Tuberculosis
Treatment,
Prevention, and
Control
Christina M. Madison,
Pharm.D., BCACP
Haley Blake, BA
Course Objectives
• Identify causes of and route of transmission of
tuberculosis (TB)
• Explain the difference between active TB disease and
latent TB infection (LTBI)
• Discuss the prevalence of tuberculosis in the United
States and Clark County
• Determine appropriate treatment for those with
Active TB disease or Latent TB Infection
Background
• TB is one of the world’s deadliest diseases
• One-third of the world’s population is infected with TB
– Accounting for approximately 2 billion people
• Each year, 8 million people around the world become ill with
TB
• 2-3 million TB related deaths worldwide each year
• TB cases continue to be reported in every state
• Estimated 10-15 million persons in U.S. infected with M.
tuberculosis
Background
• Without intervention, about 10% will develop TB disease at
some point in their lives
• Approximately, 10% of persons with competent immune
systems who do not receive treatment will develop TB at one
point in their lifetime
• TB infection and diabetes increases your risk of developing
disease to 30% in your lifetime
• TB and HIV infection increases your risk of developing TB
disease 7-10% per year that you have both diagnoses (very
high lifetime risk)
• Drug-resistant cases have been reported in every state
Terminology
• Latent TB Infection (LTBI)
• Active TB
– Pulmonary
• Disease in the lungs ONLY
– Extrapulmonary
• Disease outside the lungs
– Disseminated
• Disease in the lungs and another area of the body
• BCG Vaccine
– Bacillus Calmette-Guérin
• Routinely used in other countries where TB is
endemic
• Acid Fast Bacilli (AFB)
• Non-Tuberculosis Mycobacterium species (NTM’s)
Terminology
First Line Drugs
• Isoniazid = INH
• Rifampin = RIF
• Rifabutin = RBT
• Rifapentine = RPT
• Ethambutol = EMB
• Pyrazinamide = PZA
Second Line Drugs
• Streptomycin = SM
• Levofloxacin = LEVO
• Moxifloxacin = MOXI
• Capreomycin = CAPRO
• p-Aminosalicyclic acid = PAS
or PASER
• Ethionamide = ETH
• Amikacin
• Kanamycin
Pathogens
• Mycobacterium tuberculosis complex (MTBC)
– M. tuberculosis
– M. africanum
– M. microti
– M. bovis
• Atypical Mycobacterium species (NTM’s ≈ 150)
– AKA Mycobacterium Other Than Tuberculosis
(MOTT)
• M. kansasii
• M. gordonae
• M. avium complex
Non-Tuberculosis Mycobacterium (NTM)
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Also known as Mycobacterium Other Than Tuberculosis (MOTT)
NTM rates are not nationally reportable and exact rates are unknown
NTMs can be found in soil, food, water, and animals
Municipal water systems (including tap water)
Most infections acquired via ingestion, aspiration, or inoculation with the
organism (water sources most common)
• Human to human transmission has not been documented
• Species such as Mycobacterium avium complex are commonly associated
with HIV infection and severely immunocompromised states
– M. avium complex encompasses intracellulare, M. kansasii, and M.
gordonae
– Usually associated with pneumonia or disseminated infection
– Leading cause of NTM infection in humans
Non-Tuberculosis Mycobacterium (NTM)
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An increased number of cases of pulmonary disease from NTMs is being seen
in postmenopausal Caucasian women
Also increasing reports of NTM infections involving skin, soft tissues, and
bone/joint
Presentation can be similar to TB, especially in NTM pneumonia
Diagnosis often more difficult to obtain than TB
– Some individuals can be colonized but never have NTM disease
2007 ATS/IDSA Criteria
– Radiographic evidence of disease AND
– At least 2 sputum cultures positive, or
– One bronchoalveolar lavage (BAL) or lung biopsy or tissue specimen with
positive culture, or
– Tissue with granulomatous histopathology in conjunction with positive
culture (BAL or sputum)
Non-Tuberculosis Mycobacterium (NTM)
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Study suggests that treatment is most beneficial in those with cavitary
“classic” disease
Less effective in those with bronchiectatic form
Duration of therapy is no less than 12 months (typically 18-24 months)
Combination of the following (at least 3 medications)
– Clarithromycin or azithromycin
– Ethambutol (+/- amikacin)
– Rifabutin or Rifampin
– Please note: fluroquinolone (moxifloxacin or levofloxacin) are not
recommended due to their wide use in Community Acquired Pneumonia
(CAP) and high risk of resistance
If patient is not improving on therapy consider drug absorption difficulties
Medical consultation is available with the 4 regional TB centers:
http://www.cdc.gov/tb/education/rtmc/
Tuberculosis Epidemiology
• Over 11,000 people were diagnosed with
tuberculosis in the U.S. in 2010
• Rates of TB related death have been steadily
declining but are still a problem in the U.S.
