What are the guidelines for the management of tuberculosis in the Philippines?

Philippine Tuberculosis Guidelines and Management

Standard Treatment Regimen for Drug-Susceptible TB

The recommended first-line treatment for tuberculosis in the Philippines consists of a 6-month regimen: isoniazid, rifampin, pyrazinamide, and ethambutol for the first 2 months (intensive phase), followed by isoniazid and rifampin for 4 months (continuation phase). 1, 2, 3

Initial Intensive Phase (First 2 Months)

• Administer four drugs daily: isoniazid (5 mg/kg up to 300 mg), rifampin, pyrazinamide, and ethambutol 4, 3
• Include ethambutol in all initial regimens unless primary isoniazid resistance is documented to be less than 4% in the community 1, 4
• Given the Philippines' documented high prevalence of drug resistance (80% in one Manila study showed initial drug resistance, with 54% resistant to two or more drugs), the four-drug regimen is essential 5

Continuation Phase (Months 3-6)

• Continue isoniazid and rifampin for an additional 4 months after the intensive phase 1, 2, 3
• This two-drug regimen is only appropriate once drug susceptibility is confirmed 3

Alternative Intermittent Dosing

• Thrice-weekly directly observed therapy (DOT) can be used: 2E3H3R3Z3 for 2 months, followed by 4H3R3 for 4 months 6
• Higher doses are required for intermittent therapy: isoniazid 15 mg/kg up to 900 mg, compared to 5 mg/kg for daily dosing 7, 4
• All intermittent regimens must be given as directly observed therapy 4, 6

Directly Observed Therapy (DOT)

Universal DOT is strongly recommended for all tuberculosis patients in the Philippines to ensure adherence and prevent drug resistance. 1, 2

• A healthcare provider or designated person must observe medication ingestion 1
• Patient noncompliance is the major cause of treatment failure and drug-resistant tuberculosis 4, 8
• Fixed-dose combinations minimize the opportunity for selective medication taking 6

Monitoring and Follow-Up

Clinical Assessment

• Evaluate patients at least twice monthly for symptoms and sputum smear until asymptomatic and smear-negative 7
• Obtain sputum cultures at least monthly until negative 7
• Patients should demonstrate sputum conversion within 3 months; failure requires evaluation for noncompliance or drug resistance 7

Laboratory Monitoring

• Monitor liver function tests every 2-4 weeks during treatment due to hepatotoxicity risk with isoniazid, rifampin, and pyrazinamide 1
• Instruct patients to report immediately: loss of appetite, nausea, vomiting, jaundice, malaise, unexplained fever >3 days, or abdominal tenderness 7
• Obtain baseline and monthly liver enzymes in patients with pre-existing liver disease, alcohol use, or age >35 years 7

Diagnostic Requirements

• Obtain specimens for culture and drug susceptibility testing from all patients with suspected tuberculosis before starting treatment 7
• Three sputum samples should be examined: spot sample on day 1, overnight sample, and morning spot sample on day 2 6
• Culture is 81% sensitive and 98.5% specific, detecting 10-100 viable mycobacteria per ml 6

Special Populations

HIV Co-infection

• Extend treatment duration to at least 9 months and for at least 6 months beyond documented culture conversion (three negative cultures) 7, 2
• Offer HIV testing and counseling to all persons with confirmed or suspected tuberculosis 7
• Monitor closely for paradoxical immune reconstitution inflammatory syndrome after initiating antiretroviral therapy 6
• Rifampin induces metabolism of protease inhibitors and NNRTIs, requiring dose adjustments or alternative antiretroviral regimens 6

Pregnancy

• Use isoniazid, rifampin, ethambutol, and pyrazinamide - all are safe during pregnancy 6, 3
• Avoid streptomycin due to fetal ototoxicity 1, 6
• Add prophylactic pyridoxine 10-50 mg daily to prevent peripheral neuropathy 7, 6

Diabetes Mellitus

• Use the same drug regimen as non-diabetic patients 6
• Strict blood glucose control is mandatory 6
• Increase doses of oral hypoglycemic agents due to rifampin-induced metabolism 6
• Add prophylactic pyridoxine as diabetics are at higher risk for isoniazid-induced neuropathy 7

Renal Failure

• Adjust doses of streptomycin, ethambutol, and isoniazid according to creatinine clearance 6
• In hemodialysis patients, give ethambutol 8 hours before dialysis 6

Pre-existing Liver Disease

• Use all antituberculosis drugs if liver enzymes are normal, but perform frequent liver function monitoring 6
• If liver disease is unstable, consider non-hepatotoxic regimens with streptomycin, ethambutol, and fluoroquinolones 6

Children

• Use the same 6-month regimen with appropriately adjusted doses: isoniazid 10-15 mg/kg up to 300 mg daily 4, 3
• Avoid ethambutol in children whose visual acuity cannot be monitored 7, 6
• Extend treatment to 12 months for miliary tuberculosis, bone/joint tuberculosis, or tuberculous meningitis 3

Drug-Resistant Tuberculosis

Isoniazid-Resistant TB

Treat with rifampin, ethambutol, and pyrazinamide for 6 months, with addition of a fluoroquinolone (levofloxacin or moxifloxacin) strongly recommended. 7, 1

• The fluoroquinolone-containing regimen (fluoroquinolone, rifampin, ethambutol, and pyrazinamide for 6 months) is preferred over the three-drug regimen without fluoroquinolone 7

