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COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

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Page 1: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

COMPLICATIONS OF TB TREATMENT AND THEIR

MANAGEMENT

Dr Liza Ahmad Fisal14 July 2010

Page 2: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Complications

• Adverse drug reaction

• Aggravate pre-existing conditions

– Renal impairment

– Liver impairment

– Peripheral neuropathy

• Interact with existing drugs

Page 3: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Adverse drug reaction

May seem mild and harmless but may herald serious complications: Nausea & vomiting – hepatitis Weakness / off legs - vestibulotoxicity Rash - Stevens Johnson syndrome

Identifying the culprit can be difficult because of the overlapping adverse effects.

Page 4: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Anti-TB and their side-effects & interactions

Page 5: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Isoniazid side-effects

Sleepiness and lethary

Peripheral neuropathy (especially in predisposing conditions)

Psychosis, fits, optic neuritis

Asymptomatic ↑ ALT

Hepatitis

Arthralgia

Lupus-like syndrome

Rare – fever, rash, SJS, haemolytic anaemia, vasculitis, neutrophilia

Page 6: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Isoniazid drug interactions

Microsomal enzyme inhibitor → ↑ plasma concentration of certain drugs → drug toxicity.

Examples: Warfarin Carbamazepine Valproate Paracetamol Theophylline

Page 7: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Rifampicin side-effects

Orange discolouration of bodily fluids

Abdominal pain, nausea & vomiting

Hyperbilirubinaemia & ↑ ALP

Asymptomatic ↑ ALT

Hepatitis

Fever & flu-like symptoms (esp with intermittent dosing)

Pruritus +/- rash

Exfoliative dermatitis (esp HIV-positive)

Rare – renal impairment, haemolysis, thrombocytopenia, shock

Page 8: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Rifampicin drug interactions

Microsomal enzyme inducer → ↓ plasma concentration of certain drugs → ↓ drug efficacy.

Examples: Combined-oral contraceptives

Warfarin

Corticosteroids

Phenytoin

Sulphonylurea hypoglycaemics

Statins

Theophylline

Methadone

T4

Page 9: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Rifampicin & COC

Less efficacious → unwanted pregnancy

Higher dose of oestrogen (50mcg) or alternative methods

Throughout treatment with rifampicin and at least 1 month after rifampicin completed

Page 10: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Pyrazinamide side-effects

Gastrointestinal intolerance Photosensitivity dermatitis Rash Asymptomatic hyperuricaemia Non-gouty arthralgia Acute gout Asymptomatic ↑ ALT Hepatitis (less common, more severe) Sideroblastic anaemia.

Page 11: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Pyrazinamide & DM

Labile sugar control – careful monitoring

Page 12: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Ethambutol side-effects

Dose-dependent optic neuritis Acuity / field Colour

Peripheral neuropathy (esp in lower limbs) Rash Arthralgia. Rare - hepatitis.

Page 13: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Streptomycin side-effects

Painful injections

Infection at injection site

Circumoral paraesthesia (usually after 1st month)

Rash

Impairment of hearing and vestibular function

Vertigo more common First 2 months Potentially reversible

Nephrotoxic

Rare - haemolytic anaemia, aplastic anaemia, agranulocytosis, thrombocytopenia and lupoid reactions

Page 14: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Streptomycin drug interactions

• Avoid other ototoxic or nephrotoxic drugs

• Avoid neuromuscular blocking agents causing crisis in myasthenia gravis patients

Page 15: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Management

Page 16: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Managing anti-TB side effects

Confirm diagnosis.Determine whether side effect is minor/major.Managing minor/major side effects

accordingly.

Page 17: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Principles of management

Minor adverse effects Continue TB treatment Give symptomatic treatment. Close monitoring

Major side-effects, Stop the drug responsible or TB treatment (if drug

responsible unknown) Refer

Page 18: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010
Page 19: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010
Page 20: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Major side-effects

Skin rash with or without itching DeafnessDizzinessJaundice*Visual impairmentShock*, purpura, acute renal failure

* Potentially fatal

Page 21: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Skin

Page 22: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Itching without a rash

Symptomatic treatment – anti-histamines & emollients

Continue TB treatment

Observing the patient closely

Skin rash

Stop all anti-TB drugs

Rechallenge with anti-TB drugs

Page 23: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010
Page 24: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Scabies

Page 25: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Liver

Page 26: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Drug-induced liver injury (DILI)

