Antituberculosis Adverse Drug Reactions

Current Items and Regimens
Epidemiology of Anti-TB ADR
ADR of Specific Items
Management of Anti-TB ADR
Desensitization Protocols

•Objective:
• To estimated the incidence and risk factors, of major
side effects from 1st-line anti-TB drugs among 430
patients treated at the Montreal Chest Institute
between 1990 and 1999
Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003

•Characteristics of patients


• A 5-month regimen in 78 patients was evaluated
for treatment of drug addicts and prisoners in Hong
Kong with pulmonary TB
• Regimen: Daily Rx of 3HRZES+3HRZE

• Ethambutol 25 mg/kg/day x2 months, then 15
mg/kg/day
• Streptomycin 750 mg/day x3 months.

Hong Kong Chest Service/British Research Council Study, Tubercle 1983; 64: 265-74.

• ADR required modification of the regimens
occured in 8 (10%) patients
• Cutaneous reactions 1 patient
• Vestibular 3 patients
• Gastrointestinal 1 patient
• Abnormal liver functions 3 patients
• Hepatitis 1 patient
• Arthralgia 3 patients
• Headache 1 patient

Hong Kong Chest Service/British Research Council Study, Tubercle 1983; 64: 265-74.

• 627 patients from Hong Kong were studied
• All patients also received streptomycin.
• During the first 2 months

• 40% of patients in both groups complained of adverse
effects
• Only 5% required termination of drugs
• 4% from the combined group
• 7% from the separate formulations group
Hong Kong Chest Service/British Research Council, Am Rev Respir Dis 1991; 143: 700-6.

• 5 different 6-month regimens were compared in
randornised trials in Hong Kong
• (1) E3H3R3Z3S3
• (2) S3H3R3Z3
• (3) S3E3R3H3
• (4) E3H3R3Z3
• (5) EHRZ
numbers = weekly frequency of drug administration

Hong Kong Chest Service/British Research Council, Tubercle 1982; 63: 89-98.

• ADR:
• (1) E3H3R3Z3S3:
• (2) S3H3R3Z3:
• (3) S3E3R3H3:
• (4) E3H3R3Z3:
• (5) EHRZ:

35% of 244 patients
34% of 243 patients
18% of 238 patients
26% of 241 patients
25% of 239 patients


• Majority of ADR: Mild GI disorders not requiring
alteration of treatment
• 2nd majority of ADR: Mild cutaneous reactions
• Only 50 patients (4% of 1205 patients) had a
significant ADR -> termination of >/= 1 drugs
• 14 in regimen 1
• 15 in regimen 2
• 6 in regimen 3
• 7 in regimen 4
• 8 in regimen 5


• Hepatic reactions (abnormal LFT, regardless of symptoms, leading to
modification of regimen): 21 (1.7%) patients

• 3, 2, 0, 3 and 13 patients, from regimens 1 to 5,
respectively
• 16 patients had no symptoms, 3 patients had jaundice
• 15 patients can resumed Rx once their LFT had
returned to normal
• In all regimens, there was a slight increase of ALT
during the early treatment with subsequent decline at 2
months and after.

• Hepatic reactions

• No statistically significant difference between the 4
intermittent regimens
• No evidence that PZA-containing regimens were
associated with greater hepatic toxicity
• In 195 patients on the daily regimen with normal LFT
before treatment, 31 % subsequently had one or more
abnormal results compared with 22% of the 187
patients on the corresponding intermittent regimen
(EHRZ)

• Hepatic reactions

• No hepatic reactions in the 238 patients with
H3R3E3S3 regimen (the only non-PZA regimen)
• ALT level measured serially
• Tended to be higher on the daily regimen
compared with the intermittent regimens (small
differences and not statistically significant)
• No difference between various intermittent
regimens


• 530 patients were treated
• Using 5 regimens of 6 months duration
• The initial phase was 2 months of SHRZ or EHR
•Followed by, 4H2R2 or 4HRE or 4H1R1E1 or 4H2R2E2
First number = treatment duration in months
Subscript numbers = weekly frequency of drug administration