Multidrug-Resistant TB (MDR-TB)

MDR-TB requires at least 5 drugs in the intensive phase and 4 drugs in the continuation phase, with total treatment duration of 15-21 months after culture conversion. 7

Core MDR-TB Regimen Components:

• Include a later-generation fluoroquinolone (levofloxacin or moxifloxacin) - strong recommendation 7
• Include bedaquiline - strong recommendation 7
• Include linezolid - conditional recommendation 7
• Include clofazimine - conditional recommendation 7
• Include cycloserine - conditional recommendation 7

Treatment Duration:

• Intensive phase: 5-7 months after culture conversion 7
• Total treatment: 15-21 months after culture conversion for MDR-TB 7
• Total treatment: 15-24 months after culture conversion for pre-XDR-TB and XDR-TB 7

Shorter MDR-TB Regimen:

• A 9-month all-oral regimen may be used for fluoroquinolone-susceptible MDR-TB with extrapulmonary involvement 2
• A 6-month BPaLM regimen (bedaquiline, pretomanid, linezolid, moxifloxacin) may be used for extrapulmonary TB 2

Critical Principles for Drug-Resistant TB:

• Never add a single drug to a failing regimen - this creates de facto monotherapy and compounds resistance 7
• Add at least 2 new drugs to which the organism is susceptible when treatment failure is suspected 7
• Consult an expert in drug-resistant tuberculosis for all MDR-TB cases 7, 8, 6
• Base drug selection on prior treatment history, susceptibility testing results, and adherence evaluation 6

Extrapulmonary Tuberculosis

Treat extrapulmonary tuberculosis with the same 6-month regimen used for pulmonary disease: 2 months of isoniazid, rifampin, pyrazinamide, and ethambutol, followed by 4 months of isoniazid and rifampin. 1, 2, 3

Exceptions Requiring Extended Treatment:

• Miliary tuberculosis in children: 12 months 3
• Bone/joint tuberculosis in children: 12 months 3
• Tuberculous meningitis in infants and children: 12 months 6, 3

Adjunctive Therapy:

• Corticosteroids are beneficial for tuberculous pericarditis (preventing cardiac constriction) and tuberculous meningitis (decreasing neurologic sequelae), especially when administered early 7
• Surgery may be necessary for constrictive pericarditis, spinal cord compression from Pott's disease, or to obtain diagnostic specimens 7
• Corticosteroids are not routinely recommended for abdominal tuberculosis due to limited evidence 2

Latent Tuberculosis Infection (LTBI)

Who Should Be Tested and Treated:

Systematic testing and treatment of LTBI is strongly recommended for: 7

• People living with HIV 7
• Adult and child contacts of pulmonary TB cases 7
• Patients initiating anti-TNF therapy 7, 1
• Patients receiving dialysis 7
• Patients preparing for organ or hematological transplantation 7
• Patients with silicosis 7

Conditional recommendation for testing and treatment: 7

• Prisoners 7
• Healthcare workers 7
• Immigrants from high TB burden countries 7
• Homeless persons 7
• Illicit drug users 7

Diagnostic Testing:

• Either tuberculin skin test (TST) or interferon-gamma release assays (IGRA) can be used to test for LTBI 7
• TST interpretation: ≥5 mm induration is positive for HIV-infected persons, recent contacts, immunosuppressed persons, and those with chest radiograph suggesting old TB 7, 1
• Perform chest radiography before LTBI treatment to rule out active TB disease 7

LTBI Treatment Regimens:

Recommended regimens include: 7

• 6 or 9 months of isoniazid 7

• 12 weeks of rifapentine plus isoniazid (once weekly by DOT) 7, 9

• 3-4 months of isoniazid plus rifampin 7

• 3-4 months of rifampin alone 7

• For children, 9 months of isoniazid is the only recommended regimen 7

• Rifampin is not recommended in pregnant women 7

Common Pitfalls and Caveats

Drug Interactions:

• Rifampin accelerates clearance of methadone, coumadin, glucocorticoids, estrogens, oral hypoglycemics, digitalis, and anticonvulsants 7
• Increase methadone dosage in patients on rifampin to avoid withdrawal symptoms 7
• Isoniazid and phenytoin interaction increases serum concentration of both drugs; monitor phenytoin levels 7

Adverse Effects:

• Peripheral neuropathy from isoniazid is uncommon at 5 mg/kg but more likely in diabetes, uremia, alcoholism, malnutrition, pregnancy, and seizure disorders - give pyridoxine 50 mg daily prophylactically 7
• Hyperuricemia may occur with pyrazinamide, but acute gout is uncommon 7
• Severe cutaneous adverse reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS, AGEP) have been reported with anti-tuberculosis drug combinations including ethionamide - discontinue immediately if symptoms develop 8

Treatment Failure:

• Frequent smears and cultures are the most reliable means for detecting treatment failure 7
• Treatment failure is often due to patient noncompliance, but may also be due to drug resistance 7
• Reevaluate patients who are smear-positive at 3 months for possible nonadherence or drug-resistant organisms 7

High Drug Resistance Context:

• Given the Philippines' documented 80% initial drug resistance rate in Manila (with 54% resistant to two or more drugs), the four-drug initial regimen is non-negotiable 5
• The study from Manila showed that continuation phase with only isoniazid, pyrazinamide, and ethambutol was inadequate in this high-resistance setting, emphasizing the critical importance of rifampin in the continuation phase 5