Download 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


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
Deafness
Dizziness
Jaundice*
Visual impairment
Shock*, 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. Senior
Drug-Related Hepatotoxicity
N. 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
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



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