Tuberculosis
Mycobacterium tuberculosis -airborne transmission. Latent TB (positive PPD/IGRA, no symptoms) vs Active TB (cough, fever, night sweats, weight loss, cavitary lesions). Airborne isolation. 4-drug RIPE therapy × 6 months.
🔍 Overview
Latent vs Active TB
| Feature | Latent TB (LTBI) | Active TB |
|---|---|---|
| Symptoms | None | Cough > 2–3 wks, hemoptysis, fever, night sweats, weight loss |
| CXR | Normal | Upper lobe cavitary lesions, infiltrates, hilar LAD, Ghon complex |
| AFB smear | Negative | May be positive (3 sputum samples) |
| Infectious | No | Yes -airborne isolation required |
| PPD/IGRA | Positive | Usually positive (can be negative if immunosuppressed) |
Airborne isolation (negative pressure room, N95 for staff) for ANY suspected active TB until 3 consecutive negative AFB smears collected 8–24h apart.
Extrapulmonary TB
| Site | Presentation | Diagnosis |
|---|---|---|
| TB Meningitis | Subacute headache, cranial nerve palsies, basilar meningitis | CSF: lymphocytic, low glucose, high protein. NAAT on CSF. |
| Miliary TB | Disseminated, diffuse millet-seed nodules on CXR. Immunosuppressed patients. | Culture blood, urine, bone marrow. |
| TB Lymphadenitis (Scrofula) | Painless cervical LAD, most common extrapulmonary TB | FNA with AFB/culture. |
| Vertebral (Pott Disease) | Back pain, paraspinal abscess. Can cause cord compression. | MRI spine. |
| Pleural TB | Exudative effusion, lymphocytic, high ADA (>40) | Pleural biopsy most sensitive. |
| Pericardial TB | Effusion, may cause tamponade. Common in HIV+. | Pericardial fluid culture, biopsy. |
| Renal TB | Sterile pyuria, hematuria | Urine AFB cultures. |
| GI TB | Mimics Crohn disease. Ileocecal region most common. | Colonoscopy with biopsy, AFB culture. |
TB Meningitis: Add Dexamethasone to RIPE for TB meningitis - reduces mortality by ~30% Thwaites, 2004. Extend total treatment to 9-12 months. Miliary TB also treated for 9-12 months.
"RIPE" Mnemonic for TB Treatment: R-Rifampin, I-Isoniazid, P-Pyrazinamide, E-Ethambutol. All 4 for initial 2 months, then RI for remaining 4 months = 6 months total.
Side Effects Mnemonic - Remember by the drug's first letter:
- Rifampin = Red/orange body fluids
- INH = Injury to liver (hepatotoxicity) + Injury to nerves (peripheral neuropathy)
- Pyrazinamide = Painful joints (hyperuricemia/gout) + liver Problems
- Ethambutol = Eyes (optic neuritis)
🚨 Management
Active TB: RIPE Therapy
| Drug | Duration | Major Side Effects |
|---|---|---|
| Rifampin (Rifadin) | 6 months | Orange body fluids, hepatotoxicity, drug interactions (CYP450 inducer) |
| Isoniazid (INH) | 6 months | Hepatotoxicity, peripheral neuropathy (give Pyridoxine (Vitamin B6) 25–50 mg daily) |
| Pyrazinamide | 2 months | Hepatotoxicity, hyperuricemia/gout |
| Ethambutol (Myambutol) | 2 months | Optic neuritis -check visual acuity monthly. Red-green color blindness. |
Latent TB Treatment
- Isoniazid (INH) 300 mg daily × 9 months (classic regimen)
- Rifampin (Rifadin) 600 mg daily × 4 months (shorter, preferred)
- INH + Rifapentine (Priftin) weekly × 12 weeks (3HP regimen -DOT)
Key Evidence: Standard 6-month RIPE remains the backbone of TB treatment BTS, 1998. For LTBI, the 3HP regimen (12-week INH + rifapentine) has equivalent efficacy with superior completion PREVENT TB, 2011. Rifampin x 4 months is now preferred over 9-month INH for LTBI in adults 4R vs 9H, 2018.
🧪 Workup
- PPD (tuberculin skin test) -read at 48–72h. Induration (not redness) matters. Cutoff varies by risk.
- IGRA (QuantiFERON, T-SPOT) -blood test, single visit, not affected by BCG vaccination
- CXR -upper lobe infiltrates, cavitary lesions, Ghon/Ranke complex
- 3 sputum AFB smears and cultures -collected 8–24h apart. Culture is gold standard (takes 2–6 wks).
