What is the latest management approach for pulmonary tuberculosis (PTB) using anti-tuberculosis (TB) drugs?

Latest Management of Pulmonary Tuberculosis with Anti-TB Drugs

For drug-susceptible pulmonary TB, the standard regimen remains 2 months of rifampicin, isoniazid, pyrazinamide, and ethambutol (intensive phase), followed by 4 months of rifampicin and isoniazid (continuation phase), though a WHO-conditionally recommended 4-month rifapentine-based regimen is now available for eligible patients aged ≥12 years. 1

Drug-Susceptible Pulmonary TB: Standard 6-Month Regimen

Intensive Phase (2 months)

• Four-drug combination: Rifampicin, isoniazid, pyrazinamide, and ethambutol administered daily 1
• Dosing:
  • Rifampicin: 10 mg/kg (maximum 600 mg) daily 2
  • Isoniazid: 5 mg/kg (maximum 300 mg) daily 3
  • Pyrazinamide: 25 mg/kg daily 1, 4
  • Ethambutol: 15-25 mg/kg daily 1
• Rationale for four drugs: Ethambutol (or streptomycin) should be added unless isoniazid resistance is documented to be <4% in the community 1, 3
• Ethambutol can be discontinued once drug susceptibility confirms full susceptibility to isoniazid and rifampicin 5

Continuation Phase (4 months)

• Two-drug combination: Rifampicin and isoniazid administered daily or 2-3 times weekly 1
• Total treatment duration: 6 months for most patients with drug-susceptible pulmonary TB 1, 5

Alternative Dosing Schedules

• Twice-weekly regimens: Can be used during continuation phase (rifampicin and isoniazid twice weekly for 18 weeks) but should NOT be used in HIV-infected patients or those with smear-positive/cavitary disease 1
• Three-times-weekly regimens: Available but require caution in HIV-infected patients and those with cavitary disease due to risk of treatment failure and acquired drug resistance 1
• All intermittent regimens must be administered by directly observed therapy (DOT) 1, 3

New Shorter 4-Month Regimen for Drug-Susceptible TB

WHO conditionally recommends a 4-month regimen of rifapentine, isoniazid, pyrazinamide, and moxifloxacin for eligible persons aged ≥12 years with pulmonary drug-susceptible TB (based on Study 31/A5349 phase III trial data from May 2022) 1

Key Points About the 4-Month Regimen:

• This represents the first successful treatment-shortening regimen after multiple failed attempts with fluoroquinolones in 2014 1
• Rifapentine has a longer half-life than rifampicin, enabling treatment shortening 1
• Important caveat: This is a conditional recommendation, meaning it should be used selectively in appropriate patients 1

Isoniazid-Resistant, Rifampicin-Susceptible TB

For isoniazid-resistant TB (present in ~10.6% of all TB cases globally), WHO recommends 6 months of rifampicin, ethambutol, pyrazinamide, and levofloxacin 1

Treatment Details:

• Regimen: Rifampicin + ethambutol + pyrazinamide + levofloxacin for 6 months 1
• Addition of fluoroquinolone increases treatment success (adjusted OR: 2.8 [95% CI: 1.1-7.3]) 1
• Important limitation: This recommendation is conditional, based on very low certainty of evidence 1
• In noncavitary disease with low bacillary burden, pyrazinamide may be given only during the first 2 months if a later-generation fluoroquinolone is used 1
• If fluoroquinolone resistance or contraindications exist, use rifampicin, ethambutol, and pyrazinamide only for 6 months (expert opinion, no clinical trial evidence) 1

Multidrug-Resistant/Rifampicin-Resistant TB (MDR/RR-TB)

For MDR/RR-TB, use at least five effective drugs in the intensive phase, prioritizing bedaquiline and later-generation fluoroquinolones (levofloxacin or moxifloxacin) unless contraindicated 5

WHO Drug Classification for MDR-TB:

• Group A (highest priority): Levofloxacin/moxifloxacin, bedaquiline, linezolid 6, 7
• Group C (lower priority): Ethambutol 6, 7
• Include ethambutol only when more effective drugs cannot be assembled to achieve five effective drugs 5, 7

Shorter All-Oral MDR/RR-TB Regimen:

