Download Mycobacterium tuberculosis

Tuberculosis & other
mycobacterial infections II
Prof Meral Sönmezoğlu
Division of Infectious Diseases
Yeditepe University Hospital
Tuberculosis
• Important new findings at the global level are:
•
The absolute number of TB cases has been falling
since 2006 (rather than rising slowly as indicated in
previous global reports);
•
TB incidence rates have been falling since 2002 (two
years earlier than previously suggested);
•
Estimates of the number of deaths from TB each year
have been revised downwards;
•
In 2009 there were almost 10 million children who
were orphans as a result of parental deaths caused by
TB.
Tuberculosis
• In 2010, there were 8.8 million (range, 8.5–9.2
million) incident cases of TB,
• 1.1 million (range, 0.9–1.2 million) deaths from
TB among HIV-negative people and
• an additional 0.35 million (range, 0.32–0.39
million) deaths from HIV-associated TB.
Tuberculosis: current problems
• About 3.8 million cases per year; 90%
(and 98% of the 3 million deaths) are in
developing countries
• Multidrug resistance (“MDR-TB”)
• AIDS: atypical presentations and
distribution
• Nosocomial spread
• Foreign-born
Millennium Development Goals set for 2015
Goal : Combat HIV/AIDS, malaria and other diseases
Target: Halt and begin to reverse the incidence of
malaria and other major diseases
Indicator: Incidence, prevalence and death rates associated with
TB
Indicator: Proportion of TB cases detected and cured under
DOTS
Stop TB Partnership targets set for 2015 and 2050
By 2015: Reduce prevalence and death rates by 50%, compared with their levels in
1990
By 2050: Reduce the global incidence of active TB cases to <1 case per 1 million
population per year
History of TB
Scientific Discoveries in 1800s
• Until mid-1800s, many
believed TB was
hereditary
• 1865 Jean AntoineVillemin proved TB was
contagious
• 1882 Robert Koch
discovered M.
tuberculosis, the
bacterium that causes
TB
Mycobacterium tuberculosis
Robert Koch (March 24, 1882)
• on March 24, 1882, when he presented his findings at a
monthly meeting of the Physiological Society of Berlin, he did
so with clarity and elegant logic. The medical men present
were dumbstruck by Koch’s address. So spellbound and
conscious of the fact that they were witnesses to scientific
history, the audience could not even applaud, let alone
engage in the traditional scientific attack on another
colleague’s work.
• In the room that night was a 28-year-old dermatologist named
Paul Ehrlich, who ultimately achieved great fame as the
discoverer of Salvarsan 606, the first “magic bullet” against
syphilis. Ehrlich later recalled the evening as “the most
gripping experience” of his scientific life, and as soon as the
lecture was completed he rushed home to his makeshift
laboratory, where he spent the night developing a novel
staining technique for the tubercle bacillus (Ehrlich-ZiehlNeelsen (EZN))
STOP TB
World TB Day 24th March
1882 when Dr Robert Koch astounded the scientific
community by announcing that he had discovered the
cause of tuberculosis, the TB bacillus
Robert Koch, discoverer of the tubercle bacillus,
concluded his Nobel Lecture on December 12, 1905
Prevalence of MDR Tuberculosis among New Cases of Tuberculosis, 2007, and Countries with at
Least One Reported Case of XDR Tuberculosis as of December 2008
Donald P and van Helden P. N Engl J Med 2009;360:2393-2395
TB & HIV CO-INFECTION
• TB is the most common opportunistic infection in HIV and
the first cause of mortality in HIV infected patients (1030%)
• 10 million patients co-infected in the world.
• Immunosuppression induced by HIV modifies the
clinical presentation of TB :
1. Subnormal clinical and roentgen presentation
2. High rate of MDR/XDR
3. High rate of treatment failure and relapse (5% vs < 1% in HIV)
Treatment
22 million lives were saved through the Stop
TB Strategy, 1995-2012.
MDR-TB cases
450 000 people developed multidrugresistant tuberculosis (MDR-TB) in the world
in 2012.
Funding
2 billion US dollars per year needed to fill
resource gap for implementing existing TB
interventions.
