Drug treatment of Pulmonary Drug treatment of Pulmonary TuberculosisTuberculosis

44thth medical year Pharmacology medical year Pharmacology

TuberculosisTuberculosis

Kills ~ 3 million/yr worldwideKills ~ 3 million/yr worldwide

In UK ~ 10% drug resistanceIn UK ~ 10% drug resistance

TuberculosisTuberculosis

Primary TBPrimary TB: Initial infxn usually pulmonary (droplet spread). : Initial infxn usually pulmonary (droplet spread). Peripheral lesion forms (Ghon focus) & its draining nodes infected Peripheral lesion forms (Ghon focus) & its draining nodes infected (Ghon complex). Often asymptomatic or fever, lassitude, sweats, (Ghon complex). Often asymptomatic or fever, lassitude, sweats, anorexia, cough, sputum, erythema nodosum. AFB may be in anorexia, cough, sputum, erythema nodosum. AFB may be in sputum. Commonest non-pulmonary primary infxn is GI (affecting sputum. Commonest non-pulmonary primary infxn is GI (affecting ileocaecal junction & its LNs)ileocaecal junction & its LNs)

Post-primary TBPost-primary TB: Any form of immunocompromise may : Any form of immunocompromise may reactivate TB e.g. malignancy, DM, steroids, debilitation (HIV, reactivate TB e.g. malignancy, DM, steroids, debilitation (HIV, elderly). Lung lesions (usually upper lobe) progress & fibrose. elderly). Lung lesions (usually upper lobe) progress & fibrose. Tuberculomas contain few AFB unless erode into bronchus, where Tuberculomas contain few AFB unless erode into bronchus, where can rapidly multiply & make pt highly contagious (open TB). In can rapidly multiply & make pt highly contagious (open TB). In elderly, immunocompromised, 3elderly, immunocompromised, 3rdrd world dissemination of multiple foci world dissemination of multiple foci throughout body results in miliary TB. throughout body results in miliary TB.

TuberculosisTuberculosis

Pulmonary TBPulmonary TB: : silent or cough, sputum, malaise, weight loss, night sweats, pleurisy, silent or cough, sputum, malaise, weight loss, night sweats, pleurisy,

haemoptysis, pleural effusion, superimposed pulmonary infectionhaemoptysis, pleural effusion, superimposed pulmonary infection Miliary TBMiliary TB: : following haematogenous dissemination. Clinical features non-following haematogenous dissemination. Clinical features non-

specific. CXR: reticulonodular shadowing. Bx of lung, liver, LN or specific. CXR: reticulonodular shadowing. Bx of lung, liver, LN or marrow may give AFB/granulomatamarrow may give AFB/granulomata

Meningeal TBMeningeal TB: : Subacute onset meningitic symptoms: fever, headache, n&v, neck Subacute onset meningitic symptoms: fever, headache, n&v, neck

stiffness, photophobiastiffness, photophobia GU TBGU TB: : frequency, dysuria, loin/back pain, haematuria, sterile pyuria. 3 EMU frequency, dysuria, loin/back pain, haematuria, sterile pyuria. 3 EMU

for AFB. Renal US. Renal TB may spread to bladder, seminal for AFB. Renal US. Renal TB may spread to bladder, seminal vesicles, epididymis or fallopian tubes vesicles, epididymis or fallopian tubes

TuberculosisTuberculosis

Bone TBBone TB: vertebral collapse adjacent to paravertebral abscess : vertebral collapse adjacent to paravertebral abscess

(Pott’s vertebra). X-rays & biopsies (for AFB & culture)(Pott’s vertebra). X-rays & biopsies (for AFB & culture)

Skin TBSkin TB (lupus vulgaris): jelly-like nodules, e.g. face/neck (lupus vulgaris): jelly-like nodules, e.g. face/neck

Acute TB pericarditisAcute TB pericarditis: primary exudative allergic lesion: primary exudative allergic lesion

Chronic pericardial effusion & constrictive pericarditisChronic pericardial effusion & constrictive pericarditis: reflect : reflect

chronic granulomata. Fibrosis & calcification may be prominent with chronic granulomata. Fibrosis & calcification may be prominent with

spread to myocardium (Steroids for 11 wks with anti-TB meds spread to myocardium (Steroids for 11 wks with anti-TB meds ↓ ↓

need for pericardiectomy)need for pericardiectomy)