• Nevada ranks in the top 15 states for increased rates
of TB infection and disease
• Growing number of cases reported between the
ages of 25-44 years of age
• Higher rates of infection in men than women
• Race and ethnicity rates
– Asians > Hispanic or Latino > Black or African
American > White
No. of Cases
Reported TB Cases
United States, 1982–2010*
Year
*Updated as of July 21, 2011
TB Case Rates,* United States, 2010
D.C.
< 3.6 (2010 national average)
>3.6
*Cases per 100,000.
TB Case Rates by Race/Ethnicity*
United States, 2003–2010**
Cases per 100,000
35.0
30.0
25.0
20.0
15.0
10.0
5.0
0.0
2003
2004
2005
2006
2007
2008
2009
Hispanic or Latino
American Indian or Alaska Native
Asian
Black or African American
Native Hawaiian or Other Pacific Islander
White
*All races are non-Hispanic.
**Updated as of July 21, 2011.
2010
Countries of Birth of Foreign-born Persons
Reported with TB, United States, 2010
Mexico
(23%)
Other Countries
38%
Philippines
(11%)
Haiti
India
(3%)
Guatemala China
(3%)
(5%)
Vietnam
(8%)
(9%)
Percent of Foreign-born with TB by Time of
Residence in U.S. Prior to Diagnosis, 2010
100
80
60
40
20
0
Mexico
Philippines
Unknown*
<1 year
India
1-4 years
All Foreign-born
≥5 years
*Foreign-born TB patients for whom information on length of residence in the U.S. prior to diagnosis is unknown or
missing
TB in Clark County
Year
2009
2010
2011
Total Case
Diagnosis
87
97
85
Foreign Born
71%
69%
73%
• 11% Mexico
• 14% Mexico
• 18% Mexico
• 36% Philippines
• 22% Philippines
18 other countries
• 25% Philippines
15 other countries
Homeless
3%
9%
2%
Uncontrolled
Diabetes
22%
19%
15%
HIV/AIDS Coinfected
3%
6%
2%
Children born in US
with risk factors
8%
13%
4%
Transmission
• Spread by droplet nuclei
– Airborne infection
• Expelled by active cases of pulmonary and laryngeal TB
– Speaking: 0 to 210 particles
– Coughing: 0 to 3,500 particles
– Sneezing: 4,500 to 1,000,000 particles
• Transmitted by infectious TB person
– NOT those with latent TB infection
• Small number of bacilli may multiply intracellularly
– Can be released if the macrophage it is contained in dies
Transmission
• Tubercle bacilli can enter the blood stream and spread
throughout the body
• Easily spread through the lymphatic system
• Tissues and organs that TB can infect
– Regional lymph nodes, apex of the lungs, larynx,
kidneys, spine, brain, and bone
• Less likely (rare)
– Ingestion of unpasteurized cheese or milk and BCG
bladder irrigation
• M. bovis
Risk Factors for Transmission
• Close contacts are at highest risk of becoming
infected
– Household contact, incarceration, and/or school
• Infectiousness of person with active pulmonary TB
disease
• Environment in which exposure occurred
• Duration of exposure
• Virulence of the organism(?)