TURKEY
Tuberculosis
Tuberculosis
Tuberculosis
Tuberculosis
Tuberculosis
Tuberculosis
Tuberculosis
Tuberculosis
Mycobacterium tuberculosis
• MTB is a bacterium belonging to the
Mycobacterium genus
• Its identification is based on the following
characteristics:shape of the colonies, growth
rate, and biochemical reactivity.
• subdivided in two main groups based on their
growth rates (fast vs. slow)
Mycobacterium tuberculosis
Mycobacterium tuberculosis
• Thick lipid coat
of “Mycolic fatty acids”
• Grows very slowly
• Resists killing by
macrophages and
grows in them
Mycobacterium tuberculosis
• The rapidly growing Mycobacterium species
(Mycobacterium abscessus, M. fortuitum, M.
porcinum), whereas the majority are
nonpathogenic
• Majority of the slowly growing Mycobacterium
species are pathogenic for humans and/or
animals (e.g., all the species of the MTB complex
[MTBC], M. leprae, M. ulcerans, M. avium), and
only a few of them are nonpathogenic (e.g., M.
terrae, M. gordonae).
• MTB complex: MTB (Koch,1882), M. bovis
(Karlsen and Lessel, 1970), M. africanum [25], M.
microti (Reed, 1957),“M. canettii’
Mycobacterium tuberculosis
• rod-shaped bacteria (0.2–0.6 m wide, 1–10 m
long), nonmotile, nonencapsulated,
Grampositive,
• aerobes (growing most successfully in tissues
with a high oxygen content such as lungs), or
facultative anaerobes.
• They are facultative intracellular pathogens,
usually infecting mononuclear phagocytes
(e.g., macrophages).
Mycobacterium tuberculosis
• An obligate aerobe: prefers P02 of 130
torr
• Replicates every 20 hours
• Natural resistance to one drug is one in
every 105 to 107 cells
• Natural resistance to two or more drugs
is 1 in every 109 to 1012 cells
Tuberculosis: the basics
• The Mycobacterium tuberculosis complex:
M. tuberculosis, M. bovis, M. africanum
• Transmitted primarily by airborne droplet nuclei
• Persons with positive AFB sputum smears are
especially effective transmitters
• Between 5% and 15% of infected persons will
develop active disease (involving any organ)
within two years
TB Transmission and
Pathogenesis
No infection (70%)
Adequate
Exposure
Non-specific
immunity
Inadequate
Infection (30%)
 Not everyone who is exposed to TB will
become infected
Tuberculosis: the basics (2)
• Populations at increased risk of infection:
medically-underserved, low-income groups;
immigrants; residents of long-term care or
correctional facilities
• Infected persons with increased risk of active
disease: close contacts of cases; children < 5
years old; persons with chronic diseases (renal
failure; silicosis; diabetes); immunosuppressed;
HIV-positive persons
Immunology of tuberculosis
• Tubercle bacillus + macrophages --> processed
antigen
• Antigen recognition by lymphocytes --> activated
lymphocytes --> lymphokines
• Lymphokines--> attraction, stimulation, and
retention of macrophages at antigen site
• Activated macrophages--> lytic enzymes with
mycobactericidal but also tissue-necrosing
capacity
Mycobacterium tuberculosis
(MTB) enters the host within inhaled droplets.
Immunology of tuberculosis (2)
• Interferon-gamma probably stimulates
macrophages to produce interferon-alfa
and 1,25-dihydroxyvitamin D, both of
which are mycobacterial inhibitors
• Cytokines secreted by alveolar
macrophages: interleukin 1 (fever);
interleukin 6 (hyperglobulinemia), and
tumor necrosis factor alpha (killing of
organisms, granuloma formation, fever and
weight loss)
Primary tuberculous infection
• Inhalation leads to infection at
periphery of middle lung zone
• Pneumonia 2 to 6 weeks after infection
followed by lymphohematogenous
dissemination
• Cell-mediated immunity (manifested by
positive PPD) usually contains the
infection
• Some organisms remain viable
Pathogenesis of tuberculosis
Reactivation of tuberculosis
• Occurs most often in persons > 50
years of age; more common in men
• Higher risk in elderly persons and in
those with malnutrition, diabetes
mellitus, post-gastrectomy,
immunocompromise, alcoholism, HIV
infection, or corticosteroid therapy
TB Transmission and Pathogenesis
(2)
No infection (70%)
Adequate
Exposure
Non-specific
immunity
Early progression (5%)
Inadequate
Inadequate
Infection (30%)
Immunologic
defenses
Adequate
Containment (95%)
Residua of primary infection
• Ghon complex (after Anton Ghon, German
bacteriologist): calcified peripheral focus of
tuberculous infection with calcified regional
(hilar) lymph node (also called Ranke complex)
• Simon focus (after Georg Simon, German
pediatrician): focus at apex of lung, containing
viable organisms and manifested on x-ray as
“fibrous cap”
TB Pathogenesis (1)
Pathogenesis is defined as how an infection or
disease develops in the body.