TBTB

DiagnosisDiagnosis

If suspected obtain relevant clinical samples (sputum, pleural fluid, If suspected obtain relevant clinical samples (sputum, pleural fluid,

pleura, urine, pus, ascites, peritoneum or CSF) for culturepleura, urine, pus, ascites, peritoneum or CSF) for culture

Microbiology: Microbiology: multiple sputum for AFB, pleural aspiration & biopsy (if multiple sputum for AFB, pleural aspiration & biopsy (if

effusion). If sputum neg bronchoscopy for biopsy & BAL. Biopsy if effusion). If sputum neg bronchoscopy for biopsy & BAL. Biopsy if

suspicious lesion in liver, LN, bone marrow.suspicious lesion in liver, LN, bone marrow.

AFB = bacilli that resist acid-alcohol decolourization under AFB = bacilli that resist acid-alcohol decolourization under

auramine/ZN staining. Cultures have prolonged incubation (12 wks). auramine/ZN staining. Cultures have prolonged incubation (12 wks).

TB PCR: rapid id of rifampicin resistance. Useful for diagnosis in TB PCR: rapid id of rifampicin resistance. Useful for diagnosis in

sterile specimenssterile specimens

TBTB

Histology: Histology: caseating granulomatacaseating granulomata

Radiology: Radiology: CXR = consolidation, cavitation, fibrosis & calcification in CXR = consolidation, cavitation, fibrosis & calcification in pulmonary TBpulmonary TB

Immunological: Immunological: Tuberculin skin test/Mantoux: tuberculin purified protein derivative Tuberculin skin test/Mantoux: tuberculin purified protein derivative

(PPD) injected intradermally & cell-mediated response at 48-72h . +ve (PPD) injected intradermally & cell-mediated response at 48-72h . +ve if >/= 10mm indurationif >/= 10mm induration

+ve test indicated immunity (may be previous exposure, BCG) Strong +ve test indicated immunity (may be previous exposure, BCG) Strong +ve test = active infxn. False neg tests in immunosuppression (miliary +ve test = active infxn. False neg tests in immunosuppression (miliary TB, sarcoid, AIDS, lymphoma)TB, sarcoid, AIDS, lymphoma)

Heaf: for screening. Circle of primed needles which inject tuberculin Heaf: for screening. Circle of primed needles which inject tuberculin (no longer available)(no longer available)

First Line Antituberculous drugsFirst Line Antituberculous drugs

IsoniazidIsoniazidRifampicinRifampicinPyrazinamidePyrazinamideEthambutolEthambutolStreptomycinStreptomycin

IsoniazidIsoniazid

MOAMOA - Unknown, but may include the inhibition of myocolic acid - Unknown, but may include the inhibition of myocolic acid synthesis resulting in disruption of the bacterial cell wallsynthesis resulting in disruption of the bacterial cell wall

The most effective Bactericidal agentThe most effective Bactericidal agent Half-life: Fast acetylators: 30-100 minutes; Slow acetylators: 2-5 hoursHalf-life: Fast acetylators: 30-100 minutes; Slow acetylators: 2-5 hours Metabolized in liver excreted by kidneys Metabolized in liver excreted by kidneys Substrate of CYP2E1 (major)Substrate of CYP2E1 (major) Inhibits CYP 2C19 ; 2C8/9; 2D6 Inhibits CYP 2C19 ; 2C8/9; 2D6 Major S/E s -Major S/E s -

- Hepatitis (up to x5 - Hepatitis (up to x5 ↑AST/ALT acceptable, stop if bilirubin↑)↑AST/ALT acceptable, stop if bilirubin↑)

- Peripheral neuropathy - Peripheral neuropathy

(preventable with pyridoxine (Vit B6) - given to high risk patients)(preventable with pyridoxine (Vit B6) - given to high risk patients)

RifampicinRifampicin MOAMOA - Inhibits bacterial RNA synthesis by binding to the beta - Inhibits bacterial RNA synthesis by binding to the beta

subunit of DNA-dependent RNA polymerase, blocking RNA subunit of DNA-dependent RNA polymerase, blocking RNA transcription transcription

Substrate of CYP2A6, 2C8/9, 3A4 Substrate of CYP2A6, 2C8/9, 3A4 Induces CYP1A2 , 2A6, 2B6, 2C8/9, 2C19, 3A4 Induces CYP1A2 , 2A6, 2B6, 2C8/9, 2C19, 3A4 Major S/E s -Major S/E s -

