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Tuberculosis.Diagnostics, Treatment.
General Medicine
English Learning Programme
Phthisiology, Lecture #2
Diagnostics
• history (epidemiological, social,
alcohol, elicit drugs, comorbidities)
• physical examination
• imaging (plane X-ray, CT...)
• tuberculine skin test (TST)
• bacteriology
Tuberculin skin testing (TST)
• 2 TU v 0,1 ml (Mantoux II) intradermally!
• read after 72 hours (induration in mm)
• Interpretation issues:
• previous vaccination
• population examined
• European population:
• <5 mm = negative
• <10 mm = postvaccination positivity
• >14 mm = postinfectious positivity
• North American hispanic and
afroamericans
• >5 mm = positive
• HIV+ person
• any reaction (even erythema) = positive
Tuberculin skin testing cont.
False positivity False negativity
Systemic conditions:
• malnutrition
• imunoincompetency
• malignancy
• renal failure
• liver failure
• IBD
• ageing
Local conditions:
• Skin ageing
• Severe skin diseases
(erythrodermia...)
• Atopic skin
• Boost
• Non-TB
mycobacteriosis
Positive anergy
Negative anergy
Microbiological testing
• smear
– low sensitivity ≈ 34-62% (10000
bacilli / 1 ml)
– fast
– false positivity
• culture – the gold standard
– higher sensitity (100 bacilli / 1 ml)
– drug susceptibility testing
– time consuming
Newer microbiological methodes
radiometric culture (BACTEC)
• palmitic acid labelled
by 14C
• CO2 production
• radiometric detection
• 4-12 days
Newer microbiological methodesIGRA (Interferon Gamma Release Assay)
• presence of activated T-cells
• all specimens containing T-
cells
• incubation with M. TB antigens
(ESAT-6, CFP 10, TB 7.7)
• IFN-γ detection
• 1 day!
• detection of the infection (not
of the disease!)
Mycobacterial species identification I.
• DNA probes–species-specific DNA probes that hybridize with rRNA
released from bacteria–probes labeled with acridinium ester, measured with a
luminometer–2-3.5 h–very easy to perform, no special instrumentation is
needed–not available for all pathogenic mycobacterial species–M. tuberculosis complex probe cannot differentiate
between the members of this complex (M. tuberculosis, M. bovis, M. bovis BCG, M. africanum, and M. microti)– Enhanced M. TB Direct Test (E-MTD)– sensitivity similar to culture
Mycobacterial species identification II.
•pcr-based sequencing–PCR amplification of mycobacterial DNA with genus-
specific primers and sequencing of the amplicons
–the organism is identified by comparison of the
nucleotide sequence with reference sequences
–the target most commonly used is the gene coding for
the 16S rRNA
–members of the M. tuberculosis complex cannot be
distinguished, M. kansasii has a sequence identical to
that of a nonpathogenic species
–photometry
–6.5 h
–less sensitive than culture
–Amplicor Mycobacterium tuberculosis Test
Mycobacterial species identification III.
•DNA microarrays (biochip)–hybridization of fluorescently labeled
PCR amplicons generated from
bacterial colonies to a DNA array
containing nucleotide probes
–probes based on 82 unique 16S
rRNA sequences (discrimination of
54 mycobacterial species)
–covalent bond of the probes on solid
surface
–4 h
Direct detection of M TB –
nucleic acid amplification (NAA)
• detection of both live and dead M TB
• not replacement of smears and cultures
• do not detect non-tuberculous Mycobacteria– PCR
Specimens used for
microbiological testing• sputum
• induced sputum
• throat swab
• gastric secretions
• bronchoalveolar
lavage
• pleural fluid
• urine
• blood
• cerebrospinal fluid
• smears from the fistulas
• stool
• sanitary pad
• prostatic secretions
• ascitic or pericardial fluid
• synovial fluid
• biopsies
Pharmacological treatment
basic principles and terms
• combination treatment
• long-term treatment (short-course=6 months)
• intensive/continuation phase
• almost all administered once a day
• first/second/third line drugs
• MDR-TB = multi drug-resistant TB (resistance to izoniazid and rifampicin)
• XDR-TB = extensively drug-resistant TB (MDR-
TB + resistance to any fluoroquinolone and any
of the second-line anti-TB injectable drugs:
amikacin, kanamycin or capreomycin)
First line drugs
• H - izoniazid
• R - rifampicin
• Z - pyrazinamide
• E - ethambutol
• S - streptomycin
• 2HRZE/4(HR)3
Second line drugs
• aminoglycosides (amikacin)
• polypeptides (capreomycin, viomycin,
enviomycin)
• fluoroquinolones (ciprofloxacin,
levofloxacin, moxifloxacin)
• thioamides (ethionamide, prothionamide)
• cycloserine
• terizidone
Third line drugs
• rifabutin, rifapentin
• macrolides
• linezolid
• thioacetazone
• thioridazine
• arginine
• vitamin D
• bedaquiline
Standard treatment regimens
New patients presumed
or known to have drug-
susceptible TB
Previously treated
patients and multidrug
resistance
S 2HRZE/4HR DST or
2HRZES/1HRZE/5HREA 2HRZE/4(HR)3
HIV- 2(HRZE)3/4(HR)3
S - standard regimen
A - alternative regimen
HIV- - alternative for patients NOT living with HIV or living in an
HIV-prevalent setting
DST- drug susceptibility testing
Drug susceptibility testing (DST)
• Standard DST (6-9 weeks)
• Rapid DST - molecular-amplification
assays e.g. line probe test (2-7 days)
• If MDR prevalence > 3% then DST in all
new cases
Izoniazid• synthetic, bactericidal/bacteriostatic, intracelullar
• inhibits synthesis of mycolic a.