TB Pathogenesis (2)
Latent TB Infection (LTBI)
• Occurs when tubercle bacilli are in the body, but
the immune system is keeping them under control
• Detected by the Mantoux tuberculin skin test (TST)
or by blood tests such as interferon-gamma
release assays (IGRAs) which include:
– QuantiFERON®-TB Gold test (QFT-G)
– QuantiFERON®-TB Gold In-Tube (QFT-GIT)
– T-Spot®.TB test (T-SPOT)
TB Pathogenesis (3)
TB Disease
• Develops when immune system cannot keep
tubercle bacilli under control
– May develop very soon after infection or many
years after infection
• About 10% of all people with normal immune
systems who have LTBI will develop TB disease
at some point in their lives
• People with TB disease are often infectious
TB Transmission and Pathogenesis
(3)
No infection (70%)
Adequate
Exposure
Non-immunologic
defense
Early progression (5%)
Inadequate
Inadequate
Infection (30%)
Immunologic
defenses
Adequate
Containment (95%)
Late progression(5%)
Inadequate
Immunologic
defenses
Adequate
Continued containment (90%)
TB Pathogenesis (4)
Droplet nuclei containing tubercle bacilli are
inhaled, enter the lungs, and travel to small air
sacs (alveoli)
1
TB Pathogenesis (5)
2
Tubercle bacilli multiply in alveoli, where
infection begins
TB Pathogenesis (6)
3
brain
bone
lung
kidney
A small number of tubercle bacilli enter
bloodstream and spread throughout body
TB Pathogenesis (7)
LTBI
4
• Within 2 to 8 weeks the immune system produces
special immune cells called macrophages that
surround the tubercle bacilli
• These cells form a barrier shell that keeps the bacilli
contained and under control (LTBI)
TB Pathogenesis (8)
TB Disease
5
• If the immune system CANNOT keep tubercle bacilli under
control, bacilli begin to multiply rapidly and cause TB
disease
• This process can occur in different places in the body
LTBI vs. TB Disease
Latent TB Infection (LTBI)
TB Disease (in the lungs)
Inactive, contained tubercle bacilli Active, multiplying tubercle bacilli
in the body
in the body
TST or blood test results usually
positive
TST or blood test results usually
positive
Chest x-ray usually normal
Chest x-ray usually abnormal
Sputum smears and cultures
negative
Sputum smears and cultures may
be positive
No symptoms
Symptoms such as cough, fever,
weight loss
Not infectious
Often infectious before treatment
Not a case of TB
A case of TB
Axioms on Simon foci
• “If humans did not have apices to their
lungs, the tubercle bacillus would not
have survived as a human pathogen.”
• “Once a Simon focus has formed, one
will eventually die of tuberculosis if
something else doesn’t cause death
first.”
Caseous necrosis of tuberculosis
• This walled-off, friable,
cheesy nodule in the
subapical region (a Simon
focus) develops from
organisms spread
hematogenously from the
initial focus of infection in the
lower half of the lung.
Reactivation of this lesion
would probably destroy the
capsule, and the caseous
material would be
expectorated leaving a
cavity.
Tuberculous pleuritis
non-necrotizing granulomas
the Langhans' giant cells, the
epithelioid cells, and
the lymphocytes.