Risk Factors for Development
of TB
• Recent contact to an active case
– Especially within first two years without LTBI treatment
• Medical Conditions
– HIV infection, diabetes (most common in Clark County),
cancer, end stage renal disease, substance abuse,
rheumatoid arthritis, drug induced immunosuppression,
psoriasis, chronic respiratory illness (including COPD and
asthma)
– HIV is the strongest risk factor for development of TB
disease: 7-10% each year without LTBI treatment
• Foreign-born persons from areas where TB is common
• Visitors to TB-prevalent countries
• Residents/employees of high-risk congregate settings
– Jails, prisons, homeless shelters
• Health care workers serving high-risk clients
• Children and adolescents exposed to adults at increased risk
for infection or disease
Special Note on Pediatric Cases
• Children with active TB indicate an unidentified
contagious adult/adolescent with active TB (sentinel
event)
• Child unlikely to yield positive smears and cultures
even with gastric aspirate
• Need source case culture results for drug sensitivities
to determine child’s treatment
• Thorough contact investigation is critical to
prevention further transmission!
Tuberculosis Associated with TNF- Drugs
• The Food and Drug Administration (FDA) determined in 2002 that
tuberculosis (TB) disease is a potential adverse reaction from treatment
with tumor necrosis factor-alpha (TNF-) antagonists
– Including infliximab (Remicade), etanercept (Enbrel ), and
adalimumab (Humira )
• These agents work by inhibiting inflammatory cytokine, and are approved
for treating rheumatoid arthritis and other autoimmune diseases
• Blocking TNF-  allows for TB disease to emerge from latent MTB infection
• Routine testing for TB is now indicated for all patients prior to initiation of
anti-TNF alpha medications
• TB disease should be considered in the differential diagnosis of ALL
immunocompromised patients with unexplained febrile illness
Diagnosis
Diagnosis
• Symptoms
– Systemic
• Fever, chills, night sweats, weight loss
(unexplained), fatigue, and anorexia
– Pulmonary TB Specific
• Productive cough and prolonged cough
– 3 weeks or longer in duration
• Chest pain
• Hemoptysis
– Extrapulmonary
• Pain at the site of disease
• Enlarged lymph nodes
• Cyst of mass development
Latent TB Infection vs. Active TB Disease
A person with latent TB infection
(LTBI)
A person with active TB disease
Small amount of TB bacteria in the body (alive
but inactive)
Large amount of active TB bacteria in the
body
Cannot spread TB bacteria to others
May spread TB bacteria to others
Does not feel sick
May feel sick and may have symptoms such
as cough, fever, and/or weight loss
Usually has a skin test or blood test result
indicating TB infection
Usually has a skin test or blood test result
indicating TB infection
Typically has a normal chest x-ray
May have an abnormal chest x-ray
Sputum smears and cultures are negative
Sputum smears and cultures may be
positive
Does NOT require respiratory isolation
May require respiratory isolation
Should consider treatment for latent TB
infection to prevent TB disease
Needs treatment to treat active TB disease
Diagnosis
• TB symptoms and severity can rate from none to
overwhelming
– Approximately 10-20% have none of the “classic
symptoms”
• Illness can range from indolent to fulminate
• Symptoms and findings can be both local and
systemic
– Local in the case of disseminated TB (lymph
node, CNS, bone, and solid organ – kidney)
• TB infection /disease can involve any organ or
tissue in the body
Extrapulmonary
Abnormalities
www.radiologictechnology.org
Pulmonary vs. Extrapulmonary
Symptoms of Pulmonary TB
Disease
• Cough (>3 weeks or longer)
with or without sputum
production
• Coughing up blood
(hemoptysis)
• Chest pain
• Loss of appetite
• Unexplained weight loss
• Night sweats
• Fever
• Fatigue
Symptoms of Extra-pulmonary
TB Disease
• TB of the kidney
– Blood in the urine
• TB meningitis
– Headache or confusion
• TB of the larynx
– Causes hoarseness
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Loss of appetite
Unexplained weight loss
Night sweats
Fever
Fatigue
Pain at site of disease
Steps to Diagnosis TB Disease
• Medical evaluation
– History and risk of exposure
• Mantoux tuberculin skin test
– Purified protein derivative (PPD)
• Interferon Gamma Assays (Blood test)
– QuantiFERON  (QFT-Gold In Tube)
– T-Spot TB  Test
– Radiologic evidence
• Chest x-ray (standard screening)
• Computerized tomography (CT) scan
Steps to Diagnosis TB Disease
• Medical evaluation
– Bacteriologic exam (sputum, tissue
sample or biopsy, exudate from wound or
cyst, etc.)