• ADR occurred in 66 patients (12.4%)

• Liver toxicity 48 patients (9%) ,mostly mild and
transient
• Flu-like syndromes 2 patients both on RFP 600 mg/day
• The use of PZA in the initial phase of all the regimens
did not increase the ADR incidence
• 56% of patients receiving PZA had raised serum uric
acid levels but without arthralgia
• Only 10 patients (1.8%) did ADR lead to alteration or
withdrawal of treatment

• Common manifestation:

• Red itchy rash (papular or macular), usually involves
the trunk more than the extremities
• Periorbital swelling
• Conjunctivitis
• Rigor
• Malaise
• Vomiting
• Aching limbs

Anil M. et al., Drug Safety 12 (1): 1-25,1995

• Common manifestation:

• Headache
• Generalised lymphadenopathy
• Albuminuria
• Hepatosplenomegaly and occasionally jaundice

•

•Rare manifestation

• Exfoliative dermatitis or SJS can occur
• Especially following thioacetazone

• Timing

• Usually occur within the first 2 months
• Commonly in the first 4 weeks

• Anaphylactic reactions can occur if a drug is given
to a patient after a previous hypersensitivity
reaction


• Major target organ
• Liver
• Kidneys
• Eyes
• Vestibular system
• Nervous systems


• Hepatitis

• Usually develop within the first 3 months of treatment
• More likely to occur in combination regimens
• In 230 patients in Singapore who on 2SHRZ/HRZ or
2SHRZ/HR, hepatitis developed in 11 (3%) patients

Singapore Tuberculosis Service/British Medical Research Council., Am Rev Respir Dis 1979; 119: 579-85

• In 604 patients taking daily SHRZ, jaundice occurred in
44 patients (7%)
• Significantly more frequent than 2 patients (1% )in 304
patients taking SHZ (no RFP)

Tuberculosis Research Centre, Madras, and National Tuberculosis Institute, Bangalore., Am Rev Respir Dis 1986; 134: 27-33

• Hepatitis
• A meta-analysis of 34 studies of patients taking INH
and/or RFP. Hepatoxicity occurred:
• 0.6% in 38 257 patients receiving INH alone
• 1.6% of 2053 patients taking INH but not RFP
• 1.1 % of 1264 patients receiving RFP but not INH
• 2.55% of 6105 patients on both INH and RFP

Steele MA, et al., Chest 1991; 99: 465-71

EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249

• Hepatitis

• Deaths due to hepatitis occur infrequently
• More likely to occur with combination therapy
• But the increase in risk is so small and not outweight
benefits of combination regimen
• Hepatitis is more common in the elderly
• Pre-existing liver disease does not contraindicate the
use of anti-TB drugs but necessitates careful review and
biochemical monitoring


• Synthesised in 1912
• Most potent early bactericidal antituberculosis
agent
• Metabolised by two pathways
• Direct pathway

• Nonsignificant in fast acetylators
• Accounts for some of metabolism of slow acetylators

• Indirect pathway

• Favored by fast acetylators


Senousy, B. E. et al. Nat. Rev. Gastroenterol. Hepatol. 7, 543–556 (2010)

Direct pathway

Indirect pathway

Account for some slow
acetylator

Favored by fast
acetylator
Senousy, B. E. et al. Nat. Rev. Gastroenterol. Hepatol. 7, 543–556 (2010)

• 90% of Orientals are fast acetylators
• 45% of black and white populations are fast
acetylators
Major toxicities of INH
• Hepatic
• Dermatological
• Allergic
• Neurological

• Risk factors

• Advance age
• Liver transplant
• Previous elevation of transaminases
• Previous liver damage
• Excessive alcohol consumption

• Hepatitis B carriers: No elevated risk
• Unclear evidence of HIV-positive patient as higher
risk population

• Pregnancy and postpartum states seem to be a
period of particular risk
• Timing: Drug-induced hepatitis usually occurs
within the first 3 months of treatment but can
occur at any time during treatment


