What is the treatment approach for a patient diagnosed with tuberculosis, including multi-drug resistant (MDR) and extensively drug-resistant (XDR) forms?

Treatment of Tuberculosis Including MDR and XDR

For drug-susceptible TB, use a 4-drug regimen (isoniazid, rifampin, pyrazinamide, ethambutol) for 2 months followed by isoniazid and rifampin for 4 months; for MDR/XDR-TB, construct an all-oral regimen with at least 5 effective drugs including bedaquiline, a later-generation fluoroquinolone (levofloxacin or moxifloxacin), linezolid, and clofazimine, treating for 15-24 months after culture conversion. 1, 2, 3

Drug-Susceptible Tuberculosis

Standard Regimen

• Initiate treatment with 4 drugs: isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months (intensive phase), followed by isoniazid and rifampin for 4 months (continuation phase). 3, 4, 5
• Start treatment promptly even before diagnostic results return in patients with high clinical suspicion. 3
• For culture-negative, paucibacillary TB in HIV-uninfected adults, a 4-month regimen may suffice. 3

Critical Action Points

• Obtain drug susceptibility testing (DST) on the first isolate from all TB patients before starting therapy. 2, 5
• Administer pyridoxine (vitamin B6) supplementation to malnourished patients, alcoholics, and diabetics to prevent isoniazid-induced neuropathy. 4
• Use directly observed therapy (DOT) for all patients to ensure adherence and prevent resistance development. 6, 4

Multidrug-Resistant Tuberculosis (MDR-TB)

Rapid Diagnosis and Testing

• Perform rapid molecular testing for rifampicin and isoniazid resistance on all patients. 1
• For rifampicin-resistant or MDR-TB cases, immediately conduct genotypic/phenotypic second-line drug resistance testing. 1
• Only include drugs to which the isolate has documented or high likelihood of susceptibility—never use drugs with confirmed resistance. 1, 2

Preferred Shorter Regimen (6-9 months)

• The WHO recommends a 6-9 month all-oral bedaquiline-containing regimen as first-line treatment for eligible MDR/RR-TB patients. 6
• This shorter regimen is preferred when patients meet specific eligibility criteria (no prior extensive drug exposure, no resistance to fluoroquinolones). 6

Standard Longer Regimen Construction

Build regimens using this hierarchical drug selection process: 1, 2, 3

Core Drugs (Must Include):

• Later-generation fluoroquinolone (levofloxacin or moxifloxacin) - cornerstone agent 2
• Bedaquiline - strongly recommended 2, 3
• Linezolid 2, 3
• Clofazimine 2, 3

Additional Drugs to Reach 5 Total:

• Cycloserine 2
• Pyrazinamide (only if susceptible) 2, 7
• Ethambutol (only if other more effective drugs unavailable) 2, 7

Reserve Drugs (Use Only When Needed):

• Injectable agents: Amikacin or streptomycin if susceptible (avoid kanamycin and capreomycin) 2
• Carbapenems with amoxicillin-clavulanic acid 2
• Ethionamide/prothionamide 1
• p-aminosalicylic acid 1

Treatment Duration for MDR-TB

• Intensive phase: 5-7 months AFTER culture conversion 1, 2, 3
• Total duration: 15-21 months AFTER culture conversion 1, 2, 3
• Use at least 5 effective drugs during intensive phase, then 4 drugs during continuation phase. 1, 3

Extensively Drug-Resistant Tuberculosis (XDR-TB)

Definition

• XDR-TB is MDR-TB with additional resistance to any fluoroquinolone AND at least one second-line injectable agent (amikacin, kanamycin, or capreomycin). 6, 8

Treatment Approach

• Use the same core drug regimen as MDR-TB (bedaquiline, later-generation fluoroquinolone, linezolid, clofazimine) plus additional susceptible agents. 2, 3
• The BPaL regimen (bedaquiline, pretomanid, linezolid) may be used under operational research conditions for patients without prior bedaquiline or linezolid exposure (<2 weeks). 6
• Total treatment duration: 15-24 months AFTER culture conversion 2, 3

Adjunctive Surgery

• Consider elective partial lung resection (lobectomy or wedge resection) when clinical judgment, bacteriological, and radiographic data suggest high risk of treatment failure or relapse with medical therapy alone. 2, 3
• Perform surgery only after several months of intensive chemotherapy and only by experienced surgeons. 2

Isoniazid-Resistant, Rifampin-Susceptible TB

• Add a later-generation fluoroquinolone to a 6-month regimen of rifampin, ethambutol, and pyrazinamide. 3
• Pyrazinamide duration can be shortened to 2 months in noncavitary, lower-burden disease or if toxicity develops. 3

Special Populations

HIV Co-infection

• HIV-infected patients may have malabsorption issues requiring antimycobacterial drug level monitoring to prevent MDR-TB emergence. 4
• Treatment response may be less satisfactory; individualize therapeutic decisions. 4

Pregnancy

• Use isoniazid, rifampin, and ethambutol (avoid streptomycin due to ototoxicity and pyrazinamide due to inadequate teratogenicity data). 4

Extrapulmonary TB

• Use the same 6-9 month regimen as pulmonary TB for most extrapulmonary sites. 4
• Treat miliary TB, bone/joint TB, and tuberculous meningitis in infants and children for 12 months. 4
• Consider adjunctive corticosteroids for tuberculous pericarditis and meningitis to reduce complications. 4

Treatment Monitoring

Bacteriologic Monitoring

• Obtain monthly sputum smears and cultures for all MDR-TB patients to identify early treatment failure. 1, 6
• Repeat cultures throughout therapy to monitor response. 5

Adverse Event Management

• Active drug safety monitoring (aDSM) is mandatory given frequent and severe adverse events with DR-TB regimens. 6
• Nausea and vomiting are common; manage with practical strategies rather than permanent discontinuation. 6

Critical Pitfalls to Avoid

• Never add a single drug to a failing regimen—this creates acquired resistance to the new drug. 2
• When initiating therapy for suspected drug-resistant TB, add at least 2-3 new drugs to which susceptibility can be inferred. 2
• Never use drugs with documented resistance (molecular or phenotypic). 1, 2
• Do not use fewer than 5 effective drugs in MDR-TB intensive phase—this leads to poorer outcomes. 3
• Ensure DOT for all DR-TB patients through patient-centered approaches to prevent treatment failure and transmission. 6, 2

Infection Control

• Three strategies reduce DR-TB transmission: rapid diagnosis, prompt appropriate treatment, and improved airborne infection control. 6
• Treatment delays of 28-30 days significantly increase transmission to contacts. 6
• Begin patient counseling and education immediately to minimize transmission potential. 1

Management of MDR-TB Contacts

• Offer latent TB infection treatment to contacts of MDR-TB patients rather than observation alone. 2, 3
• Use a later-generation fluoroquinolone alone or with a second drug for 6-12 months based on source case susceptibility. 2, 3
• Do not routinely use pyrazinamide as the second drug due to increased toxicity. 2