Transcript Mycobacterium tuberculosis treatment

Drug treatment of Pulmonary
Tuberculosis
4th medical year Pharmacology
Tuberculosis
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Kills ~ 3 million/yr worldwide
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In UK ~ 10% drug resistance
Tuberculosis
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Primary TB: Initial infxn usually pulmonary (droplet spread).
Peripheral lesion forms (Ghon focus) & its draining nodes infected
(Ghon complex). Often asymptomatic or fever, lassitude, sweats,
anorexia, cough, sputum, erythema nodosum. AFB may be in
sputum. Commonest non-pulmonary primary infxn is GI (affecting
ileocaecal junction & its LNs)
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Post-primary TB: Any form of immunocompromise may
reactivate TB e.g. malignancy, DM, steroids, debilitation (HIV,
elderly). Lung lesions (usually upper lobe) progress & fibrose.
Tuberculomas contain few AFB unless erode into bronchus, where
can rapidly multiply & make pt highly contagious (open TB). In
elderly, immunocompromised, 3rd world dissemination of multiple foci
throughout body results in miliary TB.
Tuberculosis
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Pulmonary TB:
silent or cough, sputum, malaise, weight loss, night sweats, pleurisy,
haemoptysis, pleural effusion, superimposed pulmonary infection
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Miliary TB:
following haematogenous dissemination. Clinical features nonspecific. CXR: reticulonodular shadowing. Bx of lung, liver, LN or
marrow may give AFB/granulomata
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Meningeal TB:
Subacute onset meningitic symptoms: fever, headache, n&v, neck
stiffness, photophobia
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GU TB:
frequency, dysuria, loin/back pain, haematuria, sterile pyuria. 3 EMU
for AFB. Renal US. Renal TB may spread to bladder, seminal
vesicles, epididymis or fallopian tubes
Tuberculosis
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Bone TB: vertebral collapse adjacent to paravertebral abscess
(Pott’s vertebra). X-rays & biopsies (for AFB & culture)
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Skin TB (lupus vulgaris): jelly-like nodules, e.g. face/neck
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Acute TB pericarditis: primary exudative allergic lesion
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Chronic pericardial effusion & constrictive pericarditis: reflect
chronic granulomata. Fibrosis & calcification may be prominent with
spread to myocardium (Steroids for 11 wks with anti-TB meds ↓
need for pericardiectomy)
TB
Diagnosis
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If suspected obtain relevant clinical samples (sputum, pleural fluid,
pleura, urine, pus, ascites, peritoneum or CSF) for culture
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Microbiology: multiple sputum for AFB, pleural aspiration & biopsy (if
effusion). If sputum neg bronchoscopy for biopsy & BAL. Biopsy if
suspicious lesion in liver, LN, bone marrow.
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AFB = bacilli that resist acid-alcohol decolourization under
auramine/ZN staining. Cultures have prolonged incubation (12 wks).
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TB PCR: rapid id of rifampicin resistance. Useful for diagnosis in
sterile specimens
TB
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Histology: caseating granulomata
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Radiology: CXR = consolidation, cavitation, fibrosis & calcification in
pulmonary TB
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Immunological:
Tuberculin skin test/Mantoux: tuberculin purified protein derivative
(PPD) injected intradermally & cell-mediated response at 48-72h .