• Asymptomatic elevation in liver enzymes will be
seen in 10 – 22%
• These elevation usually resolve, despite drug
continuation
• About 1/5 may persistently have elevated
transaminases, which return to normal only after
stopping the medication


• Overall incidence has been estimated at 5.4%
• Mostly: urticaria, angioneurotic oedema and
morbiliform eruptions
• Up to 1.2% of patients develop erythema
• Other reactions:
• Acne
• Xerostomia
• Nonthrombocytopenia purpura
• Striae cutis atropica
• Pruritis


• Other reactions: (continued)

• Lupus erythematous-like syndrome
• Exfoliative dermatitis
• TEN/SJS
• Bullous disease
• Generalised pustular dermatosis
• Pellagra-like syndrome
• Anagen effluvium
• Associated lichenoid eruption
• Alopecia

• Chills or fever

• Sustained or recurrent
• Alone or as part of a hypersensitivity reaction with
rash
• Occurring 10 – 20 days after starting treatment
• Quickly resolve once the medication is withheld
• Reappear with rechallenge

• This reaction may even present as anaphylaxis


• Pyridoxine responsive anaemia
• Agranulocytosis
• Neutropenia
• Coombs-positive haemolytic anaemia
• Disseminated intravascular coagulation
• Pure red cell aplasia
• Hemophagocytic syndrome


• INH binds to pyridoxine and depletes pyridoxine
supplies
• Pyridoxine is required by GABA transaminase and
glutamic acid decarboxylase which synthesise GABA
• Pyridoxine deficiency -> Decreased levels of brain
GABA -> INH-induced seizures
• Pyridoxine is also involved in the metabolism of
neurotransmitters such as dopamine, serotonin and
tryptamine


• Peripheral neurotoxicity

• Dose-related
• Seen in <0.2%–1.2% of patients at conventional doses
• Usually appear after six months of treatment
• Can appear earlier at higher doses


• Risk factors:

• Increases with age
• Slow acetylator status
• Malnutrition
• Diabetes
• Renal failure
• Alcoholism
• Pregnancy and breastfeeding
• Evidence that HIV is a risk factor is inconsistent


• Paresthesias

• Burning sensation, pricking pain, numbness or tingling
• Start in the feet and can climb up to the hands and arms (in
a stocking-glove distribution)

• Accompanied by muscle aches, occasionally muscular
weakness
• Can progress to more severe symptoms such as
cerebellar ataxia



• Neurological examination findings:
• Loss of sensory modalities
• Light touch
• Pain
• Position
• Vibration

• Areflexia
• Muscle weakness
• Atrophy


• Usually reversible with withdrawal of the medication
• Except for cases that progressed to obvious muscle
weakness
• Prevention:

• Pyridoxine 25 – 50 mg once a day
• Recommended for high risk groups


• Other adverse neurological effects:

• Dysarthria
• Irritability
• Dysphoria
• Inability to concentrate
• Seizures (INH lowers the seizure threshold)
• Hallucinosis
• Psychosis


• Other adverse neurological effects: (continued)
• Memory loss
• Confusion
• Altered mental status
• Ototoxicity
• Optic neuropathy
• Other cranial neuropathies


• Symptoms:

• N/V, visual disturbances, dizziness and slurred speech
• Progression to stupor and seizures
• Occurrence: 0.5 – 2 hr after ingestion
• Progression to coma, hypotension and death in up to
21% of cases


• PE:
• Fever

• Tachycardia
• Hypotension
• Oliguria and anuria

• Lab:

• Hyperglycaemia
• High anion gap metabolic acidosis
• β-hydroxybutyric acidosis

• Initial management

• Decontamination
• Neurological, respiratory and cardiovascular support
• Fluids and bicarbonate should be given
• Correct metabolic acidosis
• Forced diuresis
• IV pyridoxine: Dosage of 1:1 with the estimated
amount of ingested INH
• Co-ingestion of pyridoxine may prevent serious ADR


