Transcript Mycobacterium tuberculosis treatment

Drug tx of Pulmonary TB
09/10/07
3rd medical year Pharmacology
TB
• 2004 14.6 million people worldwide had active TB, 1.7 million
deaths mostly developing countries.
• When TB meds misused/mismanagedemergence of
resistance
•
~10% of all new TB cases are resistant to at least one drug,
if more than one = MDR TB
• XDR TB-resistant to fluoroquinolone & at least one of
injectable agents
AFB = bacilli that resist acid-alcohol decolourization under
auramine/ZN staining.
TB
• Primary TB: Initial infxn usually pulmonary (droplet spread).
Peripheral lesion forms (Ghon focus) & its draining nodes
infected (Ghon complex). Often asymptomatic or fever,
lassitude, night sweats, anorexia, cough, sputum, erythema
nodosum. AFB may be in sputum. Commonest non-pulmonary
primary infxn is GI (affecting ileocaecal junction & its LNs)
TB
• 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.
TB
• Pulmonary TB: silent or cough, sputum, malaise,
weight loss, night sweats, haemoptysis, pleural
effusion
TB
• Miliary TB: following haematogenous
dissemination. Clinical features non-specific. CXR:
reticulonodular shadowing. Bx of lung, liver, LN or
marrow may give AFB/granulomata.
• Meningeal TB: Subacute onset meningitic
symptoms: fever, headache, n&v, neck stiffness,
photophobia
• 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.
TB
• Bone TB: vertebral collapse adjacent to
paravertebral abscess (Pott’s vertebra). X-rays &
biopsies (for AFB & culture)
• Skin TB (lupus vulgaris): jelly-like nodules, e.g.
face/neck
• Acute TB pericarditis: primary exudative allergic
lesion
• 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
• Advise HIV & hepatitis testing (with consent & counselling)
• Notify public health to arrange contact tracing & screening
• Prolonged tx necessary & adherence NB. DOT may be required if
non-adherence issue
Diagnosis
• Relevant clinical samples (sputum, pleural fluid, pleura, urine,
ascites, peritoneum or CSF) for culture
• Microbiology: 3 EMS for AFB (smear & culture), pleural
aspiration & biopsy (if effusion). If sputum neg/unable to
expectorate bronchoscopy for biopsy & BAL. Biopsy if suspicious
lesion in liver, LN, bone marrow.
• TB PCR: rapid id of rifampicin resistance.
TB
• Histology: caseating
granulomata
Radiology
• CXR =
consolidation,
cavitation,
fibrosis &
calcification in
pulmonary TB,
usually upper
lobes
Immunological
 Tuberculin skin test/Mantoux: tuberculin purified protein
derivative (PPD) injected intradermally & cell-mediated response
at 48-72h . +ve 5-14mm induration, strongly +ve >15mm
 +ve test indicated immunity (may be previous exposure, BCG)
Strong +ve test = active infxn. False neg tests in
immunosuppression (miliary TB, sarcoid, AIDS, lymphoma)
Treatment of pulmonary TB
• NB of compliance (helps cure pt & prevents
spread of resistance)
• Before tx baseline FBC, LFTs (incl alt), RP
• Isoniazid, rifampicin & pyrazinamide all
hepatotoxic
• Test colour vision (Ishihara chart) & acuity
(Snellen chart) before & after tx (ethambutol
may cause (reversible) ocular toxicity
• TB treated in 2 phases – initial phase using at
least 3-4 drugs & continuation phase using 2
drugs in fully sensitive cases
Treatment of pulmonary TB
•
Initial phase (2/12 on 3-4 drugs) – designed to ↓bacterial population asap &
prevent resistance.
 Rifampicin: MOA - Inhibits bacterial RNA synthesis by binding to the beta
subunit of RNA polymerase, blocking RNA transcription.
 Isoniazid: MOA - Unknown, but may include the inhibition of myocolic acid
synthesis resulting in disruption of the bacterial cell wall. Most effective
Bactericidal agent
 Pyrazinamide (bactericidal active against intracellular dividing forms of M.
tuberculosis, main effect only in 1st 2/12, useful in TB meningitis as good
meningeal penetration)
[Combination=RIFATER]
 If resistance likely add ethambutol (if previous TB, immunosuppressed, in
contact with organism likely to be drug resistant)
 Streptomycin rarely used (given if resistance to isoniazid established)
Treatment of pulmonary TB
• Continuation phase (4/12 on 2 drugs)
 Rifampicin + isoniazid. [Combination RIFINAH] If resistance problem
use ethambutol.
•
•
•
•
Drugs best given as combination preparations unless one of
components cannot be given (resistance/intolerance)
Monitor LFTs. If pre-existing liver disease/alcohol abuse need frequent
LFTs esp in initial phase. If no liver problem further checks necessary
only if sx fever, malaise, n&v, jaundice, deterioration.
If AST/ALT 2 times normal monitor LFTs until normal
If AST/ALT 5 times normal or bilirubin ↑ stop anti-TB meds
-if pt not unwell & non-infectious TB no tx until LFTs normal
-if pt unwell/smear positive need inpt tx until LFTs normal, eg with
streptomycin/ethambutol
-once LFTs normal challenge doses of original drugs sequentially in
order: isoniazid, rifampicin, pyrazinamide with monitoring pts clinical
condition & LFTs
Treatment of pulmonary TB
• RP checked prior to tx. Streptomycin & ethambutol best
avoided if renal impairment, but if used need to ↓ dose &
monitor drug levels.
• If +ve culture for M. tuberculosis but susceptibility results
not available after 2/12 then tx with pyrazinamide (&
ethambutol if appropriate) should continue until
susceptibilities confirmed
• Longer tx for meningitis (~ 12 mths) & resistant organisms
• NB Give pyridoxine 10 mg OD (Vit B6 ) throughout tx in high
risk pts
• Steroids indicated in meningeal & pericardial disease
• Relapse uncommon if good compliance with tx
Recommended dosage for standard
unsupervised 6-mth tx of
Pulmonary TB
- Rifater [rifampicin, isoniazid, pyrazinamide] ( for 2/12 initial phase)
Adults <40kg
3 tablets/d
40-49kg 4 tablets/d
50-64kg 5 tablets/d
>65kg
6 tablets/d
- Ethambutol (for 2/12 initial phase)
15mg/kg OD
-
Rifinah/Rimactazid [rifampicin & isoniazid] (for 4/12 continuation phase
following initial tx with Rifater)
Adults <50kg 3 tablets/d of Rifinah-150
50kg+ 2 tablets/d of Rifinah-300 or Rimactazid-300
Standard regimen may be used in pregnancy & BF. Streptomycin CI in
pregnancy (ototoxic to fetus)
DOT of Pulmonary TB
•
•
DOT in pts who can’t comply reliably with tx regimen (eg homeless,
C2H5OH abuse, mentally ill, hx of non-compliance)
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
Recommended dosage for intermittent supervised 6-mth tx
Isoniazid (for initial 2/12 & 4/12 continuation phases)
Adult & child: 15mg/kg (max 900 mg) 3 times/wk
Rifampicin (for initial 2/12 & 4/12 continuation phase)
Adult 600-900mg 3 times/wk; child 15mg/kg (max 900mg) 3 times/wk
Pyrazinamide (for 2/12 initial phase only)
Adult <50 kg 2g 3 times/wk, 50kg+ 2.5g 3 times/wk; child 50mg/kg 3
times/wk
Ethambutol (for 2/12 initial phase only)
Adult & child 30mg/kg 3 times/wk
S/E of drugs used in tx of
pulmonary TB
• Need specialist advice in renal/liver failure, pregnancy.
Drug
Main Side-effects
Rifampicin
Hepatitis (small ↑AST acceptable, stop if bilirubin↑),
orange urine & tears (contact lens staining),
inactivation OCP, ‘flu-like syndrome &
thrombocytopenic purpura if intermittent use
Isoniazid
Hepatitis, peripheral neuropathy, pyridoxine deficit,
agranulocytosis, psychosis (rare)
Ethambutol
Optic neuritis (colour vision is first to deteriorate)
Pyrazinamide Hepatitis, arthralgia, hyperuricaemia(gout is a CI),
n&v
NB Interactions
Rifampicin = hepatic enzyme p450 inducer (therefore ↓ level of)
– affects OCP( NB to warn pt of ↓ effectiveness)
corticosteroids
protease inhibitors
phenytoin
sulphonylureas
anticoagulants
methadone
Isoniazid = hepatic enzyme inhibitor (therefore ↑ level of)
-affects phenytoin
carbamazepine
anticoagulants
MDR-TB & TB in pts with
HIV/AIDS
•
•
DOT aims to prevent MDR-TB
TB is common, serious but treatable complication of HIV infxn.
Estimated that 30-50% of pts with AIDS in developing world have
concurrent TB.
•