Progression to active tuberculosis
• One year after infection: approximately 5%
• Thereafter: approximately 5% (lifetime)
• It now seems that many people eventually
outlive their tubercle bacilli and are
consequently vulnerable to reinfection
(Stead, studies in Arkansas, early 1980s)
• Tuberculin-positive persons with HIV
infection: risk is 7% to 10% per year
Insights from genotyping of
M. tuberculosis isolates
(N Engl J Med 2003; 349: 1149-1155)
• Previously, it was thought that 90% of
TB cases in industrialized nations
resulted from reactivation of infection
acquired in remote past.
• It now seems that recent transmission
causes 40% to 50% of TB cases in
urban areas.
The cavity (1)
• Formation of the cavity is the pivotal
event in the evolution of pulmonary
tuberculosis.
• Mortality of cavitary pulmonary
tuberculosis without treatment
approaches 90%.
• All therapies prior to 1948 were aimed
at closing cavities.
The cavity (2)
• Even healed, cavities are unstable.
• The walls of cavities contain extensive
sheets of bacilli (up to 1011
bacilli/gram).
• The cavity is thinnest at the point of
penetration of bronchi.
• Open cavities may persist for years,
constantly draining bacilli into the rest
of the bronchial tree.
Complications of pulmonary tuberculosis
• Cough, fever, night sweats, weight loss,
anemia
• Massive hemoptysis (erosion of a vessel in
the wall of a cavity; a dilated vessel in a
cavity (Rasmussen’s aneurysm; or an
aspergilloma)
• Progressive pulmonary disease, rarely
ARDS
• Hyponatremia due to syndrome of inappropriate
secretion of antidiuretic hormone (SIADH)
Major syndromes of extrapulmonary
tuberculosis
• Disseminated (miliary) tuberculosis
• “Serosal” tuberculosis (anatomic
spaces or cavities): pleurisy,
pericarditis, meningitis, peritonitis,
arthritis
• Tuberculosis of solid organs: renal
(genitourinary), osteomyelitis, adrenal
glands (Addison’s disease), lymph
nodes
Miliary tuberculosis: diagnostic aids
• Repeat physical examination: choroidal
tubercles, palpable lymph nodes
• Repeat CXR and tuberculin test
• Cultures: sputum (up to 63% positive), urine,
bone marrow, CSF, gastric aspirate, pleural
fluid
• Biopsy: palpable nodes, marrow, liver
• Therapeutic trial
“Cryptic miliary tuberculosis”
• An occult illness with gradual decline in
general health
• Often no significant fever
• Non-reactive tuberculin skin test
• Normal chest x-ray
Frequency order of extrapulmonary sites
1. Lymph node
2. Pleura
3. Genitourinary tract
4. Bone and joints
5. Meninges
6. Peritoneum
Tuberculous pleurisy
• Subpleural focus ruptures into the pleural space
• Usually younger adults, 3 to 7 months after
primary tuberculous infection
• Abrupt or insidious onset. DDx: pneumonia,
pulmonary infarct, tumor, others
• Natural history untreated: 65% of 141 patients
developed active tbc (Roper & Waring)
Tuberculous meningitis
• Rupture of subependymal tubercle into
subarachnoid space (“Rich focus”; Rich and
McCormack, 1933)
• The intrathecal tuberculin reaction (instillation
of PPD material into CSF of PPD-positive
volunteers)
• Usually occurs within first 6 months of
infection; now seen in older adults
Tuberculous pericarditis
• Rupture of a tuberculous mediastinal lymph
node into the pericardial sac
• Mortality 80% to 90% without treatment. Major
problems even with appropriate Rx
• Diagnosis is difficult to make short of total
pericardiectomy
• Constrictive pericarditis
• Can extend into myocardium --> fiber atrophy
Tuberculous peritonitis
• Onset is usually insidious. Mortality 45% to
55% untreated but as low as 0% to 4% with
treatment
• Polar types: plastic or adhesive type
(“doughy abdomen”) and exudative or
serous peritonitis with ascites
• Presentations: debilitating FUO; chronic
abdominal pain; ascites of unknown origin
Tuberculous arthritis
• Tuberculous focus in bone ruptures into
joint space; trauma predisposes