• Smears and culture
– **Must have at least 105 bacillary load to
detect bacteria in stained smear
– Positivity of sputum smear is directly
related to infectiousness
– Obtain 3 sputum specimens for acid-fast
bacilli (AFB)
Diagnostic Microbiology
• Obtain sputum smear and culture
• Detection of AFB in stained smears
– Provides first bacteriologic clue of TB
– Scales:
• Negative < Rare < Few < Moderate < Many
• Negative < 1+ < 2+ < 3+ < 4+
• Rapid detection of M. tuberculosis
– Nucleic acid amplification (NAA) tests/polymerase
chain reaction (PCR)
– GeneXpert  - NAA by PCR identifies targeted nucleic
acid sequences in the TB genome
• Also detects Rifampin resistance
• Cultures are used to confirm the diagnosis of TB
– Takes 6 to 8 weeks
Radiologic Evidence
• Useful tool for the diagnosis of TB disease
• CT scans can provide additional information for abnormalities that are unable to be
visualized on chest x-ray
– More expensive BUT more specific
• Abnormalities often seen in apical or posterior segments of upper lobe or superior
segments of lower lobe
– Lesions may appear anywhere in the lungs and may be cavitary
• Abnormailities seen on x-ray may be suggestive of TB disease but are NEVER
diagnostic
– May be used to exclude pulmonary TB disease in a person with normal immune
system and positive PPD or IGRA with no symptoms of disease
– Used as a screening tool and assess the need for further testing
– “Old” TB cannot be differentiated from active TB disease based on radiologic
evidence ALONE
Abnormal
Chest X-Ray
(cavitary lesion)
www.heartlandtbc.org
Abnormal CT Scan
www.heartlandtbc.org
Treatment
Treatment (Rationale)
• Appropriate treatment is necessary to manage disease transmission
– TB is a communicable respiratory illness that can be easily
transmitted from person to person
• Often difficult for patients to continue treatment once they start
feeling better
• Ensuring adherence to treatment is difficult because patients are
unable or reluctant to take multiple medications for several months
• Non-adherence to treatment is a major problem in TB control
• Patient education is key to ensuring compliance to therapy
• Directly observed therapy (DOT) is utilized to ensure patients
complete therapy (recommended by the CDC)
Treatment (Rationale)
• Directly observed therapy (DOT)
– Mandatory for all patients with active disease in some states
(communicable illness)
– Can be court ordered to comply or placed in jail until therapy
is complete
• Offering things like incentives and enablers can also help to
ensure compliance
• Patients extremely underweight at time of diagnosis
– Slow to culture convert
– Drug absorption issues
• If patient fails to improve after 6 to 8 weeks of therapy, drug
levels should be obtained
Duration of Therapy (pansensitive organism)
Area of the Body
Duration
Area of the Body
Duration
Lungs
6 months
Lymph node
6 months
Disseminated
6 months
CNS TB (Meningitis)
9-12 months
Bone and joint
6-9 months
Pericarditis
6 months
Pleural disease
6 months
Peritoneal
6 months
Genitourinary
6 months
6 months = 180 doses
6 months = 180 doses
9 months = 270 doses
9 months = 270 doses
12 months = 360 doses
12 months = 360 doses
Treatment Regimens
Initial Phase
Continuation Phase
Regimen
Drugs
Interval and Doses
Regimen
Drugs
Interval and Doses
Range of total
Doses
1
INH
RIF
PZA
EMB
7 days/week for 56
doses (8 weeks)
OR
5 days/week for 40
doses (8 weeks)
1a
INH
RIF
7 days/week for 126
doses (18 weeks) OR 5
days/week for 90
doses
182-130 (26
weeks)
1b
INH
RIF
2 days/week for 36
doses (18 weeks)
92-76 (26
weeks)
1c
INH
RPT
1 day/week for 18
doses (18 weeks)
74-58 (26
weeks)
2a
INH
RIF
2 days/week for 36
doses (18 weeks)
62-58 (26
