Drug tx of Pulmonary Drug tx of Pulmonary TBTB

Drug tx of Pulmonary Drug tx of Pulmonary TBTB

09/10/0709/10/07

3rd medical year Pharmacology3rd medical year Pharmacology

TB

• 2004 14.6 million people worldwide had active TB, 1.7 million deaths mostly developing countries.

• When TB meds misused/mismanagedemergence 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 ofcomponents 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 inpregnancy (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/wkRifampicin (for initial 2/12 & 4/12 continuation phase)Adult 600-900mg 3 times/wk; child 15mg/kg (max 900mg) 3 times/wkPyrazinamide (for 2/12 initial phase only)Adult <50 kg 2g 3 times/wk, 50kg+ 2.5g 3 times/wk; child 50mg/kg 3times/wkEthambutol (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 phenytoincarbamazepineanticoagulants

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 +ve1st 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 isoniazid-resistant 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