• Intensive phase (4-6 months): Bedaquiline, fluoroquinolone, clofazimine, pyrazinamide, ethambutol, high-dose isoniazid, and ethionamide 6
• Continuation phase (5 months): Levofloxacin, clofazimine, pyrazinamide, and ethambutol 6
• Levofloxacin is generally preferred over moxifloxacin due to fewer adverse events and less QTc prolongation 6

Standard MDR-TB Treatment Duration:

• Continue intensive phase for 5-7 months after culture conversion 5
• Total treatment duration: 15-21 months after culture conversion for standard MDR-TB 5
• Pre-XDR-TB and XDR-TB: 15-24 months total 5

Special Populations

Pediatric Patients

• Dosing adjustments:
  • Isoniazid: 10-15 mg/kg (maximum 300 mg) daily 3
  • Rifampicin: 10-20 mg/kg (maximum 600 mg) daily 2
• The SHINE trial demonstrated that 16 weeks (4 months) was non-inferior to 6 months in children with drug-susceptible, non-severe TB 1
• Ethambutol should not be used in children whose visual acuity cannot be monitored 3

HIV-Infected Patients

• Use the same regimen as HIV-negative patients 3
• Critical: Do NOT use twice-weekly regimens in HIV-infected patients 1
• Pyridoxine (vitamin B6) 25-50 mg daily should be administered to all HIV-infected patients receiving isoniazid 5
• For patients on protease inhibitors or NNRTIs, substitute rifabutin for rifampicin with appropriate dose adjustments 5
• HIV-infected patients may have malabsorption issues requiring therapeutic drug monitoring 3

Pregnant Women

• Avoid: Streptomycin (causes congenital deafness) and pyrazinamide (inadequate teratogenicity data) 3
• Recommended regimen: Isoniazid, rifampicin, and ethambutol 3
• Include ethambutol unless primary isoniazid resistance is unlikely (resistance rate <4%) 3

Critical Monitoring and Safety

Hepatotoxicity Monitoring

• Essential, especially during the first 2 months of treatment 5
• All first-line drugs can cause hepatotoxicity 1

Drug-Specific Monitoring:

• Ethambutol: Monthly monitoring for ocular toxicity (optic neuritis); discontinue immediately if visual impairment detected 5, 7
• Fluoroquinolones: Monitor for tendinopathy, peripheral neuropathy, and QTc prolongation 6, 5
• Isoniazid: Monitor for peripheral neuropathy; pyridoxine supplementation recommended in high-risk patients 5, 3

Drug Interactions

• Rifampicin: Extensive interactions with oral contraceptives, anticoagulants, and antiretroviral drugs requiring dose adjustments 5
• Physical incompatibility exists between diltiazem and rifampicin during IV administration 2

Directly Observed Therapy (DOT)

DOT is recommended for all patients with TB to ensure compliance, prevent drug resistance, and enhance TB control 1, 3, 8

• DOT involves observing the patient swallow anti-TB medications 1
• Can be administered with daily, twice-weekly, or thrice-weekly regimens 1
• Virtual treatment monitoring using digital technologies is becoming more common as a patient-centered alternative 8
• All intermittent regimens (less than daily) MUST be administered by DOT 1, 3

Common Pitfalls and How to Avoid Them

Drug Resistance Prevention:

• Always start with four drugs unless isoniazid resistance is documented to be <4% in the community 1, 3
• Perform drug susceptibility testing on all initial isolates 3
• Never add a single drug to a failing regimen 1
• If resistance develops, change to agents to which bacilli are susceptible 3

Treatment Completion:

• Patient noncompliance is a major cause of drug-resistant TB 3
• Use DOT, case management interventions, patient education, field visits, and incentives/enablers to ensure adherence 1
• Treatment should be continued longer if patient remains sputum/culture positive, resistant organisms are present, or patient is HIV-positive 2

Avoiding Fluoroquinolone Monotherapy:

• Never use fluoroquinolones as monotherapy or add them to failing regimens, as this rapidly selects for resistance 9
• Older fluoroquinolones (especially ciprofloxacin) should NOT be used as they result in higher relapse rates and longer time to sputum-culture conversion 9

Renal Impairment:

• Dose adjustments necessary for both levofloxacin and ethambutol in renal impairment 6
• Rifampicin dosing information for renal failure patients should be consulted 2