• Adults: spine 50%, hips 15%
• Children: Knees 15%
• Insidious joint pain and swelling, most often
involving large weight-bearing joints
• Absence of proteolytic enzymes explains
preservation of joint space
Genitourinary tuberculosis
• Tubercle of the glomerulus ruptures into
the calyceal system
• May progress to involve the entire kidney
(“autonephrectomy”) and/or may spread
throughout the GU tract (prostatitis,
epididymitis, salpingitis)
• Insidious onset
Tuberculous osteomyelitis
 Subchondral osteoporosis with
surrounding ring of sclerosis
 Spine: anterior involvement of vertebral
bodies with disk collapse (Pott’s
disease)
 Suspect: Monoarticular arthritis of
insidious onset; paraspinous mass;
back pain
Tuberculosis of the adrenal glands
(Addison’s disease)
• Tuberculosis formerly the major
cause of the disease as described
by Thomas Addison (now rare;
most common cause is idiopathic
[autoimmune])
• Wasting, hyperpigmentation, low
blood pressure, hyponatremia,
hyperkalemia
Tuberculosis in HIV-positive patients
• Present in 5% to 35% of patients
diagnosed with AIDS
• Precedes diagnosis of AIDS in 67% of
patients
• Although most of these cases result from
reactivation, CXR often resembles
progressive primary tuberculosis
• Multiple drug resistance a major problem
Diagnosis of TB Disease
Medical Evaluation
Bacteriologic Examination
101
Tuberculosis
• Primary
– Lung tubercles, caseous, tuberculin skin
reaction
• Secondary (reactivation)
– Consumption: Coughing and chronic
weight loss
• Dissemination
– Extrapulmonary TB (lymph nodes,
kidneys, bones, genital tract, brain,
meninges)
AFB smears
• Three morning specimens
• Fluorescent methods are more
sensitive than traditional Kinyoun or
Ziehl-Neelsen method
• Predictive value of a positive test
decreases strikingly as prevalence of
the disease decreases (Bayes’ s
theorem)
TB Skin Test
Tuberculin skin test guidelines
• 5 mm for close contacts; for persons
with compatible chest x-rays; and for
HIV-infected persons
• 10 mm for recently-infected persons,
persons with high-risk medical
conditions, and high-risk patients
under 35 years of age
• 15 mm for low-risk persons under
age 35
Tubercule formation
A tubercle in the lung is a
“granuloma”
consisting of a central core of TB
bacteria inside an enlarged
macrophage, and an outer wall
of fibroblasts, lymphocytes,
and neutrophils
Rapid laboratory confirmation
• Fluorochrome smear on concentrated
specimens
• Rapid methods of detection: Bactec system;
polymerase chain reaction
• Rapid mechanisms of identification: DNA
probes; HPLC
• Rapid methods of susceptibility testing
• Handle reports as critical laboratory values
Nontuberculous mycobacteria (NTM)
• Synonyms: atypical mycobacteria,
mycobacteria other than tuberculosis
(MOTT), nontuberculous mycobacteria
(NTM)
• Numerous species; widespread
• Can be difficult to treat
• “MAC” = M. avium-intracelluare
complex
Non tuberculos mycobacteria
• M. avium Complex
(MAC)
•
M. gordonae
•
M. haemophilum
•
M. immunogenum
•
M. malmoense
•
M. marinum
•
M. mucogenicum
• M. chelonae
•
M. nonchromogenicum
•
M. scrofulaceum
• M. fortuitum
•
M. simiae
•
M. smegmatis
•
M. szulgai
•
M. terrae complex
•
M. ulcerans
•
M. xenopi
• M. kansasii
• M. abscessus
• M. genavense
Pulmonary disease due to NTM in
immunocompetent persons
• Isolation of organism from sputum does
not necessarily imply disease
• M. avium-intracelluare (especially in the
Southeast) and M. kansasii (especially in
the west) cause disease resembling
tuberculosis (clinically milder but more
difficult-to-treat)
Mycobacterium avium-intracelluare
(“MAC”) in HIV disease
• Disseminated “MAC” infection with
or without pulmonary involvement
• Prolonged fever, weight loss,
hepatosplenomegaly, diarrhea,
abdominal pain
• Positive blood cultures; AFB also
found in bone marrow, liver, and
often stool
Lymphadenitis due to NTM
• Usually due to M. scrofulaceum or M.