weeks)
2b
INH
RPT
1 day/week for 18
doses (18 weeks)
44-40 (26
weeks)
2
INH
RIF
PZA
EMB
7 days/week for 14
doses (2 weeks), then
2 days/week for 12
doses (6 weeks)
OR
5 days/week for 10
doses (2 weeks), then
2 days/week for 12
doses (6 weeks)
Resistance
• Multi-drug resistant (MDR) TB
– Resistant to at least INH and RIF (or rifamycin
class)
• Extensively drug resistant (XDR) TB
– Resistant to INH and RIF
– FQN (fluroquinolones)
• Levofloxacin and moxifloxacin
– At least one 2nd line injectible agent
• Aminoglycoside
– Streptomycin, Amikacin, Kanamycin
• Capreomycin (polyp eptide – aminoglycoside
“like”
Resistance
• Totally drug resistant (TDR)
– Resistant to ALL 10 drugs with known activity
against TB
– First case identified in Europe in 2006
• Cases have been identified in Italy (2007),
Japan (2008), Iran (2009), and India (2012)
– Seen in young otherwise healthy patients
– Also known as extremely drug resistant (XXDR)
• A drug resistant organism can be passed on from
person to person OR
• Drug resistance can be acquired due to
inappropriate treatment
Duration of Therapy
(Drug Resistance)
Pattern of
Resistance
Suggested Regimen
Duration of
Therapy
INH (+/- SM)
RIF, EMB, PZA (FQN can be
added to strengthen the
regimen)
6 months
INH and RIF (+/- SM) FQN, PZA, EMB, injectable
agent (IA), +/- an alternative
agent
18-24
months
INH, RIF (+/- SM),
and EMB or PZA
FQN, PZA or EMB if active,
IA, +/- 2 alternative agents
24 months
RIF
INH, EMB, FQN, supplement
with PZA (first 2 months)
**If extensive disease, an IA
can be used (2-3) months
Treatment – Side Effects
• Isoniazid (INH)
– Elevated LFTs and clinical hepatitis, peripheral
neuropathy, optic neuritis, arthralgias, CNS changes,
drug induced pseudo-lupus, and diarrhea
• Rifampin (RIF)
– Rash, nausea, anorexia, abdominal pain, hepatotoxicity,
thrombocytopenia, and orange discoloration of ALL
bodily fluids
• Pyrazinamide (PZA)
– Hepatotoxicity, nausea/vomiting, GI upset, non-gouty
polyarthralgia, acute gouty arthritis (hyperuricemia),
photosensitivity, and rash
• Ethambutol (EMB)
– Visual disturbances (decrease in red-green
discrimination) can be exacerbated during renal failure,
peripheral neuritis, and skin reactions
•
TB and HIV
Rifabutin NOT Rifampin
– Should be used in HIV co-infected patients
– Due to drug-drug interactions with Highly Active Antiretroviral Therapy
(HAART) for HIV treatment
– Adverse effects
• Leukopenia, thrombocytopenia, rash, skin discoloration, hepatoxicity, eye
toxicities, arthralgias, and rug interactions (40% less than RIF)
– Counseling points
• May be taken with or without food
• It is normal for your tears, urine, and other bodily fluids may turn orange in
color
• Skin may become discolored
• Be aware of possible drug-drug interactions (inform doctor of all
medications you are taking)
• Avoid the use of hormonal contraceptives due to decreased effectiveness
– Rifapentine NOT routinely used in the US for active TB disease
– Used in LTBI therapy (INH/RPT once weekly x 12 weeks)
Treatment of LTBI
Drug
Duration
Interval
Minimum Doses
Comments
Isoniazid
(INH)
9 months
Daily
270
•Preferred regimen is daily treatment x9
months
•Recommended regimen for special
populations (HIV infected patients and
children)
•Directly Observed Therapy (DOT) must be
used with twice-weekly dosing
76 if twice weekly
(equivalent to 3.5
daily doses)
6 months
Daily
180
52 if twice weekly
(equivalent to 3.5
daily doses)
Rifampin
(RIF)
4 months
Daily
120 (within 6 month
period)
•For persons who cannot tolerate INH or have
been exposed to INH-resistant TB
•Should not be used in HIV infected patients
(high risk of drug interactions)
•Twice weekly or thrice weekly regimens
should be avoided