- Hepatitis (up to x5 - Hepatitis (up to x5 ↑AST/ALT acceptable, stop if bilirubin↑)↑AST/ALT acceptable, stop if bilirubin↑)

- - orange urine & tears (contact lens staining; useful for assessing orange urine & tears (contact lens staining; useful for assessing compliance)compliance)

- inactivation OCP- inactivation OCP

- flu-like syndrome- flu-like syndrome

- thrombocytopenic purpura if intermittent use- thrombocytopenic purpura if intermittent use

PyrazinamidePyrazinamide MOAMOA - Converted to pyrazinoic acid in susceptible strains of - Converted to pyrazinoic acid in susceptible strains of

Mycobacterium which lowers the pH of the environment; exact Mycobacterium which lowers the pH of the environment; exact

mechanism of action has not been elucidated mechanism of action has not been elucidated

Crosses Blood brain barrier wellCrosses Blood brain barrier well

Active against intracellular dividing forms of M. tuberculosisActive against intracellular dividing forms of M. tuberculosis

Bacteriostatic or bactericidal depending on tissue concentrationBacteriostatic or bactericidal depending on tissue concentration

Major S/E s -Major S/E s -

- Hepatitis (up to x5 - Hepatitis (up to x5 ↑AST/ALT acceptable, stop if bilirubin↑)↑AST/ALT acceptable, stop if bilirubin↑)

- Arthralgia- Arthralgia

-hyperuricaemia(gout is a CI)-hyperuricaemia(gout is a CI)

- n&v- n&v

EthambutolEthambutol

MOAMOA - Suppresses mycobacteria multiplication by interfering with - Suppresses mycobacteria multiplication by interfering with

RNA synthesis RNA synthesis

Major S/E s -Major S/E s -

- Optic neuritis (colour vision is first to deteriorate)- Optic neuritis (colour vision is first to deteriorate)

- test acuity prior to treatment with Snellen chart + Ishihara chart- test acuity prior to treatment with Snellen chart + Ishihara chart

- avoid in patients who cannot report visual change- avoid in patients who cannot report visual change

StreptomycinStreptomycin

MOAMOA - Aminoglycoside - - Aminoglycoside - Inhibits bacterial protein synthesis by Inhibits bacterial protein synthesis by

binding directly to the 30S ribosomal subunits causing faulty peptide binding directly to the 30S ribosomal subunits causing faulty peptide

sequence to form in the protein chain sequence to form in the protein chain

Major S/E s -Major S/E s -

- ototoxic; nephrotoxic; neurotoxic- ototoxic; nephrotoxic; neurotoxic

- C/I in pregnancy- C/I in pregnancy

NB InteractionsNB Interactions

Rifampicin = hepatic enzyme p450 inducer (therefore Rifampicin = hepatic enzyme p450 inducer (therefore ↓ ↓ level of)level of)

- affects affects OCP( NB to warn pt of OCP( NB to warn pt of ↓ effectiveness)↓ effectiveness) corticosteroidscorticosteroids protease inhibitorsprotease inhibitors

phenytoin anticoagulantsphenytoin anticoagulants sulphonylureas methadonesulphonylureas methadone

Isoniazid = hepatic enzyme inhibitor (therefore Isoniazid = hepatic enzyme inhibitor (therefore ↑ ↑ level of)level of)

- affects affects phenytoinphenytoin

carbamazepinecarbamazepineanticoagulantsanticoagulants

Basic PrinciplesBasic Principles

TB is a Notifiable illnessTB is a Notifiable illness

Obtain bacteriological confirmation and drug susceptibility testing Obtain bacteriological confirmation and drug susceptibility testing

wherever possiblewherever possible

Specialist supervised treatmentSpecialist supervised treatment

Advise HIV testing (with consent & counselling)Advise HIV testing (with consent & counselling)

Notify public health to arrange contact tracing & screeningNotify public health to arrange contact tracing & screening

Prolonged tx necessary & adherence NB. DOT may be required if Prolonged tx necessary & adherence NB. DOT may be required if

non-adherence issuenon-adherence issue

Treatment of pulmonary TBTreatment of pulmonary TB

NB of compliance (helps pt & prevents spread of resistance)NB of compliance (helps pt & prevents spread of resistance)

Before tx baseline FBC, LFTs, RPBefore tx baseline FBC, LFTs, RP

Isoniazid, rifampicin & pyrazinamide all hepatotoxicIsoniazid, rifampicin & pyrazinamide all hepatotoxic

