All DR-TB cases should be discussed at a local, regional, or national consilium 1

Treatment Monitoring

Monthly sputum cultures are essential to identify early evidence of treatment failure. 1

• Assess clinical response (decrease in cough, systemic symptoms, weight gain) at each visit 1
• Record weight monthly 1
• Radiographic monitoring to assess treatment response 1
• Active drug safety monitoring (aDSM) is mandatory given the frequent and often severe adverse events with DR-TB regimens 1

Adverse Event Management

Nausea and vomiting are common with DR-TB medications and should not lead to permanent discontinuation; manage by excluding serious causes (hepatotoxicity, increased intracranial pressure in children) and implementing practical strategies. 1, 9

Management Strategies:

• Change dosing schedule (give at bedtime or with main meal) 1, 9
• Give medications with a small snack (may slightly affect plasma concentrations but clinically acceptable) 1, 9
• Premedicate adult patients with antiemetics before TB dose (beware QT prolongation) 1, 9
• Check liver function tests immediately if vomiting is new-onset or accompanied by abdominal pain or jaundice 9

For linezolid-induced tremors in lower extremities, consider dose reduction or switch to alternative regimen in consultation with MDR-TB expert while maintaining efficacy against the resistant strain. 10

Patient-Centered Care and Adherence

Directly observed therapy (DOT) applied through patient-centered approaches is mandatory for all DR-TB patients to ensure adherence, prevent treatment failure, and reduce transmission risk. 1, 7

• Provide comprehensive health education, counseling, and shared decision-making 1
• Address language and cultural barriers 1
• Consider video-observed therapy (VOT) when face-to-face DOT is not feasible 1
• Offer material support, nutritional support, psychological support, and drug/alcohol services as needed 1
• Case management should address physical, psychological, social, material, and informational needs 1

Special Populations

Pregnant Women:

• Avoid pyrazinamide due to inadequate teratogenicity data 7
• Never use streptomycin (causes congenital deafness) 7
• Initial regimen should consist of isoniazid and rifampin, with ethambutol added unless primary isoniazid resistance is unlikely 7

HIV-Infected Patients:

• Screen antimycobacterial drug levels, especially in patients with advanced HIV disease, to prevent emergence of MDR-TB due to malabsorption 7
• Response may not be as satisfactory as immunocompetent hosts; therapeutic decisions must account for this 7

Pediatric Patients:

• Dosage of 10-20 mg/kg daily in 2-3 divided doses or 15 mg/kg/24 hours as single daily dose for ethionamide 8
• Children benefit slowly from treatment advances; more work is needed 5

Infection Control

Three main strategies reduce DR-TB transmission: rapid diagnosis, prompt appropriate treatment, and improved airborne infection control. 1

• Treatment initiation delays of 28-30 days are significantly associated with increased transmission to contacts 1
• Effective therapy renders patients with DR-TB rapidly noninfectious, making outpatient therapy possible 1

Emerging Resistance Concerns

Emerging bedaquiline resistance is being reported in several countries, raising concerns that DST and/or regimens are not sufficiently robust to avoid accrual of resistance. 1

• New drugs are in clinical development, but long development times and mechanism of action overlap mean there is no certainty of success 1
• Appropriate use of current antimicrobial armamentarium is critical for future generations 1