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TB: Management in an era of multiple drug resistance
Bob Belknap M.D.
Denver Public Health
November 2012
Objectives: 1. Explain the steps for diagnosing latent
and active TB role of interferon-gamma release assays
(IGRAs) sensitivity of sputum smears and nucleic acid
amplification tests (NAATs) 2. List the first-line drugs used for latent and
active TB treatment 3. Describe the resistance patterns that
define MDR and XDR TB.
Case 1: 52 y/o male
Born in the Pacific Islands; some travel in the U.S. military
Known (+) TST (h/o BCG)
1 month of cough, fever, weight loss
Refused admission
Case 1: 52 y/o male
Hospitalized 2 weeks later
QuantiFERON negative
Lung bx shows granulomas, AFB smear (-)
Presumed to have hypersensitivity pneumonitis or sarcoidosis
Case 1: 52 y/o male Clinically worse after
1 month on steroids Died shortly after
readmission
What went wrong?
Missed Opportunity for Prevention (2)
Known (+) TST but never treated for LTBI
h/o BCG - protects children from dying of TB but does not protect from infection
The TST is considered reliable for diagnosing LTBI if the BCG was given > 1 year prior
Reactions due to BCG wane over time so the CDC recommends interpreting (+) tests the same as persons without BCG
Interferon-gamma Release Assays (IGRAs) 1.Blood tests for detecting TB infection 2.Requires 1 visit 3.Results retrievable electronically 4.Better in BCG-vaccinated
Objective 1 – Diagnosing LTBI (1) Think about TB risks
Risk for Infection :
Born or travelled to TB endemic countries, known close contact to TB
Risk for Progression :
HIV, DM, ESRD, TNF-α blocker, silicosis, fibrotic disease on x-ray
Objective 1 – Diagnosing LTBI (2) TST or IGRA
Rule out active TB Symptom review CXR on everyone sputum collection if the CXR is abnormal or the
person is symptomatic
Determine prior history of treatment for LTBI or TB disease
Assess risks of toxicity
Case 2 - 25 yr old female
Radiology reading: Fibrotic opacity in the right upper lobe with pleural thickening consistent with scarring from old TB
Case 2 - 25 yr old female
3 sputa grew MTB
If you collect sputa, wait to start LTBI Rx
Objective 2 – LTBI treatment options Isoniazid (INH) daily x 9 months
Longest history / most data
More completion rates
INH/Rifapentine once weekly by DOT x 12 weeks
Safe and effective but cost limited due to DOT
Rifampin daily x 4 months
Remember to look for drug-drug interactions
Case 1: 52 y/o male
Hospitalized 2 weeks later
QuantiFERON negative
Lung bx shows granulomas, AFB smear (-)
Presumed to have hypersensitivity pneumonitis or sarcoidosis
Objective 1 – Diagnosing Active TB Risk for Infection :
Born or travelled to TB endemic countries, known close contact to TB
Risk for Progression :
HIV, DM, ESRD, TNF-α blocker, silicosis, fibrotic disease on x-ray
Concerning Symptoms
1. History (including travel) 2. Physical examination (non-specific) 3. Chest x-ray 4. TB Skin Test (aka TST, PPD) or Interferon-γ Release Assay (IGRA) 5. Bacteriologic or histologic examination * Avoid empiric fluoroquinolones
Objective 1: Diagnosing Active TB
“Concerning” Symptoms
General: fever, night-sweats, weight loss, fatigue
Pulmonary: Cough > 3wks, hemoptysis, shortness of breath, chest pain
Extrapulmonary - lymphadenopathy, headache, stiff neck, altered mental status, hematuria, chest or abdominal pain
Symptom/sign HIV positive (%) HIV negative (%) Dyspnea Fever Sweats Weight loss Diarrhea Hepatomegaly Splenomegaly Lymphadenopathy
97 79 83 89 23 41 40 35
81 62 64 83
4 21 15 13
Chest 1994;106:1471-6
TB Symptoms and HIV
19
TST and IGRA: Sensitivity for Active TB
Meta-analysis Data presented for TST and the commercially
available assays (QFT-GIT and T-SPOT)
