What is the recommended treatment regimen for a patient with newly diagnosed, uncomplicated pulmonary tuberculosis, considering factors such as disease severity, potential drug resistance, and compromised immune systems, such as HIV/AIDS?

Treatment of Tuberculosis

Drug-Susceptible Pulmonary TB: Standard First-Line Regimen

For newly diagnosed, uncomplicated pulmonary tuberculosis with drug-susceptible organisms, treat with a 6-month regimen: isoniazid, rifampin, pyrazinamide, and ethambutol for 2 months (intensive phase), followed by isoniazid and rifampin for 4 months (continuation phase). 1, 2

When to Include or Omit Ethambutol

• Include ethambutol (or streptomycin in young children) in the initial 4-drug regimen until drug susceptibility results are available unless isoniazid resistance in your community is documented to be <4% AND the patient has no prior TB treatment, no exposure to drug-resistant cases, and is not from a high-prevalence drug resistance region 1, 3

• If these low-risk criteria are met, a 3-drug regimen (isoniazid, rifampin, pyrazinamide) may be considered for the initial 2 months 1, 3

Dosing Specifications

• Rifampin: 10 mg/kg daily (maximum 600 mg/day) for adults; 10-20 mg/kg daily (maximum 600 mg/day) for children 2

• Administer oral medications once daily, either 1 hour before or 2 hours after meals with a full glass of water 2

• All doses should be given via directly observed therapy (DOT) to ensure adherence and prevent resistance development 1, 4, 3

HIV Co-Infection Considerations

HIV-infected patients should receive the same 6-month regimen but require careful monitoring for clinical and bacteriologic response. 3

• If slow or suboptimal response occurs, extend treatment to 9 months total, with at least 6 months beyond documented culture conversion 1, 3

• The critical difference is heightened vigilance for treatment failure, not automatic prolongation for all HIV patients 3

Isoniazid-Resistant TB (Rifampin-Susceptible)

When isoniazid resistance is confirmed but rifampin susceptibility is maintained, treat with rifampin, ethambutol, pyrazinamide, and a later-generation fluoroquinolone (levofloxacin preferred) for 6 months. 4

• This represents a modification from the standard regimen by substituting a fluoroquinolone for isoniazid 4

Multidrug-Resistant TB (MDR-TB)

Core Principles for MDR-TB Treatment

MDR-TB (resistance to at least isoniazid AND rifampin) requires immediate consultation with a TB specialist and treatment with at least 5 effective drugs in the intensive phase. 1, 5

Preferred All-Oral Shorter Regimen (9-12 months)

For eligible MDR-TB patients, use the shorter all-oral bedaquiline-containing regimen: 1, 6

Eligibility criteria (ALL must be met):

• Confirmed MDR/RR-TB without fluoroquinolone resistance 1, 6
• No previous exposure to second-line TB drugs for >1 month 1, 6
• No extensive pulmonary disease, severe extrapulmonary TB (spinal/CNS/miliary) 1
• Not pregnant 1
• Age >6 years 1

Regimen composition (4-6 month intensive phase):

• Bedaquiline (daily for 2 weeks, then 3 times weekly for 22 weeks) 1
• Levofloxacin or moxifloxacin (levofloxacin preferred for less QTc prolongation) 1, 6
• Clofazimine 1
• Pyrazinamide 1
• Ethambutol 1
• High-dose isoniazid 1
• Ethionamide 1

Continuation phase (5 months):

• Levofloxacin/moxifloxacin, clofazimine, pyrazinamide, ethambutol 1

Longer Individualized Regimen (18-24 months)

For patients who do NOT meet shorter regimen criteria, construct an individualized longer regimen using the WHO drug group prioritization: 1, 5, 6

Group A drugs (include ALL THREE):

• Levofloxacin OR moxifloxacin 1, 5, 6
• Bedaquiline 1, 5, 6
• Linezolid 1, 5, 6

Group B drugs (add at least ONE):