Test colour vision (Ishihara chart) & acuity (Snellen chart) before & Test colour vision (Ishihara chart) & acuity (Snellen chart) before &

after tx (ethambutol may cause (reversible) ocular toxicityafter tx (ethambutol may cause (reversible) ocular toxicity

Consider pyridoxine 10 mg OD (Vit B6 ) to prevent isoniazid Consider pyridoxine 10 mg OD (Vit B6 ) to prevent isoniazid

neuropathyneuropathy

Treatment regimensTreatment regimens

Six month regimen (all forms except CNS)Six month regimen (all forms except CNS) - two months of 3 or 4* drugs- two months of 3 or 4* drugs

(Isoniazid + Rifampicin + Pyrazinamide +/- Ethambutol)(Isoniazid + Rifampicin + Pyrazinamide +/- Ethambutol)

- four months of 2 drugs (Isoniazid + Rifampicin) - four months of 2 drugs (Isoniazid + Rifampicin)

- best given as combination preparations- best given as combination preparations

12 month regimen (meningeal TB)12 month regimen (meningeal TB) - two months of 4 drugs- two months of 4 drugs

- ten months of 2 drugs- ten months of 2 drugs

* If resistance likely or immunosuppressed

Additional pointsAdditional points

Criteria for using fourth drug in first 2 monthsCriteria for using fourth drug in first 2 months - previous TB, immunosuppressed, in contact with organism- previous TB, immunosuppressed, in contact with organism

likely to be drug resistantlikely to be drug resistant

CorticosteroidsCorticosteroids

- severe TB meningitis- severe TB meningitis

- constrictive pericarditis- constrictive pericarditis

Directly Observed Therapy of Directly Observed Therapy of

Pulmonary TBPulmonary TB

DOT in pts who can’t comply reliably with tx regimen (eg homeless, DOT in pts who can’t comply reliably with tx regimen (eg homeless,

C2H5OH abuse, mentally ill, hx of non-compliance) C2H5OH abuse, mentally ill, hx of non-compliance)

Given isoniazid, rifampicin, pyrazinamide & ethambutol (or Given isoniazid, rifampicin, pyrazinamide & ethambutol (or

streptomycin) 3 times/wk under supervision for initial 2/12 then streptomycin) 3 times/wk under supervision for initial 2/12 then

isoniazid & rifampicin 3 times/wk for further 4/12isoniazid & rifampicin 3 times/wk for further 4/12

TB in HIV positive patientsTB in HIV positive patients

30-50% of pts with AIDS in developing world have concurrent TB30-50% of pts with AIDS in developing world have concurrent TB

Increased reactivation of latent TBIncreased reactivation of latent TB

Mantoux may be –ve Mantoux may be –ve

Smears may be –ve for AFBSmears may be –ve for AFB

NB to culture organism & assess drug sensitivities/resistanceNB to culture organism & assess drug sensitivities/resistance

Previous BCG doesn’t prevent infectionPrevious BCG doesn’t prevent infection

Atypical presentation & findingsAtypical presentation & findings

Extrapulmonary & disseminated disease more commonExtrapulmonary & disseminated disease more common

TB in HIV positive patientsTB in HIV positive patients

Confirmed M. tuberculosis infxn sensitive to 1Confirmed M. tuberculosis infxn sensitive to 1stst line drugs should be tx line drugs should be tx with standard 6-mth regimen; regimen may need modification if with standard 6-mth regimen; regimen may need modification if resistant organismresistant organism→ specialist advice→ specialist advice

Compliance issues; drug absorptionCompliance issues; drug absorption

CYP 3A P450 induced by rifampicin – lower levels of protease inhibitorsCYP 3A P450 induced by rifampicin – lower levels of protease inhibitors

More toxicity from HAART tx & anti-TB tx due to interactionsMore toxicity from HAART tx & anti-TB tx due to interactions→ → specialist specialist adviceadvice

HAART tx reconstitutes CD4 count & immune fn, may lead to HAART tx reconstitutes CD4 count & immune fn, may lead to paradoxical worsening of TB symptoms (Immune reconstitution paradoxical worsening of TB symptoms (Immune reconstitution inflammatory response)inflammatory response)

