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