- NAAT (GeneXpert/Xpert MTB/RIF) -rapid PCR, also detects rifampin resistance
- HIV test -all TB patients (TB-HIV coinfection common)
PPD Interpretation Cutoffs
| Cutoff | Population |
|---|---|
| ≥ 5 mm | HIV+, close contacts, immunosuppressed, CXR with old TB, organ transplant recipients |
| ≥ 10 mm | Recent immigrants (< 5 yrs), IVDU, healthcare workers, residents of congregate settings, children < 4 yrs, high-risk medical conditions (diabetes, ESRD, silicosis) |
| ≥ 15 mm | Low-risk individuals with no known TB exposure or risk factors |
GeneXpert MTB/RIF Ultra: Rapid PCR with results in < 2 hours. Sensitivity ~96% for smear-positive, ~67% for smear-negative pulmonary TB Dorman, 2018. Simultaneously detects rifampin resistance. WHO recommends as initial diagnostic test for all suspected TB.
💊 Medications
| Drug | Dose | Key Monitoring |
|---|---|---|
| Isoniazid (INH) | 5 mg/kg (max 300 mg) daily | LFTs monthly. Give B6 (pyridoxine) to prevent neuropathy. |
| Rifampin (Rifadin) | 10 mg/kg (max 600 mg) daily | LFTs. CYP450 inducer -check all drug interactions. |
| Pyrazinamide | 25 mg/kg daily | LFTs, uric acid (causes hyperuricemia). |
| Ethambutol (Myambutol) | 15–20 mg/kg daily | Visual acuity and color vision monthly. |
| Pyridoxine (Vitamin B6) | 25–50 mg daily | Given with INH to prevent peripheral neuropathy. |
📋 On Rounds
Pimp Questions
Why do you give pyridoxine (B6) with isoniazid?
INH inhibits pyridoxal phosphokinase → depletes active vitamin B6 (pyridoxine) → peripheral neuropathy (stocking-glove distribution). Risk factors: malnutrition, pregnancy, HIV, diabetes, alcoholism, renal failure. Give B6 25–50 mg daily to all patients on INH as prophylaxis.
What is the most feared side effect of ethambutol?
Optic neuritis -presents as decreased visual acuity, red-green color blindness, central scotomas. Usually dose-dependent and reversible if caught early. Check baseline visual acuity and color vision, then monthly. Discontinue immediately if visual changes occur.
When is a PPD considered positive at ≥5 mm?
HIV+, close contacts of active TB, immunosuppressed (TNF inhibitors, transplant), CXR with old healed TB. These are the highest-risk groups for reactivation. Lower-risk groups use ≥10 mm or ≥15 mm cutoffs.
Why is IGRA preferred over PPD in BCG-vaccinated patients?
BCG cross-reacts with PPD tuberculin, causing false positive PPD. IGRA uses M. tuberculosis-specific antigens (ESAT-6, CFP-10) not present in BCG or most NTM, so no cross-reactivity. Single blood draw, no return visit needed.
What is the 3HP regimen and why is it preferred for LTBI?
Isoniazid + Rifapentine weekly x 12 doses (DOT). PREVENT TB, 2011 showed equal efficacy to 9-month INH with better completion (82% vs 69%). Shorter = better adherence.
What drug interactions does rifampin cause?
Potent CYP3A4/2C9 inducer. Reduces levels of: warfarin, OCPs, HIV protease inhibitors, calcineurin inhibitors (cyclosporine, tacrolimus), methadone, azole antifungals. In HIV patients, substitute Rifabutin (Mycobutin) instead.
How do you monitor for hepatotoxicity during RIPE therapy?
Baseline LFTs, then monthly if risk factors (alcohol, liver disease, HIV, age >35). Hold all hepatotoxic drugs if AST/ALT >3x ULN with symptoms or >5x ULN without symptoms. Rechallenge sequentially: RIF first, then INH, then PZA.
What defines MDR-TB vs XDR-TB?
MDR-TB = resistant to rifampin + isoniazid. XDR-TB (2021 WHO definition) = MDR + resistant to fluoroquinolone + bedaquiline/linezolid. XDR mortality up to 50-80% in some settings.
When should you suspect TB meningitis?
Subacute headache + cranial nerve palsies (especially CN VI) + basilar meningitis. CSF: lymphocytic pleocytosis, low glucose, high protein, high ADA. Confirm with CSF NAAT. Start empiric RIPE + Dexamethasone per Thwaites, 2004.
Case 1: Active Pulmonary TB
Patient: 34M immigrant, 3-month cough, night sweats, 15 lb weight loss. CXR: upper lobe cavitation. AFB smear 3+ positive. GeneXpert MTB/RIF positive, rifampin sensitive.
Management:
- Airborne precautions - negative pressure room, N95 for all staff
- Start RIPE therapy: Rifampin (Rifadin) + Isoniazid (INH) + Pyrazinamide (PZA) + Ethambutol (Myambutol) × 2 months, then Rifampin + Isoniazid × 4 months
- Add Pyridoxine (B6) 25–50 mg daily with INH to prevent neuropathy
- DOT (directly observed therapy) mandatory - improves adherence, prevents resistance
- Report to health department - legally required for all active TB cases
- HIV test in all TB patients
Key lesson: GeneXpert confirms TB and rules out rifampin resistance within hours. Start RIPE, isolate, report - do all three same day.
