Transcript COMPLICATIONS AND MANAGEMENT 14 JULY 2010

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
Adverse drug reaction
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May seem mild and harmless but may herald
serious complications:
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Nausea & vomiting – hepatitis
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Weakness / off legs - vestibulotoxicity
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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
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Sleepiness and lethary
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Peripheral neuropathy (especially in predisposing conditions)
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Psychosis, fits, optic neuritis
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Asymptomatic ↑ ALT
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Hepatitis
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Arthralgia
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Lupus-like syndrome
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Rare – fever, rash, SJS, haemolytic anaemia, vasculitis,
neutrophilia
Isoniazid drug interactions
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Microsomal enzyme inhibitor → ↑ plasma
concentration of certain drugs → drug toxicity.
Examples:
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Warfarin
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Carbamazepine
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Valproate
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Paracetamol
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Theophylline
Rifampicin side-effects
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Orange discolouration of bodily fluids
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Abdominal pain, nausea & vomiting
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Hyperbilirubinaemia & ↑ ALP
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Asymptomatic ↑ ALT
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Hepatitis
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Fever & flu-like symptoms (esp with intermittent dosing)
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Pruritus +/- rash
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Exfoliative dermatitis (esp HIV-positive)
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Rare – renal impairment, haemolysis, thrombocytopenia, shock
Rifampicin drug interactions
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Microsomal enzyme inducer → ↓ plasma
concentration of certain drugs → ↓ drug efficacy.
Examples:
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Combined-oral contraceptives
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Warfarin
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Corticosteroids
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Phenytoin
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Sulphonylurea hypoglycaemics
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Statins
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Theophylline
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Methadone
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T4
Rifampicin & COC
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Less efficacious → unwanted pregnancy
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Higher dose of oestrogen (50mcg) or alternative methods
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Throughout treatment with rifampicin and at least 1 month after
rifampicin completed
Pyrazinamide side-effects
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Gastrointestinal intolerance
Photosensitivity dermatitis
Rash
Asymptomatic hyperuricaemia
Non-gouty arthralgia
Acute gout
Asymptomatic ↑ ALT
Hepatitis (less common, more severe)
Sideroblastic anaemia.
Pyrazinamide & DM
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Labile sugar control – careful monitoring
Ethambutol side-effects
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Dose-dependent optic neuritis
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Acuity / field
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Colour
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Peripheral neuropathy (esp in lower limbs)
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Rash
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Arthralgia.
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Rare - hepatitis.
Streptomycin side-effects
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Painful injections
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Infection at injection site
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Circumoral paraesthesia (usually after 1st month)
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Rash
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Impairment of hearing and vestibular function
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Vertigo more common
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First 2 months
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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
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Confirm diagnosis.
Determine whether side effect is minor/major.
Managing minor/major side effects accordingly.
Principles of management
Minor adverse effects
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Continue TB treatment
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Give symptomatic treatment.
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Close monitoring
Major side-effects,
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Stop the drug responsible or TB treatment (if
drug responsible unknown)
Refer
Major side-effects
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Skin rash with or without itching
Deafness
Dizziness
Jaundice*
Visual impairment
Shock*, purpura, acute renal failure
* Potentially fatal
Skin
Itching without a rash
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Symptomatic treatment – anti-histamines &
emollients
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Continue TB treatment
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Observing the patient closely
Skin rash
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Stop all anti-TB drugs
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Rechallenge with anti-TB drugs
Scabies
Liver
Drug-induced liver injury (DILI)
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Rare but potentially fatal adverse effect
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Hepatotoxicity ALT > 3 x ULN
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ALP > 2 X ULN
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Culprits - Isoniazid, Rifampicin, Pyrazinamide
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Combining hepatotoxic drugs increases toxicity
V. J. Navarro and J. R. Senior
Drug-Related Hepatotoxicity
N. Engl. J. Med., February 16, 2006; 354(7): 731 - 739
Natural history DILI
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Drug-induced acute liver failure:
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Significant morbidity
High mortality - 20% survival in the absence of liver
transplantation
The clinical course after withdrawal of the drug is
variable:
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Better after discontinuation
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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
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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?
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Stop:
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ALT > 3 x ULN with symptoms*
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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
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Re-introduce anti-TB when:
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LFTs normalised
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Asymptomatic
Bridge if persistent abnormal LFTs or serious
TB:
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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
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Rifampicin-induced thrombocytopenia,
hemolytic anemia, acute renal failure, shock
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Isoniazid-induced lupus
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Ethambutol-induced optic neuropathy
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Pyrazinamide-induced acute gouty arthritis
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Streptomycin-induced vestibuloneuropathy
Modified Girling’s Protocol
Drug
Challenge dose (mg)
Day 1
Day 2
Isoniazid
50
300
Rifampicin
75
300
Pyrazinamide
250
1000
Ethambutol
100
400
Streptomycin
125
500
Day 3
Optimal dose
Changing regimen
• EHRZ (Dose 1-14)
Dose
Regimen
Notes
• SEO (Dose 15-21)
1-14
EHRZ
1st regimen
• H introduced once LFT
normalised
15-21
SEO
Bridging regimen
22
SEO + H1
D1 rechallenge with
H
• R introduced when
patient tolerate H,
usually day 4 of
rechallenge.
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
New regimen
• SHERO
• SHER – 2SHER/6HR
• HER – 2HER/7HR
Reference
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Diagnosis, management and prevention of druginduced 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