avium-intracelluare
• “Scrofula”: cervical lymphadenitis,
usually in children
• Usual treatment of choice: surgical
excision without chemotherapy
Swimming pool and fish-tank granuloma
• Caused by Mycobacterium marinum
• Small violet nodule or pustule at the site
of minor trauma may evolve into crusted
ulcer or abscess
• Multiple lesions can resemble
lymphocutaneous sporotrichosis
Infections related to injections or
surgery
• “M. fortuitum complex”: Mycobacterium
fortuitum, M. chelonae, M. abscessus (all
“rapidly-growing mycobacteria”)
• Opportunistic pathogens causing wound
infections (which can be epidemic) and
skin infections
Tuberculosis
Elimination requires long
antibiotic treatment with
“cocktail” of antibiotics
because
of the resistance that
develops.
What’s New? (1)
• Provider/program responsibility for successful
treatment, not the patient
• Patient-centered case management with
emphasis on directly observed therapy (DOT)
• Evidence-based ratings of treatment options
• Role of two-month sputum cultures to identify
patients at increased relapse risk
What’s New? (2)
• Extend treatment for patients with drugsusceptible pulmonary TB at increased risk for
relapse
• Role of new drugs (rifabutin, rifapentine, and
fluoroquinolones)
• Practical aspects of therapy: drug
administration, fixed-dose combinations,
adverse effects monitoring and management,
and drug interactions
What’s New? (3)
• Treatment completion defined primarily by
number of doses ingested within specified time
• Description of special treatment situations:
– HIV/AIDS
– Children
– Extrapulmonary TB
– Culture-negative TB
– Pregnancy and breast feeding
– Hepatic and renal disease
What’s New? (4)
• Updated guidelines for management of drugresistant TB
• Recommendations compared with those of the
World Health Organization (WHO) and the
International Union Against TB and Lung
Disease (IUATLD); WHO DOTS strategy
described
• Current research status to improve treatment
Antituberculosis Drugs
First-Line Drugs
Second-Line Drugs
• Isoniazid
• Streptomycin
• Rifampin
• Cycloserine
• Pyrazinamide
• p-Aminosalicylic acid
• Ethambutol
• Ethionamide
• Rifabutin*
• Amikacin or kanamycin*
• Rifapentine
• Capreomycin
• Levofloxacin*
• Moxifloxacin*
• Gatifloxacin*
* Not approved by the U.S. Food and Drug Administration for use in the
treatment of TB
Drug Abbreviations
Ethambutol
EMB
Isoniazid
INH
Pyrazinamide
PZA
Rifampin
RIF
Rifapentine
RPT
Streptomycin
SM
Role of New Drugs (1)
• Rifabutin: For patients receiving medications
having unacceptable interactions with rifampin
(e.g., persons with HIV/AIDS)
• Rifapentine: Used in once-weekly
continuation phase for HIV-negative adults
with drug-susceptible noncavitary TB and
negative AFB smears at completion of initial
phase of treatment
Role of New Drugs (2)
• Fluoroquinolones (Levofloxacin,
Moxifloxacin, Gatifloxacin): Used when
-first-line drugs not tolerated;
-strains resistant to RIF, INH, or EMB; or
-evidence of other resistance patterns with
fluoroquinolone susceptibility
Factors Guiding Treatment Initiation
• Epidemiologic information
• Clinical, pathological, chest x-ray findings
• Microscopic examination of acid-fast bacilli
(AFB) in sputum smears
• Nucleic acid amplification test (when performed)
When to Consider Treatment Initiation
• Positive AFB smear
• Treatment should not be delayed because of
negative AFB smears if high clinical suspicion:
– History of cough and weight loss
– Characteristic findings on chest x-ray
– Emmigration from a high-incidence country
Baseline Diagnostic Examinations for TB
• Chest x-ray
• Sputum specimens (= 3 obtained 8-24 hours
apart) for AFB microscopy and mycobacterial
cultures
• Routine drug-susceptibility testing for INH, RIF,
and EMB on initial positive culture
Other Examinations to Conduct When TB
Treatment Is Initiated (1)
• Counseling and testing for HIV infection
• CD4+ T-lymphocyte count for HIV-positive
persons
• Hepatitis B and C serologic tests, if risks
present
Other Examinations to Conduct When TB
Treatment Is Initiated (2)
• Measurements of aspartate aminotransferase
(AST), alanine aminotransferase (ALT),
bilirubin, alkaline phosphatase, serum
creatinine, and platelet count
• Visual acuity and color vision tests (when
EMB used)
Treatment Regimens
• Four regimens recommended for treatment of
culture-positive TB, with different options for
dosing intervals in continuation phase
• Initial phase: standard four drug regimens
(INH, RIF, PZA, EMB), for 2 months, (except
one regimen that excludes PZA)
• Continuation phase: additional 4 months or (7
months for some patients)
Why Extend Continuation-Phase
Treatment for 3 Months?
