*Fredrick M.

Abrahamian, DO,
FACEP
Associate Professor of Medicine, David
Geffen School of Medicine at UCLA, Los
Angeles, California; Director of
Education, Department of Emergency
Medicine, Olive View-UCLA Medical
Center, Los Angeles, California

MDR and MDX: TB Resistant Strains

Tuberculosis is on the rise internationally.

While in the US it seems stable, more and more
people are immigrating to the United States.
Come and hear about this concern and also the
latest Federal TB Task Force recommendations
to combat extensively drug-resistant
tuberculosis. Do I need to admit this patient, or
can I send them home? HIV and TB are like a
perfect storm. The speaker will discuss what is
new with TB, including MDR and MDX TB,
and what may be on the horizon.

Describe the worldwide and national prevalence

of TB.
Illustrate the multi-drug resistance form of TB.
Discuss various treatments for all types of TB.
Discuss strategies of some public health issues
around treatment.

WE-77
9/29/2010
8:00 AM - 8:50 AM
Mandalay Bay Convention Center

*Consultant: Forest Laboratories, Schering-Plough;

Speaker's Bureau-Merck
 MDR & XDR:
TB Resistant Strains
Fredrick M. Abrahamian, D.O., FACEP
Associate Professor of Medicine
UCLA School of Medicine
Director of Education
Department of Emergency Medicine
Olive View-UCLA Medical Center

Tuberculosis
#1 cause of death from infectious diseases
in the world
 ~ 2 million TB-related deaths worldwide
~ 1/3 of world’s population is infected
~ 9 million new cases each year
~ 10-15 million infected in U.S.

MMWR. 2010;59(10):289-294.

TB: U.S., 2009

MMWR. 2010;59(10):289-294.

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 MMWR. 2010;59(10):289-294.

High Risk for TB

Medically underserved, low-income

IV drug users
Alcoholics
Homeless
Immigrants from high-risk areas
Underlying medical illness
HIV

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 Mycobacterium tuberculosis

Slow-growing, intracellular bacterium

Transmitted by droplet nuclei
Small size
 Remains suspended in air
Risk of infection with greater concentrations
& longer exposure
 Small, poorly ventilated areas

Latent TB Infection

No symptoms
Can not spread TB to others
Positive TB skin test (usually)
Normal CXR & negative sputum
Risk of progressing to active TB

Active TB Disease

Typical symptoms:
 Cough, weight loss, fatigue
 Hemoptysis, night sweats
Can spread TB to others
Positive TB skin test (usually)
Positive CXR & sputum (usually)

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 Extrapulmonary TB
Lymphadenitis
Genitourinary
 Sterile pyuria
Musculoskeletal
 Pott’s disease of the spine
Meningitis
 Subacute, cranial nerve signs
 Lymphocytic pleocytosis

TB & HIV

Greater likelihood of progressing to active TB

 8% per year vs. 5-10% over lifetime
Atypical presentations
More extrapulmonary TB
Atypical CXR findings
Often mistaken for PCP or other pneumonia

Multidrug-Resistant (MDR) TB
Resistant to at least INH & rifampin
 2008: 107 cases (1.1% of all culture + cases)
~ 8% resistance to INH reported in U.S.
High risk:
 Prior Hx of TB (risk increases 4 fold)
 Known exposure to MDR TB
 Immigrant: Asia, Africa, S. America
 Homeless
 Prison
MMWR. 2010;59(10):289-294.

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 MDR TB in
Healthcare Workers

PPD conversions in MDR TB outbreak

 33% healthcare workers at 1 hospital
 50% at another
At least 17 healthcare with active MDR TB
At least 5 healthcare deaths from MDR TB

Extensively Drug-Resistant TB
(XDR TB)

Resistance to at least INH & rifampin

Resistance to any fluoroquinolone
Resistance to at least one 2nd-line injectable drug
(e.g., amikacin, capreomycin, or kanamycin)
No cases reported in 2009
4 cases reported in 2006; 2 in 2007; & 4 in 2008

MMWR. 2010;59(10):289-294.