• Initial management

• Anticonvulsants (benzodiazepines or barbiturates)
may be used to treat seizures
• INH-induced seizures may respond to pyridoxine alone
• Peritoneal or haemodialysis should be considered
• Prevention measures should be applied


• Drug interactions

• INH inhibits mainly CYP 2C19 and CYP 3A

• Lupus-like syndrome: rare (< 1%)
• Lupus pleuritis
• Lupus nephritis

• Histamine poisoning syndrome: Rare
• Flushing of head and neck
• Generalised throbbing headache
• Rapid heart beat
• Trembling


• Occupational asthma
• Acute worsening of severe asthma
• Ocular lens dislocation secondary to
hyperhomocysteinemia
• Pancreatitis
• Hypoglycemia in a newborn


• Semisynthetic antibiotic which inhibits DNAdependant RNA polymerase
• A hepatic enzyme inducer -> reduce the serum
concentration and efficacy of multiple other drugs
• Causes orange discoloration of tears, sweat and
urine


• Semisynthetic antibiotic which inhibits DNAdependant RNA polymerase
• A hepatic enzyme inducer -> reduce the serum
concentration and efficacy of multiple other drugs
• Causes orange discoloration of tears, sweat and
urine.


• ADR from RIF alone for LTBI in various populations
• Rates of 22 – 26%
• Discontinuation of therapy by 1 – 14%

• In multi-drug regimens

• ADR leading to drug discontinuation is 1.7 – 3.3%

• Most common ADR to daily treatment:
• Cutaneous
• Hepatic
• Hypersensitivity reactions


• Transient increased serum bilirubin on the 1st day
of treatment
• But normalise within 2 weeks

• May induce hepatocellular dysfunction early in
the treatment
• Resolves without drug discontinuation
• Risk factors:

• Increased risk in alcohol abuse and prior liver disease
• No data of using RFP alone in HIV or HCV patients
• Equivocal evidence in HBV patient

• Most common RFP ADR
• Common presentation:

• Flushing of the face and neck
• Sometimes with pruritis or a rash
• Occur in 0.3 – 10% of patients and is often transient
• Usually occur within a few hours after ingestion, early
in the course of treatment

• Dose-dependant
• Occur more frequently in intermittent regimens


• Other manifestation:

• Urticaria
• Maculopapular lesions
• Pemphigus and pemphigus foliaceus
• Porphyria cutanea tarda
• Chronic papular acneiform lesions
• Generalised burning sensation
• Alopecia areata
• Ocular symptoms: Exudative conjunctivitis
• Stevens-Johnson syndrome may also occur

• Reports of Rash, fever, lymphadenopathy,
hepatosplenomegaly and elevated transaminases
• Desensitisation may be successful
• Just case reports of:
• Anaphylaxis
• Lupus erythematosus
• Red-man syndrome


• Thrombocytopenia: Most common

• 0.08% of patients on a daily regimen
• 1 – 6% of patients on a twice-weekly regimen
• Happens within 3 h after a dose
• Platelet counts return to normal within 36 h
• Mechanism?

• Intravascular immune phenomenon
• Associated with antirifampin Ab
• Platelet-membrane GPIb/IX complex: Target for the drugdependent Ab

• Reversible if the RFP is withdrawn


• Other presentations:

• Haemolytic anaemia
• Neutropenia (rare)
• Hypoprothrombinemia

• RFP interferes with vitamin K absorption and metabolism


• Common presentations:

• Loss of appetite
• Nausea, vomiting and diarrhoea
• Mild abdominal pain
• Lead to regimen modification in up to 9% of patients
• Can appear at any time in the course of treatment
• More common with the intermittent regimens

• Rare presentations:

• Eosinophilic colitis
• Pseudomembranous colitis
• Pill-induced oesophagitis

• Presentations:

