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Presentation on theme: "COMPLICATIONS OF TB TREATMENT AND THEIR MANAGEMENT"— Presentation transcript:

Dr Liza Ahmad Fisal 14 July 2010

2 Complications Adverse drug reaction Aggravate pre-existing conditions
Renal impairment Liver impairment Peripheral neuropathy Interact with existing drugs

3 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.

4 Anti-TB and their side-effects & interactions

5 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

6 Isoniazid drug interactions
Microsomal enzyme inhibitor → ↑ plasma concentration of certain drugs → drug toxicity. Examples: Warfarin Carbamazepine Valproate Paracetamol Theophylline

7 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

8 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

9 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

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

11 Pyrazinamide & DM Labile sugar control – careful monitoring

12 Ethambutol side-effects
Dose-dependent optic neuritis Acuity / field Colour Peripheral neuropathy (esp in lower limbs) Rash Arthralgia. Rare - hepatitis.

13 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

14 Streptomycin drug interactions
Avoid other ototoxic or nephrotoxic drugs Avoid neuromuscular blocking agents causing crisis in myasthenia gravis patients

15 Management

16 Managing anti-TB side effects
Confirm diagnosis. Determine whether side effect is minor/major. Managing minor/major side effects accordingly.

17 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



20 Major side-effects Skin rash with or without itching Deafness
Dizziness Jaundice* Visual impairment Shock*, purpura, acute renal failure * Potentially fatal

21 Skin

22 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


24 Scabies

25 Liver

26 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

27 V. J. Navarro and J. R. Senior
Drug-Related Hepatotoxicity N. Engl. J. Med., February 16, 2006; 354(7):

28 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)

29 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.

30 What to do? Stop: Screen: 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

31 WHO management of drug-induced hepatitis
Re-introduce anti-TB when: LFTs normalised Asymptomatic Bridge if persistent abnormal LFTs or serious TB: SEO

32 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

33 If rechallenge unsuccessful, give alternative regime:
2 hepatotoxics 2HRE/7HR 2SHRE/6HR 6-9REZ 1 hepatotoxic 2SHE/10HE 0 hepatotoxic 18-24 SEO

34 Drug rechallenge

35 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

36 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

37 Modified Girling’s Protocol
Drug Challenge dose (mg) Day 1 Day 2 Day 3 Isoniazid 50 300 Optimal dose Rifampicin 75 Pyrazinamide 250 1000 Ethambutol 100 400 Streptomycin 125 500

38 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 + H1 D1 rechallenge with H 23 SE0 + H2 D2 rechallenge with H 24 SEO + H3 D3 rechallenge with H 25 SHEO + R1 D1 rechallenge with R 26 SHEO + R2 D2 rechallenge with R 27 SHEO + R3 D3 rechallenge with R 28 SHERO New regimen

39 New regimen SHERO SHER – 2SHER/6HR HER – 2HER/7HR

40 Reference Diagnosis, management and prevention of drug-induced liver injury S Verma, N Kaplowitz Gut 2009;58: ATS Hepatotoxicity of Antituberculosis Therapy Subcommittee An Official ATS Statement: Hepatotoxicity of Antituberculosis Therapy Am. J. Respir. Crit. Care Med. 2006; 174: WHO 2009 Treatment of tuberculosis: guidelines - 4th ed

41 Thank you


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