+ve if >/= 10mm induration
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+ve test indicated immunity (may be previous exposure, BCG)
Strong +ve test = active infxn. False neg tests in
immunosuppression (miliary TB, sarcoid, AIDS, lymphoma)
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Heaf: for screening. Circle of primed needles which inject tuberculin
(no longer available)
First Line Antituberculous drugs
Isoniazid
 Rifampicin
 Pyrazinamide
 Ethambutol
 Streptomycin
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Isoniazid
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MOA - Unknown, but may include the inhibition of myocolic acid
synthesis resulting in disruption of the bacterial cell wall
The most effective Bactericidal agent
Half-life: Fast acetylators: 30-100 minutes; Slow acetylators: 2-5 hours
Metabolized in liver excreted by kidneys
Substrate of CYP2E1 (major)
Inhibits CYP 2C19 ; 2C8/9; 2D6
Major S/E s - Hepatitis (up to x5 ↑AST/ALT acceptable, stop if bilirubin↑)
- Peripheral neuropathy
(preventable with pyridoxine (Vit B6) - given to high risk patients)
Rifampicin
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MOA - Inhibits bacterial RNA synthesis by binding to the beta subunit
of DNA-dependent RNA polymerase, blocking RNA transcription
Substrate of CYP2A6, 2C8/9, 3A4
Induces CYP1A2 , 2A6, 2B6, 2C8/9, 2C19, 3A4
Major S/E s - Hepatitis (up to x5 ↑AST/ALT acceptable, stop if bilirubin↑)
- orange urine & tears (contact lens staining; useful for assessing
compliance)
- inactivation OCP
- flu-like syndrome
- thrombocytopenic purpura if intermittent use
Pyrazinamide
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MOA - Converted to pyrazinoic acid in susceptible strains of
Mycobacterium which lowers the pH of the environment; exact
mechanism of action has not been elucidated
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Crosses Blood brain barrier well
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Active against intracellular dividing forms of M. tuberculosis
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Bacteriostatic or bactericidal depending on tissue concentration
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Major S/E s - Hepatitis (up to x5 ↑AST/ALT acceptable, stop if bilirubin↑)
- Arthralgia
-hyperuricaemia(gout is a CI)
- n&v
Ethambutol
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MOA - Suppresses mycobacteria multiplication by interfering with
RNA synthesis
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Major S/E s - Optic neuritis (colour vision is first to deteriorate)
- test acuity prior to treatment with Snellen chart + Ishihara chart
- avoid in patients who cannot report visual change
Streptomycin
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MOA - Aminoglycoside - Inhibits bacterial protein synthesis by
binding directly to the 30S ribosomal subunits causing faulty peptide
sequence to form in the protein chain
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Major S/E s - ototoxic; nephrotoxic; neurotoxic
- C/I in pregnancy
NB Interactions
Rifampicin = hepatic enzyme p450 inducer (therefore ↓ level of)
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affects
OCP( NB to warn pt of ↓ effectiveness)
corticosteroids
protease inhibitors
phenytoin
anticoagulants
sulphonylureas
methadone
Isoniazid = hepatic enzyme inhibitor (therefore ↑ level of)
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affects
phenytoin
carbamazepine
anticoagulants
Basic Principles
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TB is a Notifiable illness
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Obtain bacteriological confirmation and drug susceptibility testing
wherever possible
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Specialist supervised treatment
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Advise HIV testing (with consent & counselling)
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Notify public health to arrange contact tracing & screening
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Prolonged tx necessary & adherence NB. DOT may be required if
non-adherence issue
Treatment of pulmonary TB
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NB of compliance (helps pt & prevents spread of resistance)
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Before tx baseline FBC, LFTs, RP
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Isoniazid, rifampicin & pyrazinamide all hepatotoxic
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Test colour vision (Ishihara chart) & acuity (Snellen chart) before &
after tx (ethambutol may cause (reversible) ocular toxicity
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Consider pyridoxine 10 mg OD (Vit B6 ) to prevent isoniazid
neuropathy
Treatment regimens
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Six month regimen (all forms except CNS)
- two months of 3 or 4* drugs
(Isoniazid + Rifampicin + Pyrazinamide +/- Ethambutol)
- four months of 2 drugs (Isoniazid + Rifampicin)
- best given as combination preparations
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12 month regimen (meningeal TB)
- two months of 4 drugs
- ten months of 2 drugs