Interactions of HIV & TB
Mantoux may be –ve in HIV +ve pt with TB
Increased reactivation of latent TB
Atypical presentation & findings on CXR (lobar/bibasal pneumonia, hilar
LN)
Previous BCG doesn’t prevent infxn
Smears may be –ve for AFB. NB to culture organism & assess drug
sensitivities/resistance
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
Extrapulmonary & disseminated disease more common
More toxicity from HAART tx & anti-TB tx due to interactions→
specialist advice
HAART tx reconstitutes CD4 count & immune fn, may lead to
paradoxical worsening of TB symptoms (Immune reconstitution
inflammatory response, IRIS)






•
•
•
•
•
MDR-TB & TB in pts with
HIV/AIDs
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
Amikacin
Rifampicin
Moxifloxacin, Ofloxacin
Pyrazinamide
Cycloserine
Ethambutol
Ethionamide, prothionamide
Streptomycin
PAS
Preventing TB in HIV +ve pts
• 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 (e.g. 300mg/d PO, children 5mg/kg, max 300mg
given with pyroxidine) for 9 mths. If known isoniazidresistant TB contact give rifampicin
Chemoprophylaxis for
asymptomatic TB infxn
•
Immigrant/contact screening may id pts with no symptoms/no CXR
findings, but +mantoux
•
In LTBI ~10% will go onto develop active disease
•
Chemoprophylaxis useful to kill organisms & prevent disease progression
•
Chemoprophylaxis may be required in latent disease & receiving tx with
immunosuppressants (eg cytotoxics, TNF blockers, long term tx with
steroids)
•
1 or 2 anti-TB agents used for shorter period than with symptomatic
disease (e.g. rifampicin 600mg OD PO & isoniazid 300mg OD PO
[Rifinah] for 4 mths or isoniazid 300mg OD PO alone for 9 mths)
•
Standard anti-TB tx should be initiated once any evidence active
disease (clinical/radiological)
BCG vaccine
• BCG is live attenuated strain derived from M. bovis → stimulates
development of hypersensitivity to M. tuberculosis
• 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
 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