MDR-TB & TB in pts with HIV/AIDsMDR-TB & TB in pts with HIV/AIDs Isolation necessary if TB pts near HIV+ve ptsIsolation necessary if TB pts near HIV+ve pts MDR-TB high mortality. Need negative pressure ventiated roomMDR-TB high mortality. Need negative pressure ventiated room Test TB cultures against 1Test TB cultures against 1stst & 2 & 2ndnd line chemotherapeutic agents line chemotherapeutic agents May need 5+ drugs in MDR-TB. Liaise early with Microbiologist/Infectious May need 5+ drugs in MDR-TB. Liaise early with Microbiologist/Infectious

Disease specialist. Duration usually 9-24 mths.Disease specialist. Duration usually 9-24 mths. FU for 1yr if MDR TB, long term if also HIV +veFU for 1yr if MDR TB, long term if also HIV +ve

11stst line anti-TB agents line anti-TB agents 22ndnd line anti-TB agents line anti-TB agents

IsoniazidIsoniazid OfloxacinOfloxacin

RifampicinRifampicin CiprofloxacinCiprofloxacin

PyrazinamidePyrazinamide CycloserineCycloserine

EthambutolEthambutol EthionamideEthionamide

StreptomycinStreptomycin Aminosalicylic acidAminosalicylic acid

Preventing TB in HIV +ve ptsPreventing TB in HIV +ve pts

Primary prophylaxis against TB indicated in some HIV +ve pts ( if no Primary prophylaxis against TB indicated in some HIV +ve pts ( if no BCG + mantoux >5mm, if BCG + mantoux >10mm, if recent BCG + mantoux >5mm, if BCG + mantoux >10mm, if recent exposure to active TB)exposure to active TB)

Isoniazid given with pyroxidine for 9 monthsIsoniazid given with pyroxidine for 9 months

If known isoniazid-resistant TB contact give rifampicinIf known isoniazid-resistant TB contact give rifampicin

Chemoprophylaxis for asymptomatic TBChemoprophylaxis for asymptomatic TB

Immigrant/contact screening may id pts with no Immigrant/contact screening may id pts with no symptoms/CXR findingssymptoms/CXR findings

Chemoprophylaxis useful to kill organisms & Chemoprophylaxis useful to kill organisms & prevent disease progressionprevent disease progression

Chemoprophylaxis may be required in latent Chemoprophylaxis may be required in latent disease & receiving tx with immunosuppressants disease & receiving tx with immunosuppressants (eg cytotoxics, long term tx with steroids)(eg cytotoxics, long term tx with steroids)

ChemoprophylaxisChemoprophylaxis

Positive tuberculin test (cf BCG); Positive tuberculin test (cf BCG);

normal CXR; asymptomaticnormal CXR; asymptomatic

1 drug x six months 1 drug x six months OROR

2 drugs for three months2 drugs for three months

BCG vaccineBCG vaccine

BCG is live attenuated strain derived from M. bovis BCG is live attenuated strain derived from M. bovis → → stimulates stimulates development of hypersensitivity to M. tubercolosisdevelopment of hypersensitivity to M. tubercolosis

Given intradermallyGiven intradermally Within 2-4wks swelling at injection site, progresses to papule about Within 2-4wks swelling at injection site, progresses to papule about

10mm diam & heals in 6-12 wks10mm diam & heals in 6-12 wks BCG recommended if immunisation not previously carried out & neg BCG recommended if immunisation not previously carried out & neg

for tuberculoprotein hypersensitivityfor tuberculoprotein hypersensitivity Infants in area of TB incidence > 40/100,000Infants in area of TB incidence > 40/100,000 Infants with parent/grandparent born in country with incidence of TB Infants with parent/grandparent born in country with incidence of TB

>40/100,000>40/100,000 Contacts of pts with active pulmonary TBContacts of pts with active pulmonary TB Health care staffHealth care staff Veterinary staffVeterinary staff Prison staffPrison staff If intending to stay for >1 mth in country with high incidence TBIf intending to stay for >1 mth in country with high incidence TB

BCG vaccineBCG vaccine

Live vaccines CI if: Live vaccines CI if:

-acute infxn-acute infxn

-pregnant women-pregnant women

-pts with impaired immune fn-pts with impaired immune fn

-BCG also CI if generalised septic skin conditions-BCG also CI if generalised septic skin conditions

BTS GuidelinesBTS Guidelines

http://www.brit-thoracic.org.uk/c2/uploads/Chemotherapy.pdf

http://www.brit-thoracic.org.uk/c2/uploads/TB.pdf