* If resistance likely or immunosuppressed
Additional points
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Criteria for using fourth drug in first 2 months
- previous TB, immunosuppressed, in contact with organism
likely to be drug resistant
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Corticosteroids
- severe TB meningitis
- constrictive pericarditis
Directly Observed Therapy of
Pulmonary TB
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DOT in pts who can’t comply reliably with tx regimen (eg homeless,
C2H5OH abuse, mentally ill, hx of non-compliance)
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Given isoniazid, rifampicin, pyrazinamide & ethambutol (or
streptomycin) 3 times/wk under supervision for initial 2/12 then
isoniazid & rifampicin 3 times/wk for further 4/12
TB in HIV positive patients
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30-50% of pts with AIDS in developing world have concurrent TB
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Increased reactivation of latent TB
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Mantoux may be –ve
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Smears may be –ve for AFB
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NB to culture organism & assess drug sensitivities/resistance
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Previous BCG doesn’t prevent infection
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Atypical presentation & findings
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Extrapulmonary & disseminated disease more common
TB in HIV positive patients
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Confirmed M. tuberculosis infxn sensitive to 1st line drugs should be tx
with standard 6-mth regimen; regimen may need modification if
resistant organism→ specialist advice
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Compliance issues; drug absorption
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CYP 3A P450 induced by rifampicin – lower levels of protease inhibitors
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More toxicity from HAART tx & anti-TB tx due to interactions→ specialist
advice
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HAART tx reconstitutes CD4 count & immune fn, may lead to
paradoxical worsening of TB symptoms (Immune reconstitution
inflammatory response)
MDR-TB & TB in pts with HIV/AIDs
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Isolation necessary if TB pts near HIV+ve pts
MDR-TB high mortality. Need negative pressure ventiated room
Test TB cultures against 1st & 2nd line chemotherapeutic agents
May need 5+ drugs in MDR-TB. Liaise early with Microbiologist/Infectious
Disease specialist. Duration usually 9-24 mths.
FU for 1yr if MDR TB, long term if also HIV +ve
1st line anti-TB agents
2nd line anti-TB agents
Isoniazid
Ofloxacin
Rifampicin
Ciprofloxacin
Pyrazinamide
Cycloserine
Ethambutol
Ethionamide
Streptomycin
Aminosalicylic acid
Preventing TB in HIV +ve pts
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Primary prophylaxis against TB indicated in some HIV +ve pts ( if no
BCG + mantoux >5mm, if BCG + mantoux >10mm, if recent
exposure to active TB)
Isoniazid given with pyroxidine for 9 months
If known isoniazid-resistant TB contact give rifampicin
Chemoprophylaxis for asymptomatic TB
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Immigrant/contact screening may id pts with no
symptoms/CXR findings
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Chemoprophylaxis useful to kill organisms &
prevent disease progression
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Chemoprophylaxis may be required in latent
disease & receiving tx with immunosuppressants
(eg cytotoxics, long term tx with steroids)
Chemoprophylaxis
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Positive tuberculin test (cf BCG);
normal CXR; asymptomatic
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1 drug x six months OR
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2 drugs for three months
BCG vaccine
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BCG is live attenuated strain derived from M. bovis → stimulates
development of hypersensitivity to M. tubercolosis
Given intradermally
Within 2-4wks swelling at injection site, progresses to papule about
10mm diam & heals in 6-12 wks
BCG recommended if immunisation not previously carried out & neg
for tuberculoprotein hypersensitivity
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Infants in area of TB incidence > 40/100,000
Infants with parent/grandparent born in country with incidence of TB
>40/100,000
Contacts of pts with active pulmonary TB
Health care staff
Veterinary staff
Prison staff
If intending to stay for >1 mth in country with high incidence TB
BCG vaccine
Live vaccines CI if:
-acute infxn
-pregnant women
-pts with impaired immune fn
-BCG also CI if generalised septic skin conditions
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BTS Guidelines
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http://www.brit-thoracic.org.uk/c2/uploads/Chemotherapy.pdf
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http://www.brit-thoracic.org.uk/c2/uploads/TB.pdf