Case 2: Latent TB - Immunosuppressed Patient
Patient: 52F with RA, positive IGRA, no symptoms, normal CXR. About to start Adalimumab (Humira) (anti-TNF biologic).
Management:
- Rule out active disease first - symptom screen + CXR (active TB must be excluded before treating latent)
- Preferred regimen: Rifampin (Rifadin) × 4 months or 3HP - Isoniazid + Rifapentine (Priftin) weekly × 12 doses (directly observed)
- Complete LTBI treatment BEFORE starting biologic - anti-TNF agents profoundly impair granuloma formation, risking TB reactivation
- Minimum 4 weeks of LTBI treatment should precede biologic initiation when possible
Key lesson: Biologic therapy (especially anti-TNF) is a major reactivation risk. Screen with IGRA before every biologic start. Treat and complete LTBI therapy first.
Case 3: Drug-Resistant TB (MDR-TB)
Patient: 28M with known TB, returns after incomplete treatment. GeneXpert and DST: MDR-TB - resistant to both Rifampin and Isoniazid.
Management:
- Infectious disease + public health consultation essential - do not manage MDR-TB alone
- Regimen per WHO 2022 guidance: Bedaquiline (Sirturo) + Linezolid (Zyvox) + Levofloxacin (Levaquin) as core agents
- Minimum 18-month treatment course - substantially longer than drug-sensitive TB
- Monitor for drug toxicities: bedaquiline (QTc prolongation), linezolid (bone marrow suppression, neuropathy), levofloxacin (tendinopathy, QTc)
- Airborne isolation maintained; DOT mandatory throughout
Key lesson: MDR-TB = resistant to rifampin + INH. Treatment is prolonged, toxic, and complex - always requires specialist and public health co-management. Incomplete prior treatment is the #1 driver of drug resistance.
⚡ Summary
Isolate First, Ask Later
Airborne isolation, negative pressure room and N95 for staff, for ANY suspected active TB. Continue until 3 consecutive negative AFB smears collected 8 to 24 h apart, or the diagnosis is excluded. The isolation decision is made on suspicion, not on confirmation, because the exposure happens while the workup is pending.
Latent or Active
Latent: positive PPD or IGRA, no symptoms, normal chest x-ray, not infectious. Active: cough beyond 2 to 3 weeks, hemoptysis, fever, night sweats, weight loss, with cavitary or upper lobe disease and positive smears. Never treat latent TB without excluding active disease first: single-drug therapy in undiagnosed active TB generates resistance.
Diagnose Fast With GeneXpert
GeneXpert MTB/RIF Ultra gives a result in under 2 hours and simultaneously detects rifampin resistance, which is why WHO recommends it as the initial test. Sensitivity is about 96% in smear-positive but only about 67% in smear-negative pulmonary TB, so a negative result does not exclude disease. Still send 3 sputum samples for smear and culture, because culture remains the gold standard and is what gives full susceptibilities.
RIPE for 2 Months, Then RI for 4
Rifampin, Isoniazid, Pyrazinamide, Ethambutol for the first 2 months, then rifampin and isoniazid for 4 more, 6 months total. Ethambutol can be dropped once susceptibility confirms a fully sensitive organism. Use directly observed therapy, because incomplete treatment is what creates multidrug resistance.
Know the Toxicity by First Letter
Rifampin: Red or orange body fluids, and it is a potent CYP inducer that wrecks warfarin, oral contraceptives, azoles and antiretrovirals. Isoniazid: Injury to the liver, and Injury to nerves, so give pyridoxine 25 to 50 mg daily to prevent the peripheral neuropathy. Pyrazinamide: Painful joints from hyperuricemia, plus hepatotoxicity. Ethambutol: Eye, optic neuritis with loss of red-green discrimination, so check visual acuity and color vision at baseline and monthly.
Extend the Course for Certain Sites
TB meningitis and miliary TB are treated for 9 to 12 months. Bone and joint TB for 6 to 9 months. Add dexamethasone in TB meningitis, which reduces mortality by roughly 30% (Thwaites), and in pericarditis. Extend pulmonary treatment to 9 months if there is cavitation with a positive culture at 2 months, since that combination predicts relapse.
Latent TB Has Shorter Options Now
3HP, 12 weekly doses of isoniazid plus rifapentine, has equivalent efficacy with much better completion rates (PREVENT TB). Rifampin daily for 4 months is another short option with less hepatotoxicity than isoniazid. 9 months of isoniazid still works but completion is poor, and a regimen that is not finished is not a treatment.
Read the PPD Against the Right Cutoff
5 mm in HIV, recent contacts, fibrotic changes on chest x-ray, transplant recipients and anyone on prolonged steroids or a TNF inhibitor. 10 mm in recent immigrants from high-prevalence countries, injection drug users, healthcare and congregate-setting residents, and high-risk comorbidities. 15 mm in people with no risk factors. IGRA is preferred in BCG-vaccinated patients, because BCG causes a false positive PPD and does not affect the IGRA.
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