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Number of XDR TB - U.S., 1993-2006

MMWR. 2007;
56(11):250-253.

TB Transmission in ED

1983 outbreak: Patient in ED for 4 hours

 16 PPD skin test conversions
 112 previously negative ED employees
 5 developed active TB
 3 of 4 physicians involved with patient
converted PPD skin test

TB Infection Control

Early identification of TB patients

Initiate isolation
Initiate effective TB therapy
Use precautions for risky procedures

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 TB Isolation &
Suspicion of TB in ED

Median time to isolation & therapy (hours)

TB Dx Other Dx p
Isolation 5 (2-10) 21 (11-111) < .001
Therapy 12 (9-22) 128 (68-374) < .001

Moran GJ, et al. Ann Emerg Med. 1995;26:290-295.

Predictors of Time to Isolation

Median Time to
Variable Presence p
Isolation (hr)
TB contact Yes 1.5 (1-3) .0001
No 8 (4-14)
X-ray + TB Yes 6.5 (2-11) .0010
No 17 (7-132)
HIV Risk Yes 17 (7-132) .0084
No 6.5 (2-11)

Moran GJ, et al. Ann Emerg Med. 1995;26:290-295.

Isolation Room

Negative pressure
6 air exchanges per hour
Exhaust directly to outside
Need N-95 respirator

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 TB Infection Control in U.S. EDs

~ 60% have triage isolation policies

< 20% have AFB isolation rooms
< 20% have HEPA filters or UV lights
< 20% use particulate respirator masks
< 20% skin test ED employees q6 months
~ 60% perform sputum induction in ED

Moran GJ, et al. Ann Emerg Med. 1995;26:283-289.

Reducing Risk of TB Transmission

Triage protocols to rapidly identify TB patients

Rapid isolation of TB patients
Isolation rooms
HEPA filters
UV lights
Avoid high-risk procedures

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 Isolation & Infection Control
Many unnecessary admissions to isolation
On average, only ~ 68% of TB patients are isolated
Instrument to predict which patients do NOT have TB
 No TB Hx. or previous positive TB skin test result
 Non-immigrant
 Not homeless
 Not recently incarcerated
 No recent weight loss
 No apical infiltrate or cavitary lesion on CXR
Moran GJ, et al. Ann Emerg Med. 2009;53:625-632.

Testing for TB Disease & Infection

Indications for PPD Testing

Suggestive symptoms or CXR

Contact with active TB
HIV
Diabetes, renal failure, immunosuppressed
Exposure Risk: Immigrants, homeless,
prison, long-term care facility, healthcare
workers

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 Administering the Tuberculin
Skin Test

Inject intradermally 0.1 ml of 5 TU PPD

tuberculin
Produce wheal 6 mm to
10 mm in diameter
Anergy skin testing no
longer routinely recommended

Reading the Tuberculin Skin Test

Read reaction 48-72 hours after injection
Measure only induration
Record reaction in millimeters

Tuberculin Reaction

≥ 5 mm is classified as positive in:

 HIV+
 Recent close contact
 Persons with fibrotic changes on CXR
consistent with old healed TB
 Immunosuppressed (e.g., > 15 mg/day
of prednisone for 1 month or longer)

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 Tuberculin Reaction
≥ 10 mm is classified as positive in:
 Immigrants from high-prevalence countries
 Injection drug users
 Individual at high-risk congregate settings
 Mycobacteriology laboratory personnel
 High risk conditions (DM, CA, renal failure)
 Children < 4 years of age
 Children exposed to adults in high-risk
categories

Tuberculin Reaction

≥ 15 mm is classified as positive in:

 Persons with no known risk factors
for TB

Bacille Calmette-Guerin (BCG)

Most commonly used TB vaccine
Used in many countries with high TB risk
Provides only partial protection
BCG history does not change interpretation
of PPD results:
 Given in areas at risk for TB
 BCG usually causes reaction < 10 mm
 Reaction wanes with time