• Fever
• Chills
• Headache
• Dizziness
• Bone pain
• Shortness of breath: Rare
• Occasionally, progress to hypotension and shock
• Begin 1 – 2 h after each dose of RFP
• Can last up to 8 h

• Presentations:

• Typically appears after the 3rd month of therapy
• Dose-related
• Higher incidence in longer intervals between doses
• Evidence points to an Ab-mediated cause
• Rx:
• Stop RFP: rarely needed
• Temporary interruption of therapy
• Dose reduction
• Change to daily regimen


• Acute tubular necrosis

• S/S: Fever, nausea, vomiting, diarrhoea, abdominal
pain, haemolytic anaemia and thrombocytopenia
• Often associated with:
• Intermittent regimen
• Daily regimen that is taken irregularly
• Restarted treatment after an interval of cessation

• Often need dialysis temporarily
• Majority were recover


•Other presentations:

• RPGN with anti-RIF Ab
• Acute interstitial nephritis
• Light chain proteinuria
• Minimal change nephrotic syndrome

• RFP-associated acute renal failure occurred in
0.05% of patients treated for TB


• CYP450 enzymes inducer

• -> increases metabolism of many other compounds
• -> reduces their serum concentration and efficacy

• In HIV patients:

• RFP should not be used with

• PIs (except: LPV/r, SQV/r)
• NNRTIs (except: ddI, TDF, ABC, EFV)

• If these agents must be used, change rifampin to
rifabutin

• May enhance hepatotoxicity of acetaminophen

• Myopathy
• Organic brain syndrome
• Oligomenorrhea and amenorrhea
• Interstitial pneumonitis and ARDS
• Exudative conjunctivitis
• Shock-like syndrome
• Fatigue
• Myalgia
• Headache

• Hyperglycaemia
• Hypothyroidism


• First synthesised in 1952
• Major PZA metabolite, pyrazinoic acid, inhibits
renal excretion of uric acid
• Major side effects:
• Hepatotoxicity
• Rash
• Arthralgias


• Dose-related
• Liver failure and death can occur
• Incidence of PZA-induced hepatitis leading to
drug discontinuation: 1.3 – 2.5%
• Some of cases of hepatitis presented with a
hypersensitivity reaction manifested as:
• Fever and eosinophilia
• Granulomatous hepatitis

•Pre-existing liver disease increases the risk

• Sensation of burning
• Red-brown discoloration on sun-exposed areas
• Darkening of the skin
• Pellagra
• Hypersensitivity dermatitis
• Photoallergy
• Flushing with nausea, dyspnea and abdominal
discomfort followed by an itchy rash
• Incidence of rash: 0.1 – 5%

• Arthralgias: Common

• Affect both small and large joints
• Occur during the first 1-2 months of treatment
• Concomitant RFP administration does not influence
this effect
• Arthralgia symptoms is unrelated to uric acid level
• 8% of patients can develop joint symptoms
• 2% of patients discontinued PZA
• Less frequent with intermittent regimens
• Rx: NSAIDS (while PZA is continued)

• Effects on serum uric acid level

• Average of 2.5-fold elevation
• Occur in up to 86% of patients
• May precipitate gout episodes, particularly with preexisting gout
• In children:
• > 90% develop elevation in uric acid
• But only 10% exceeded normal range


• Nausea in 1 – 5%
• Fever in 0.6%
• Sideroblastic anaemia
• Lupus erythematosus
• Convulsions
• Photodermatitis
• Myoglobinuric renal failure
• Aseptic meningitis
• Gastrointestinal disturbances
• Leukopenia
• Acute porphyria

• Discovered in 1961
• Main adverse effect: Ocular toxicity
• Probably a result of Cu or Zn binding


• Dose-dependent
• Incidence rate of 0.3%
• Usually present after the 2nd month of treatment
• May occur up to 1 year after Eth initiation
• Non-inflammatory process that affects central
axial fibers of the optic nerve:
• Most common form
• Reduced visual acuity
• Central scotoma
• Loss of green vision (reported as white or grey)
• Occasionally loss of red vision (reported as pink)