Rare but potentially fatal adverse effect Hepatotoxicity ALT > 3 x ULN ALP > 2 X ULN Culprits - Isoniazid, Rifampicin, Pyrazinamide Combining hepatotoxic drugs increases toxicity

Page 27: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

V. J. Navarro and J. R. SeniorDrug-Related HepatotoxicityN. Engl. J. Med., February 16, 2006; 354(7): 731 - 739

Page 28: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Natural history DILI

Drug-induced acute liver failure: Significant morbidity High mortality - 20% survival in the absence of liver

transplantation

The clinical course after withdrawal of the drug is variable: Better after discontinuation Worsen for weeks before improvement is seen

Resolution of cholestatic injury take longer compared to the hepatitis form (?cholangiocytes regenerate more slowly)

Page 29: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Natural history of DILI

Patients rarely develop chronic liver disease after an acute severe DILI.

Patients with cholestatic/mixed liver disease were more prone to developing chronic injury (9%), than those with the hepatocellular form (4%)

Prolonged DILI was mostly seen in patients with cholestatic/mixed types of hepatotoxicity.

Page 30: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

What to do?

Stop: ALT > 3 x ULN with symptoms* ALT > 5 x ULN without symptoms

• Screen:

– Hepatitis A, B, C

– USS HBS

– Other hepatotoxics – other drugs, TCM, alcohol

Page 31: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

WHO management of drug-induced hepatitis

Re-introduce anti-TB when: LFTs normalised Asymptomatic

Bridge if persistent abnormal LFTs or serious TB: SEO

Page 32: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

• Re-introducing anti-TB

– One at a time

– In this order: Rifampicin → Isoniazid → Pyrazinamide

– Monitor LFTs

– If symptoms recur or LFTs become abnormal as the drugs are reintroduced, the last drug added should be stopped

– If OK on Rifampicin & Isoniazid and hepatitis was severe, omit challenging with Pyrazinamide

Page 33: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

• If rechallenge unsuccessful, give alternative regime:

– 2 hepatotoxics• 2HRE/7HR• 2SHRE/6HR• 6-9REZ

– 1 hepatotoxic• 2SHE/10HE

– 0 hepatotoxic• 18-24 SEO

Page 34: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Drug rechallenge

Page 35: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Rechallenging

* Rechalleging with anti-TB drug is done when the drug responsible is unknown.

• Identifying culprit drug necessary to continue TB treatment

• Girling protocol and its modified version is used

Page 36: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Contraindications to drug rechallenge

Rifampicin-induced thrombocytopenia, hemolytic anemia, acute renal failure, shock

Isoniazid-induced lupus Ethambutol-induced optic neuropathy Pyrazinamide-induced acute gouty arthritis Streptomycin-induced vestibuloneuropathy

Page 37: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Drug Challenge dose (mg)

Day 1 Day 2 Day 3

Isoniazid 50 300

Optimal dose

Rifampicin 75 300

Pyrazinamide 250 1000

Ethambutol 100 400

Streptomycin 125 500

Modified Girling’s Protocol

Page 38: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Changing regimen

• EHRZ (Dose 1-14)

• SEO (Dose 15-21)

• H introduced once LFT normalised

• R introduced when patient tolerate H, usually day 4 of rechallenge.

Dose Regimen Notes

1-14 EHRZ 1st regimen

15-21 SEO Bridging regimen

22 SEO + H1D1 rechallenge with H

23 SE0 + H2D2 rechallenge with H

24 SEO + H3D3 rechallenge with H

25 SHEO + R1D1 rechallenge with R

26 SHEO + R2D2 rechallenge with R

27 SHEO + R3D3 rechallenge with R

28 SHERO New regimen

Page 39: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

New regimen

• SHERO

• SHER – 2SHER/6HR

• HER – 2HER/7HR

Page 40: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Reference

Diagnosis, management and prevention of drug-induced liver injury S Verma, N Kaplowitz Gut 2009;58:1555-1564

ATS Hepatotoxicity of Antituberculosis Therapy Subcommittee An Official ATS Statement: Hepatotoxicity of Antituberculosis Therapy Am. J. Respir. Crit. Care Med. 2006; 174: 935-952

WHO 2009 Treatment of tuberculosis: guidelines - 4th ed

Page 41: COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT Dr Liza Ahmad Fisal 14 July 2010

Thank you