complications of tb treatment and their management dr liza ahmad fisal 14 july 2010
TRANSCRIPT
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COMPLICATIONS OF TB TREATMENT AND THEIR
MANAGEMENT
Dr Liza Ahmad Fisal14 July 2010
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Complications
• Adverse drug reaction
• Aggravate pre-existing conditions
– Renal impairment
– Liver impairment
– Peripheral neuropathy
• Interact with existing drugs
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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.
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Anti-TB and their side-effects & interactions
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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
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Isoniazid drug interactions
Microsomal enzyme inhibitor → ↑ plasma concentration of certain drugs → drug toxicity.
Examples: Warfarin Carbamazepine Valproate Paracetamol Theophylline
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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
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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
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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
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Pyrazinamide side-effects
Gastrointestinal intolerance Photosensitivity dermatitis Rash Asymptomatic hyperuricaemia Non-gouty arthralgia Acute gout Asymptomatic ↑ ALT Hepatitis (less common, more severe) Sideroblastic anaemia.
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Pyrazinamide & DM
Labile sugar control – careful monitoring
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Ethambutol side-effects
Dose-dependent optic neuritis Acuity / field Colour
Peripheral neuropathy (esp in lower limbs) Rash Arthralgia. Rare - hepatitis.
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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
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Streptomycin drug interactions
• Avoid other ototoxic or nephrotoxic drugs
• Avoid neuromuscular blocking agents causing crisis in myasthenia gravis patients
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Management
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Managing anti-TB side effects
Confirm diagnosis.Determine whether side effect is minor/major.Managing minor/major side effects
accordingly.
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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
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Major side-effects
Skin rash with or without itching DeafnessDizzinessJaundice*Visual impairmentShock*, purpura, acute renal failure
* Potentially fatal
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Skin
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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
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Scabies
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Liver
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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
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V. J. Navarro and J. R. SeniorDrug-Related HepatotoxicityN. Engl. J. Med., February 16, 2006; 354(7): 731 - 739
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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)
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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.
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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
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WHO management of drug-induced hepatitis
Re-introduce anti-TB when: LFTs normalised Asymptomatic
Bridge if persistent abnormal LFTs or serious TB: SEO
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• 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
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• If rechallenge unsuccessful, give alternative regime:
– 2 hepatotoxics• 2HRE/7HR• 2SHRE/6HR• 6-9REZ
– 1 hepatotoxic• 2SHE/10HE
– 0 hepatotoxic• 18-24 SEO
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Drug rechallenge
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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
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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
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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
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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
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New regimen
• SHERO
• SHER – 2SHER/6HR
• HER – 2HER/7HR
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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
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Thank you