• Cavitary disease and positive sputum culture
at 2 months associated with increased relapse
in clinical trials
• Extended continuation phase decreased
relapses in silicotuberculosis (from 20% to 3%)
When to Extend Continuation-Phase
Treatment for 3 Months?
• Cavitary pulmonary disease and positive sputum
cultures at completion of initial phase
• Initial phase excluded PZA
• Once-weekly INH and rifapentine started in
continuation phase and sputum specimen
collected at the end of initial phase is culture
positive
• HIV-infected with positive 2-month sputum culture
Algorithm to Guide Duration of ContinuationPhase Treatment for
Culture-Positive TB Patients
High clinical suspicion for active TB
Place patient on initial-phase regimen:
INH, RIF, EMB, PZA for 2 months
NO
Give continuationphase treatment of
INH/RIF daily or twice
weekly for 4 months
Is
specimen
collected at end
of initial phase (2
months) culture
positive?
YES
Algorithm to Guide Duration of ContinuationPhase Treatment for Culture-Positive TB
Patients (Continued)
NO
NO
Is the
patient HIV
positive?
Give continuationphase treatment of
INH/RIF daily or twice
weekly for
4 months
Was
there
cavitation
on initial
CXR?
YES
YES
Give continuation-phase
treatment of INH/RIF
daily or twice weekly for
7 months
Give continuationphase treatment of
INH/RIF daily for
7 months
Treatment of Culture-Positive TB (1)
(Rated: AI in HIV-negative, AII in HIV-positive patients)
Initial Phase
2 months - INH, RIF, PZA, EMB daily (56 doses, within 8 weeks)
Continuation Phase
Options:
1) 4 months - INH, RIF daily (126 doses, within 18 weeks)
2) 4 months - INH, RIF twice / week (36 doses, within 18 weeks)
3) 7 months - INH, RIF daily (217 doses, within 31 weeks)*
4) 7 months - INH, RIF twice / week (62 doses, within 31 weeks)*
* Continuation phase increased to 7 months if initial chest x-ray shows cavitation
and specimen collected at end of initial phase (2 months) is culture positive
Common Adverse Reactions to
Drug Treatment (1)
Caused by
Any drug
Adverse Reaction
Signs and Symptoms
Allergy
Skin rash
Ethambutol
Eye damage
Isoniazid,
Hepatitis
Pyrazinamide,
or
Rifampin
Blurred or changed vision
Changed color vision
Abdominal pain
Abnormal liver function test
results
Fatigue
Lack of appetite
Nausea
Vomiting
Yellowish skin or eyes
Dark urine
Common Adverse Reactions to
Drug Treatment (2)
Caused by
Isoniazid
Adverse Reaction
Peripheral
neuropathy
Pyrazinamide Gastrointestinal
intolerance
Streptomycin
Signs and Symptoms
Tingling sensation in hands and
feet
Upset stomach, vomiting, lack
of appetite
Arthralgia
Joint aches
Arthritis
Ear damage
Gout (rare)
Balance problems
Hearing loss
Ringing in the ears
Kidney damage
Abnormal kidney function test
results
Common Adverse Reactions to
Drug Treatment (3)
Caused by
Rifamycins
Adverse Reaction
Signs and Symptoms
Thrombocytopenia Easy bruising
• Rifabutin
Slow blood clotting
• Rifapentine Gastrointestinal
intolerance
• Rifampin
Drug interactions
Upset stomach
Interferes with certain
medications, such as birth
control pills, birth control
implants, and methadone
treatment
Drug Interactions
• Relatively few drug interactions substantially
change concentrations of antituberculosis drugs
• Antituberculosis drugs sometimes change
concentrations of other drugs
-Rifamycins can decrease serum concentrations
of many drugs, (e.g., most of the HIV-1 protease
inhibitors), to subtherapeutic levels
-Isoniazid increases concentrations of some
drugs (e.g., phenytoin) to toxic levels
TUS 2012
• Çocukluk döneminde akciğer dışı
tüberkülozun en sık görülen şekli
aşağıdakilerden hangisidir?