• Clofazimine 1, 5
• Cycloserine or terizidone 1, 5

Group C drugs (add if needed to reach 5 total drugs):

• Ethambutol 1
• Delamanid 1
• Pyrazinamide (if susceptibility confirmed) 1
• Imipenem-cilastatin or meropenem (ALWAYS with amoxicillin-clavulanate) 1
• Amikacin or streptomycin (ONLY if susceptibility confirmed) 1
• p-aminosalicylic acid 1

Treatment duration:

• Standard MDR-TB: 15-21 months after culture conversion 5, 6
• Pre-XDR/XDR-TB: 15-24 months after culture conversion 5, 6
• Intensive phase: 5-7 months after culture conversion 5

Drugs to AVOID in MDR-TB

Strong recommendations AGAINST using:

• Kanamycin or capreomycin (injectable agents) 1, 5, 6
• Macrolides (azithromycin, clarithromycin) 1, 5
• Amoxicillin-clavulanate alone (only use with carbapenems) 1, 5

Conditional recommendations AGAINST using (if better alternatives available):

• Ethionamide/prothionamide 1, 5
• p-aminosalicylic acid 1, 5

BPaL Regimen for Pre-XDR/XDR-TB

The bedaquiline-pretomanid-linezolid (BPaL) regimen for 6 months may be used as a last resort for pre-XDR/XDR-TB patients when an effective regimen cannot be constructed using standard recommendations, with <2 weeks prior exposure to bedaquiline or linezolid 1

• This requires operational research conditions or exceptional programmatic circumstances with intensive monitoring 1

Extrapulmonary TB

Most extrapulmonary TB sites are treated with the same 6-month drug-susceptible regimen as pulmonary TB. 4, 3

Critical exceptions requiring 9-12 months of treatment:

• TB meningitis 4
• Miliary TB 4
• Bone/joint TB 4
• Spinal TB 4

Treatment Failure and Relapse

Treatment failure is defined as continued or recurrent positive cultures after 3-4 months of appropriate therapy. 1

When treatment failure occurs:

• NEVER add a single drug to a failing regimen—this rapidly creates additional resistance 1, 4
• Add at least 2-3 new drugs to which susceptibility is likely 1
• Send isolates for first- AND second-line drug susceptibility testing 1
• Empirical retreatment should include a fluoroquinolone, an injectable agent (if not previously used and susceptibility likely), and an additional oral agent 1

Pregnancy Considerations

Pregnant women with TB require effective treatment but with regimen modifications: 1

• Avoid streptomycin (causes congenital deafness) 1
• Avoid pyrazinamide (teratogenicity not established) 1
• Use isoniazid, rifampin, and ethambutol for minimum 9 months 1
• For drug-resistant TB in pregnancy, individualize with expert consultation, prioritizing oral agents with established safety profiles 1

Monitoring Requirements

Essential monitoring throughout treatment:

• Monthly sputum cultures until negative 4
• Baseline and ongoing assessment for hepatotoxicity (transaminases) 4
• For MDR-TB regimens: baseline and serial ECG for QTc prolongation, electrolytes, complete blood count, visual acuity and color vision 6
• Patient education on symptoms of hepatotoxicity and other adverse effects 4

Critical Pitfalls to Avoid

• Using fewer than 4 drugs initially when drug resistance risk exists 1
• Omitting ethambutol when isoniazid resistance is >4% in the community 1
• Adding a single drug to a failing regimen 1, 4
• Using fewer than 5 effective drugs in MDR-TB intensive phase 5, 6
• Omitting any Group A drug (fluoroquinolone, bedaquiline, linezolid) in longer MDR-TB regimens 6
• Insufficient treatment duration (<15 months after culture conversion for MDR-TB) 5, 6
• Using kanamycin or capreomycin in MDR-TB regimens 1, 5, 6
• Inadequate monitoring for linezolid toxicity (myelosuppression, neuropathy) 6