• Other form:

• Periaxial toxicity
• Peripheral constriction of visual field, especially
bitemporal defects
• Little or no decrease in visual acuity
• Normal red-green discrimination

• Both are forms of retrobulbar neuritis

• -> optic disks and fundi are normal in all cases


• Usually reversible
• Occasionally, visual impairment, even blindness
can be permanent
• Subclinical disturbances in color vision found
• Risk factors:

• Higher with daily treatment than intermittent regimen
• Sex and clinical factors such as type of disease or renal
function were not predictive


• Special concerns: In children, especially young
children
• Difficulty in assessment of visual acuity
• Uncertainty in reporting of symptoms
• A reviewed studies found a very low incidence of
ocular toxicity even in children < 5 years of age

Trebucq A., Int. J. Tuberc. Lung Dis. (1997) 1:12-15.

• Relatively uncommon
• Rash occurred in 0.15% in one large study
• Reactions include:
• Hair loss
• Urticaria
• Erythema multiforme
• Angioedema
• Hyperhydrosis
• Skin striae


• Reactions include:

• Bullous eruption
• PruritisLichenoid eruption
• Erythema multiforme with eosinophilia and elevated
liver enzymes


• Macular toxicity
• Cholestasis with jaundice
• Aplastic anaemia
• Neutropenia
• Thrombocytopenia
• Pulmonary infiltrates with eosinophilia
• Exacerbation of lupus
• Hyperuricemia

• Headache dependant on intracranial pressure
• Relieved by CSF removal

• Tubulointerstitial nephritis with anuric renal
failure


• Isolated from Streptomyces griseus in 1944
• Most common adverse effects are
• Ototoxicity,
• Rash
• Nephrotoxicity


• Dose-dependant
• Vestibulocochlear toxicity, with vestibular damage
• Vertigo

• Cochlear toxicity

• Present as hearing loss
• Might not be clinically significant


• Morbiliform rash
• Maculopapular rash
• Erythematous rash
• Urticarial lesions
• Pruritis
• Scaling
• Lichenoid eosinophilia
• Mouth ulcers
• Purpura
• Stevens-Johnson
• DRESS


• Occur in 1 –5% of cases
• Occurred, both in patients and in personnel
administering drug
• A case of anaphylaxis by contact with
streptomycin through compromised skin barrier
was reported

• Nephrotoxicity:

• Renal damage in 0.1 – 1%
• Transient Cr elevation

• Hematological reactions:
• Neutropenia
• Hemolytic anemia
• Eosinophilia
• Thrombocytopenia
• Granulocytopenia
• Pancytopenia
• Aplastic anaemia


• Neurotoxicity:

• Transient giddiness
• Perioral numbness
• Neuromuscular blockade (rare)

• Lupoid reactions


• Streptomycin

• Already presented!

• Kanamycin

• Synthesized in 1957

• Amikacin

• Semi-synthetic compound derived from
kanamycin
• Has been used since 1972

• Common ADRs: As of Streptomycin
Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656

• Used as salvage drugs in the treatment of
tuberculosis since 1985

•Essential structure

Ciprofloxacin

Levofloxacin

• GI effects:

• Most common side effects of fluoroquinolones
• N/V, aerophagy, anorexia, abdominal discomfort, and
diarrhea: 3-17% of the patients
• Increased transaminase levels: 1-3% of the patients
• Pseudomembranous colitis: rare

• CNS effects:

• Dizziness, headache, insomnia, tremors, mood
disorder: 0.9-11% of patients
• Hallucinations, delusions, and convulsions: rare

• Cutaneous effects:

• Erythema, pruritus, and rash: 0.4-2.2%
• Phototoxicity in UV exposure
• Urticaria, angioedema, anaphylactic reactions, and
vasculitis are uncommon

• Musculoskeletal effects:

• Arthralgia: 2% (always reversible)
• Achilles tendinopathy and Achilles tendon rupture:
• Rare and often associated with previous steroid use,
rheumatoid arthritis, kidney failure, and hemodialysis