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 Chest Radiograph

Abnormalities often seen in apical or

posterior segments of upper lobe or
superior segments of lower lobe
May have unusual appearance in HIV+
persons
Can not confirm diagnosis of TB

CXR: AIDS & TB

Hilar / mediastinal adenopathy 59%
No infiltrate 35%
Middle / lower lung infiltrate 29%
Upper lobe infiltrate 18%
No abnormality 12%
Typical TB findings 6%

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 Specimen Collection
Obtain 3 sputum specimens for
smear examination & culture
Persons unable to cough up sputum,
induce sputum, bronchoscopy or
gastric aspiration
Follow infection control precautions
during specimen collection

AFB Smear

AFB (shown in red) are tubercle bacilli

Cultures
Use to confirm diagnosis
Culture all specimens, even if smear negative
Results in 4 to 14 days when liquid medium
systems used

Colonies of
M. tuberculosis
growing on media

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 TB Preventive Treatment

To reduce likelihood of progression to active

disease
Consider risk of TB vs. toxicity of therapy
INH x 9 months for most
If INH resistance likely: Rifampin + PZA

Positive PPD: Indications for Rx

Any new converter
HIV+
Recent contact with infectious TB
Old TB on CXR
Increase risk of active TB:
 DM, CA, steroids, renal failure
Age < 35
? older patients: Monitor for hepatotoxicity

Treatment of Active TB

Requires multiple drugs

Start with 4 drugs, then reduce to 2 drugs
based on susceptibility
Culture & susceptibility takes ~ 8 wks
Compliance important
Directly Observed Therapy (DOT) when
possible

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 1st Line TB Drugs

Adult dose
Isoniazid 300 mg/d
Rifampin 600 mg/d
Pyrazinamide 25 mg/kg/d (max 2.5 gm)
Ethambutol 15-25 mg/kg/d
Streptomycin 15 mg/kg/d

2nd Line TB Drugs

Capreomycin Kanamycin
Ciprofloxacin Amikacin
Clofazimine Levofloxacin
Cycloserine Ofloxacin
Ethionamide Aminosalicylic acid
Rifabutin
Rifapentine

3rd Line TB Drugs

Linezolid
Imipenem
Amoxicillin/clavulanate
Macrolides

Schecter GF, et al. Clin Infect Dis. 2010;50:49-55.

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 Treatment of Active TB
Common regimen:
 INH, Rifampin, PZA, Ethambutol daily x 8 wks
 Then INH + Rifampin for 18 weeks
(assuming organism is susceptible)
Longer duration of therapy for TB meningitis,
miliary TB, or bone/joint TB infection
Dexamethasone beneficial with TB meningitis

Prasad K, et al. Cochrane Database Syst Rev. 2008.

Thwaites GE, et al. N Engl J Med. 2004;351:1741-1751

Treatment of MDR & XDR TB

Treatment must be individualized

Requires combination of 2nd or 3rd
line agents
Expert consultation
Directly Observed Therapy

Response to Treatment

Requires monthly bacteriologic assessment until

cultures convert to negative
After 3 months of therapy, if cultures are + or Sxs
not resolved, reevaluate for:
 Potential drug-resistant disease
 Non-adherence to drug regimen
If cultures do not convert to negative despite 3
months of therapy, DOT needs to be initiated

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 Period of Infectivity

TB patients are considered no longer

infectious if:
 On adequate therapy
 Significant clinical response to therapy
 3 consecutive negative sputum smears

Fitzwater SP, et al. Clin Infect Dis. 2010;51:371-378.

Take Home Points

Initial treatment of active TB with 4 drugs:
 INH, RIF, PZA, ETB
Treatment of MDR & XDR TB:
 Requires combination of various agents
Treatment of latent infection:
 INH (optimal therapy: 9 months)
Tuberculin skin test reaction:
 Induration ≥ 5 mm considered + in a patient
taking > 15 mg/day of prednisone for ≥ 1 month

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