• clinically available since 1952
• well resorbed from GIT, usually orally admin., i.v.
available
• 4-6 mg/kg (up to 900 mg/day)
• AE: – GIT intollerance
– hepatotoxicity
– CNS effects (precipitation of seizures, mental
disorders, peripheral neuropathy)
– anaemia
– drug-induced SLE
– allergy
Rifampicin• semisynthetic bactericidal antibiotic
• inhibition of RNA-polymerase
• clinically available since 1967
• well resorbed from GIT, i.v. available
• 8-12 mg/kg (up to 600 mg/day)
• AE: – GIT intollerance
– hepatotoxicity
– flu-like sy.
– allergy (shock, purpura)
– renal failure
– adrenal dysfunction
– orange-red colour of the body fluids
Pyrazinamide• bacteriostatic, cross haematoencephalic barrier
• effective in acid environment
• fast development of acquired resistance
• inhibition of fatty acid syntetase
• well resorbed from GIT
• 20-30 mg/kg (up to 2000 mg/day)
• AE: – GIT intolerance
– hepatotoxicity
– hyperuricaemia
– allergy, photosensitivity
– anaemia
Ethambutol
• bacteriostatic, synthetic
• obstructs the formation of cell wall
• well resorbed from GIT
• 15-20 mg/kg (up to 1600 mg/day)
• AE: – optic neuritis
– hyperurikaemia
Streptomycin
• bacteriostatic, in neutral- alcaline environment
working aminoglycoside antibiotic
• protein synthesis inhibitor
• clinically available since 1947 (first
antituberculotic)
• not resorbed from GIT – exclusivelly i.m.
• 1000 mg/day (500-750 mg/day in elderly)
• AE: – vestibulocochlear nerve toxicity (deafness, tinnitus,
vertigo, ataxia)
– nephrotoxicity
Corticosteroids
• meningitis, pericarditis, pleurisy, extremely
advanced TB - prednisolone 20-60 mg/day
tapered off over 4-8 weeks.
• peritonitis, miliary disease, osteomyelitis,
laryngeal TB, lymphadenitis and
genitourinary disease?
Surgical treatment
• pneumothorax
• plombage of pleural
cavity (porcelain balls)
• thoracoplasty
• phrenic nerve crushing
• resection
0
10
20
30
40
50
60
70
80
90
100
1990
2000
2005
2008
2009
2010
not evaluated [%]
defaulted [%]
failed [%]
died [%]
completed [%]
cured [%]
Global treatment outcomes
(new smear-positive cases)
Treatment using short-course chemotherapy
• standardized treatment
• protection of rifampicin
– DOTS
– fixed-dose combination
– at least 3 other drug in smear +
– prohibition of sale
Basic Principles of Treatment
• Provide safest, most effective therapy in
shortest time
• Multiple drugs to which the organisms
are susceptible
• Never add single drug to failing regimen
• Ensure adherence to therapy
Directly Observed Therapy (DOT)
• watch patient swallow each dose of medication
• consider DOT for all patients
• DOT should be used with all intermittent regimens
• DOT can lead to reductions in relapse and acquired drug resistance
• Use DOT with other measures to promote adherence