Results:
Diel, Chest April 2010 137(4): 952
% (95% CI) TST 70( 67-72) QFT-GIT 84 (81-87) T-SPOT 88 (85-90)
Case 1: 52 y/o male
AFB smear (-) on lung biopsy
Smear Sensitivity 50% from sputa Less from tissue Worse in HIV (+)
All BAL (+) patients were diagnosed by induced sputa
BAL missed 2 patients No difference in yield between sputa
collected over 3 days vs. 1 day
Empirical TB treatment without a positive smear or culture Clinical reasons at risk for life-threatening TB, including ones often
never confirmed (e.g. < 50% of TB meningitis is culture positive)
Public health reasons return to work/school while cultures are pending,
children at home, staying in a congregate setting (nursing home or homeless shelter)
Objective 2: First-line TB Therapy
Medication Side Effects
Rifampin (Rif) P450 inducer,hepatitis, rash, flu-like symptoms, hypersensitivity
Isoniazid (INH) Fatigue, peripheral neuropathy, hepatitis
Pyrazinamide (PZA) GI upset, rash, hepatitis, uric acid elevation (rare gout attack)
Ethambutol (EMB) Rare optic neuritis
Standard Treatment of Tuberculosis
1. Intensive Phase INH, Rifampin, Pyrazinamide and Ethambutol x
2 months First 2 to 3 weeks are spent in home isolation –
can’t work, go to school or be out in public places
2. Continuation Phase INH and Rifampin x 4 months
Case 3 - 18y/o male
Born in Somalia, moved from Chicago
Empty bottle of rifampin 600 mg, #30 filled at Chicago health dept 2 months earlier
Says his chest X-ray was abnormal & sputum cultures negative
Denies any symptoms or signs of TB
Case 3 - 18y/o male
Smears: Neg/Neg/1+
Fax report from Chicago: 3 negative smears & cultures
Is this active TB? Is it drug resistant?
Culture and Susceptibility Testing
Method Time to Detection
Time to Susceptibility
Comments
Solid Media
3-4 weeks 3-4 weeks Gold standard
Broth 10-14 d 5-10 days
Molecular 1 day 1 day Newer technologies are making this more feasible
Case 3 - 18y/o male
Confirmed TB resistant to INH and Rif in 72 hours
Cx (+) MTB resistant to INH, Rifampin, PZA, EMB and streptomycin
Is this XDR-TB ?
Objective 3: Drug Resistant Tuberculosis
Multi-drug Resistant (MDR) Resistant to at least INH and Rifampin
Extensively Drug Resistant (XDR) Resistant to INH and Rifampin plus Fluoroquinolones Second-line injectable agent
(amikacin, kanamycin, or capreomycin)
Treatment of Suspected Drug-resistant TB Consider when a patient has a prior history of
TB treatment and appears to have relapsed
Consult an expert in TB treatment
Never add a single drug to a failing regimen (eg. fluoroquinolones)
News Alerts POSTED: 1:16 pm June 11, 2007 Colorado Springs Student From Nepal Dies From TB COLORADO SPRINGS, Colo. -- Tuberculosis was confirmed as the cause of death of a patient who died shortly after arriving at the emergency room on Friday.
A previously healthy student died of a preventable & treatable illness
Why do people still die of TB in the U.S.? – Clinician Factors Failure to diagnose and treat latent infection Delays considering TB in the differential Delays working up symptomatic patients Misperception about the accuracy of our
diagnostic tests Empiric use of fluoroquinolones Failure to report suspect cases to the health
department and to start empiric TB treatment Failure to monitor appropriately while on
treatment
Contact Information
Denver Metro TB Clinic 602-7240 Randall Reves MD (clinic director) 602-7257 Bob Belknap MD (ID physician) 602-7244 CDC Division of TB Elimination - guidelines http://www.cdc.gov/nchstp/tb/default.htm
Resources
CDC www.cdc.gov/tb/ Francis J Curry Center www.currytbcenter.ucsf.edu/ Stop TB Partnership www.stoptb.org WHO http://www.who.int/tb/en/
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