•
A) Tüberküloz menenjit
B) Renal tüberküloz
C) Tüberküloz lenfadenit
D) Tüberküloz peritonit
E) Tüberküloz perikardit
TUS 2012
• Çocukluk döneminde akciğer dışı
tüberkülozun en sık görülen şekli
aşağıdakilerden hangisidir?
•
A) Tüberküloz menenjit
B) Renal tüberküloz
C) Tüberküloz lenfadenit
D) Tüberküloz peritonit
E) Tüberküloz perikardit
TUS 2012
• Tüberküloz enterit, bağırsakta en sık
aşağıdaki lokalizasyonların hangisinde
görülür?
•
A) Duodenum
B) Proksimal-orta jejunum
C) Sigmoid kolon ve rektum
D) Transvers kolon
E) Distal ileum ve çekum
TUS 2012
• Tüberküloz enterit, bağırsakta en sık
aşağıdaki lokalizasyonların hangisinde
görülür?
•
A) Duodenum
B) Proksimal-orta jejunum
C) Sigmoid kolon ve rektum
D) Transvers kolon
E) Distal ileum ve çekum
TUS 2012
• Antitüberküloz tedavi alan bir hastada gelişen
hepatotoksisiteden sorumlu olma ihtimali en az
olan ilaç aşağıdakilerden hangisidir?
• A) Rifampisin
• B) İzoniazid
• C) Etambutol
• D) Pirazinamid
• E) Rifabutin
TUS 2012
• Antitüberküloz tedavi alan bir hastada gelişen
hepatotoksisiteden sorumlu olma ihtimali en az
olan ilaç aşağıdakilerden hangisidir?
• A) Rifampisin
• B) İzoniazid
• C) Etambutol
• D) Pirazinamid
• E) Rifabutin
TUS 2012
• Aşağıdaki hastalıklardan hangisinde kapalı
plevral biyopsinin tanı değeri en yüksektir?
•
A) Tüberküloz plörezisi
B) Romatoid artrite bağlı plörezi
C) Şilotoraks
D) Parapnömonik efüzyon
E) Asbest’e ikincil efüzyon
TUS 2012
• Aşağıdaki hastalıklardan hangisinde kapalı
plevral biyopsinin tanı değeri en yüksektir?
•
A) Tüberküloz plörezisi
B) Romatoid artrite bağlı plörezi
C) Şilotoraks
D) Parapnömonik efüzyon
E) Asbest’e ikincil efüzyon
TUS 2013
• Aşağıdaki tüberküloz ilaçlarından
hangisinin kullanımı sırasında konvülsiyon
gelişebilir?
•
A) Rifampin
B) Pirazinamid
C) Streptomisin
D) İzoniazid
E) Etambutol
TUS 2013
• Aşağıdaki tüberküloz ilaçlarından
hangisinin kullanımı sırasında konvülsiyon
gelişebilir?
•
A) Rifampin
B) Pirazinamid
C) Streptomisin
D) İzoniazid
E) Etambutol
• Among the traditional forms of first-line
antituberculosis therapy, isoniazid is most
often associated with nervous system effects,
most prominently peripheral neuropathy,
psychosis and seizures.
• Adverse events are reported with other
antituberculosis therapies, the most prominent
being optic neuropathy with ethambutol and
ototoxicity and neuromuscular blockade with
aminoglycosides.
• The second-line agent with the most adverse
effects is cycloserine, with psychosis and
seizures, the psychosis in particular limiting its
usage. Fluoroquinolones are rare causes of
seizures and delirium.
TUS 2014
TUS 2014