• Cardiovascular effects:
• QT prolongation: Rare

• Leading to VT, including polymorphic ventricular tachycardia
(torsades de pointes)
• Dose-dependent
• Risky group:
• Kidney failure
• Liver failure
• Cardiomyopathy
• HypoMg, hypoK
• Using class IA antiarrhythmic drugs or class III antiarrhythmic drugs
• Using terfenadine, erythromycin, cisapride, or tricyclic
antidepressants


• Nephrologic effects:

• Interstitial nephritis: rare

• Endocrine effects:

• Changes in glycemia levels in patient using oral
hypoglycemic agents or insulin

• Hematologic effects:

• Leukopenia and eosinophilia: <1% of the cases


• Cutaneous reactions and allergies:

• Erythema, pruritus, and rash occur in 0.4-2.2%
• Phototoxicity can occur by UV exposure
• Urticaria, angioedema, anaphylactic reactions, and
vasculitis are uncommon

• Musculoskeletal effects:

• Arthralgia: About 2% (always reversible)
• Achilles tendinopathy and Achilles tendon rupture

• Rare
• Often associated with predisposing factors: previous steroid
use, rheumatoid arthritis, kidney failure and hemodialysis

• Synthesized in 1952,
• Cycloserine

• Structural analogue of D-alanine amino acid

• Terizidone

• Combination of 2 cycloserine molecules


• CNS effects:

• Headache, vertigo, dysarthria somnolence,
convulsion, mental confusion, and memory deficit
• Changes in pressure and quantity of proteins in CSF

• PNS effects:

• Peripheral neuropathy

• Psychiatric adverse effects:

• Psychotic states with catatonic, paranoid, and
depressive reactions, with a risk of suicide

• Pyridoxine can aid in neuroprotective effects

• Used as a 2nd line drug in the treatment of TB
since 1956
• Its structure is analogous to INH


• GI effects:

• Metallic taste in the mouth, excessive salivation,
severe N/V, loss of appetite, and abdominal pain
• Hepatotoxicity : About 4.3%,
• Especially in patient with liver disease or alcoholism

• Neurotoxicity:

• Peripheral neuritis, optic neuritis, diplopia, irritability,
anxiety, depression, hallucinations, convulsions, and
psychosis: 1-2%
• Pyridoxine can reduce neurotoxicity

• Cardiovascular effects:
• Postural hypotension


• Gynecomastia, alopecia, hypothyroidism, impotence,
or menorrhagia
• Disturb patient’s glycemic control

• Cutaneous reactions:

• Acne, photosensitivity, and exanthema

• Hematologic reactions:

• Thrombocytopenia and purpura

• A polypeptide antibiotic
• Obtained from Streptomyces capreolus
• Used as an antituberculosis drug since 1959


• Nephrotoxicity: 20-25% of the patients

• Renal tubular damage, proteinuria, electrolyte
disturbances (decreased serum Ca, Mg and K)

• Cutaneous effects:
• Urticaria, maculopapular rash, pain, edema, and
abscess at the site of application

• Ototoxicity

• Especially vestibular


• Used as an anti-TB drug since 1946
• Used to be 1st line drug in a combination regimen
with INH and streptomycin


• GI effects:

• Anorexia, diarrhea, N/V
• Hepatitis: 0.3-0.5%
• Malabsorption syndrome

• Hypothyroidism

• Especially when administered with ethionamide

• Allergic reactions

• Fever, rash, and pruritus

• Hematologic effects:

• Hemolytic anemia, agranulocytosis, leukopenia,
thrombocytopenia,

• Cardiovascular effects: Pericarditis
• Neurological effects: Encephalopathy
• Respiratory effects: Eosinophilic pneumonia
• Ocular effects: Optic neuritis
• Caution!:
• Patients with G6PD deficiency
• Patients who are allergic to aspirin


•Prevention
•INH-induced peripheral neuropathy
•Risky population:

•Pregnant women
•HIV infection
•Alcohol dependency
•Malnutrition
•Diabetes
•Chronic liver disease
•Renal failure

•Preventive treatment: Pyridoxine 10-25 mg/day
along with anti-TB drugs

• Management of cutaneous reactions
• Itching without a rash

• Symptomatic treatment with antihistamines and
skin moisturizing
• Continue TB treatment
• Observing the patient closely

• If a skin rash develops

• All anti-TB drugs must be stopped

• Management of cutaneous reactions
• Once the reaction has resolved

• Rechallenge Anti-TB drugs 1 by 1
• Start with the least likely causative drug at small
dose
• Gradually increase the dosage over 3 days
• Repeat the procedure by adding in 1 drug at a time
for the causative drug identification

• Management of hepatitis

• Ruling out other possible causes is necessary
• If TB drugs are the cause of hepatitis
• All drugs should be stopped
• If it is considered unsafe to stop TB treatment, a
non-hepatotoxic regimen should be used
• Streptomycin + ethambutol + fluoroquinolone

• Wait for LFT to revert to normal and clinical
symptoms (nausea, abdominal pain) to resolve
before reintroducing the anti-TB drugs


• If TB drugs are the cause of hepatitis

• If LFT is not available, wait an extra 2 weeks after
resolution of jaundice and upper abdominal
tenderness before restarting TB treatment
• If the signs and symptoms do not resolve and the
liver disease is severe, use the mentioned nonhepatotoxic regimen for 18–24 months


• Once hepatitis has resolved

• Drugs are reintroduced one at a time
• If symptoms recur or LFT become abnormal, the
last drug added should be stopped
• Maybe: RFP -> 3–7 days -> INH

• In patients with jaundice but tolerate the
reintroduction of RFP and INH, it is advisable to
avoid PZA


• Alternative regimens: Depends on drug
implication

• If RFP is implicated: 2HES/10HE
• If INH is implicated: Consider 6–9 months of RZE
• If PZA is discontinued before complete intensive
phase, HR therapy may be extended to 9 months
• If neither INH nor RFP can be used, the mentioned
non-hepatotoxic regimen should be used for 18–24
months

สานักโรคเอดส์ วัณโรค และโรคติดต่อทางเพศสัมพันธ์ กรมควบคุมโรค กระทรวงสาธารณสุข, แนวทางเวชปฏิบติการรักษาวัณโรคในผู้ใหญ่ พ.ศ.2554
ั

• 1st Rapid oral INH desensitization protocol

CL Holland, et al., Chest 1990; 98:1518-19)

• 1st Rapid oral RFP desensitization protocol

CL Holland, et al., Chest 1990; 98:1518-19)

•Single day protocol

J Matz, et al. Am J Respir Crit Care Med Vol 149. pp 815-817, 1994

•Single day protocol: Patient characteristics


•Single day protocol: Outcome


• A successful oral 7days desensitization
protocol in
immediate-type
reaction to RFP

S Buergin, et al., Int Arch Allergy Immunol 2006;140:20–26

S Buergin, et al., Int Arch Allergy Immunol 2006;140:20–26

• A rapid oral desnsitization protocol

S Bavbek, et al., Int Arch Allergy Immunol 2012;157:209–212

Latest accessible
desensitization
protocol specific to
streptomycin

…..1963!!!
S Lal, et, al., Tubercle, Lond., (1963), 44, 360-362

• A protocol for 8 patients with SJS while on 4-drug anti-TB therapy

MM Kura, et al., Int J Derm, 2001, 40, 482-484

• TB: Still a major health problem
• Currently available drugs are effective treatment but may
cause serious ADRs:
• Hepatitis
• Cutaneous reactions
• GI intolerance
• Hematological reactions
• Nephrological effects
• Neurological effects

• ADRs must be recognised early, treated promptly and TB
treatment must be adjusted properly (but might need
application based on other drug’s available data)

Antituberculosis Adverse Drug Reactions

Antituberculosis Adverse Drug Reactions

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