Treatment of LTBI
Drug
Duration
Interval
Minimum
Doses
Comments
INH + RIF
4 months
Daily
120
4 months
Twice weekly
(equivalent to
3.5 daily
doses)
76
•Recommended regimen for persons with
chest radiograph findings suggestive of
previous TB disease
•Directly Observed Therapy (DOT) must be
used with twice-weekly dosing
12 weeks
Once weekly
11 (within
a 16 week
period)
INH + Rifapentine
(3HP)
Note: Regimen found to
be non-inferior to INH
daily x9 months (MMWR
December 9, 2011)
•Alternative regimen for high risk individuals
meeting specific criteria
•Treatment regimen can only be received by
Directly Observed Therapy (DOT)
 For those patients with known exposure/close contact to a multi-drug resistant case with
positive laboratory evidence of infection, prophylaxis will be determined on a case by
case basis by expert TB clinicians.
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Summary
TB is one of the world’s deadliest diseases
Worldwide over 1.4 million deaths from TB in 2010
Worldwide 2 billion people are infected
Mycobacterium tuberculosis complex encompasses 4 major organisms
(M. tuberculosis, M. africanum, M. bovis, and M. microti)
MTB is transmitted via respiratory droplets from person to person
Risk factors for developing disease include:
– HIV infection, diabetes, cancer, ESRD, substance abuse, rheumatoid
arthritis, and drug induced immunosuppression
Diagnosis of disease can be done via the following tests: PPD skin test,
IGRA (QFT or T-Spot), chest x-ray, sputum smears and culture
Appropriate screening for patients receiving anti-TNF alpha agents
– Black box warning for development of active TB disease
Summary
• First line anti-tuberculosis drugs
– INH, RIF, PZA, EMB
• Rifampin and/or other rifamycin agents are associated with
several drug interactions
– Patients should report ALL medications they are taking to
avoid possible interactions
• Duration of therapy for anti-tuberculosis treatment is based on
resistance patters of the organism as well as site of disease
– Pulmonary vs. extrapulmonary
• Patients may be resistant to adherence to therapy
– Directly observed therapy (DOT) will assist with compliance
Summary
• Appropriate therapy is imperative to decreasing the incidence
of acquired drug resistance
– MDR: resistant to INH and RIF
– XDR: resistant to INH, RIF, FQN, and at least 1 injectable
second line agent
• Any persistent febrile illness Tuberculosis as the diagnosis
should be considered
• When in doubt contact the local health authority in your area
References
•
•
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Online Tuberculosis Information System (OTIS), National
Tuberculosis Surveillance System, United States, 1993-2009. U.S.
Department of Health and Human Services (US DHHS), Centers
for Disease Control and Prevention (CDC), Division of TB
Elimination, CDC WONDER Online Database, April 2011.
Accessed at http://wonder.cdc.gov/tb-v2009.html on Feb 23,
2012 1:19:16 PM
Core Curriculum on Tuberculosis: What the Clinician Should
Know. U.S. Department of Health and Human Services (US
DHHS), Centers for Disease Control and Prevention (CDC),
Division of TB Elimination, 2011
TB Today, National Prevention Information Network, U.S.
Department of Health and Human Services (US DHHS), Centers
for Disease Control and Prevention (CDC), Division of TB
Elimination,, March 2011. Accessed at
http://www.cdcnpin.org/scripts/tb/tb.asp on February 23, 2012.
1:59 PM.
National Tuberculosis Indicators Project (NTIP), U.S. Department
of Health and Human Services (US DHHS), Centers for Disease
Control and Prevention (CDC), Division of TB Elimination.
Accessed at https://webappx.cdc.gov on March 13, 2012 11:29
AM. Restricted access.