Antituberculosis Adverse Drug Reactions

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Adverse drug reactions to Antituberculosis Drugs
Presented by Wat Mitthamsiri, MD
November 22, 2013

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Antituberculosis Adverse Drug Reactions

  1. 1. Current Items and Regimens Epidemiology of Anti-TB ADR ADR of Specific Items Management of Anti-TB ADR Desensitization Protocols
  2. 2. •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
  3. 3. •Characteristics of patients Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003
  4. 4. •Characteristics of patients Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003
  5. 5. •Characteristics of patients Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003
  6. 6. Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003
  7. 7. Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003
  8. 8. • 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.
  9. 9. • 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.
  10. 10. • 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.
  11. 11. • 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.
  12. 12. • 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 Hong Kong Chest Service/British Research Council, Tubercle 1982; 63: 89-98.
  13. 13. • 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 Hong Kong Chest Service/British Research Council, Tubercle 1982; 63: 89-98.
  14. 14. • 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. Hong Kong Chest Service/British Research Council, Tubercle 1982; 63: 89-98.
  15. 15. • 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) Hong Kong Chest Service/British Research Council, Tubercle 1982; 63: 89-98.
  16. 16. • 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 Hong Kong Chest Service/British Research Council, Tubercle 1982; 63: 89-98.
  17. 17. • 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 Hong Kong Chest Service/British Research Council, Am Rev Respir Dis 1991; 143: 700-6.
  18. 18. • 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 Hong Kong Chest Service/British Research Council, Am Rev Respir Dis 1991; 143: 700-6.
  19. 19. • 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
  20. 20. • Common manifestation: • Headache • Generalised lymphadenopathy • Albuminuria • Hepatosplenomegaly and occasionally jaundice • •Rare manifestation • Exfoliative dermatitis or SJS can occur • Especially following thioacetazone Anil M. et al., Drug Safety 12 (1): 1-25,1995
  21. 21. • 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 Anil M. et al., Drug Safety 12 (1): 1-25,1995
  22. 22. • Major target organ • Liver • Kidneys • Eyes • Vestibular system • Nervous systems Anil M. et al., Drug Safety 12 (1): 1-25,1995
  23. 23. • 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
  24. 24. • 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
  25. 25. EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  26. 26. • 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 Anil M. et al., Drug Safety 12 (1): 1-25,1995
  27. 27. Yee, Valiquette, Pelletier, et al., Am J Respir Crit Care Med Vol 167. pp 1472–1477, 2003
  28. 28. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  29. 29. Senousy, B. E. et al. Nat. Rev. Gastroenterol. Hepatol. 7, 543–556 (2010)
  30. 30. 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)
  31. 31. • 90% of Orientals are fast acetylators • 45% of black and white populations are fast acetylators Major toxicities of INH • Hepatic • Dermatological • Allergic • Neurological EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  32. 32. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  33. 33. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  34. 34. EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  35. 35. EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  36. 36. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  37. 37. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  38. 38. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  39. 39. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  40. 40. • Pyridoxine responsive anaemia • Agranulocytosis • Neutropenia • Coombs-positive haemolytic anaemia • Disseminated intravascular coagulation • Pure red cell aplasia • Hemophagocytic syndrome EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  41. 41. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  42. 42. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  43. 43. • Peripheral neurotoxicity • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  44. 44. • Peripheral neurotoxicity • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  45. 45. • Peripheral neurotoxicity • Neurological examination findings: • Loss of sensory modalities • Light touch • Pain • Position • Vibration • Areflexia • Muscle weakness • Atrophy EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  46. 46. • Peripheral neurotoxicity • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  47. 47. • Other adverse neurological effects: • Dysarthria • Irritability • Dysphoria • Inability to concentrate • Seizures (INH lowers the seizure threshold) • Hallucinosis • Psychosis EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  48. 48. • Other adverse neurological effects: (continued) • Memory loss • Confusion • Altered mental status • Ototoxicity • Optic neuropathy • Other cranial neuropathies EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  49. 49. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  50. 50. • PE: • Fever • Tachycardia • Hypotension • Oliguria and anuria • Lab: • Hyperglycaemia • High anion gap metabolic acidosis • β-hydroxybutyric acidosis EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  51. 51. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  52. 52. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  53. 53. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  54. 54. • Occupational asthma • Acute worsening of severe asthma • Ocular lens dislocation secondary to hyperhomocysteinemia • Pancreatitis • Hypoglycemia in a newborn EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  55. 55. • Synthesised in 1966 • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  56. 56. • Synthesised in 1966 • 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. EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  57. 57. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  58. 58. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  59. 59. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  60. 60. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  61. 61. • Reports of Rash, fever, lymphadenopathy, hepatosplenomegaly and elevated transaminases • Desensitisation may be successful • Just case reports of: • Anaphylaxis • Lupus erythematosus • Red-man syndrome EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  62. 62. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  63. 63. • Other presentations: • Haemolytic anaemia • Neutropenia (rare) • Hypoprothrombinemia • RFP interferes with vitamin K absorption and metabolism EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  64. 64. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  65. 65. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  66. 66. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  67. 67. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  68. 68. •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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  69. 69. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  70. 70. • Myopathy • Organic brain syndrome • Oligomenorrhea and amenorrhea • Interstitial pneumonitis and ARDS • Exudative conjunctivitis • Shock-like syndrome • Fatigue • Myalgia • Headache EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  71. 71. • Hyperglycaemia • Hypothyroidism EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  72. 72. • First synthesised in 1952 • Major PZA metabolite, pyrazinoic acid, inhibits renal excretion of uric acid • Major side effects: • Hepatotoxicity • Rash • Arthralgias EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  73. 73. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  74. 74. • 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% EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  75. 75. • 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) EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  76. 76. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  77. 77. • Nausea in 1 – 5% • Fever in 0.6% • Sideroblastic anaemia • Lupus erythematosus • Convulsions • Photodermatitis • Myoglobinuric renal failure • Aseptic meningitis • Gastrointestinal disturbances • Leukopenia • Acute porphyria EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  78. 78. • Discovered in 1961 • Main adverse effect: Ocular toxicity • Probably a result of Cu or Zn binding EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  79. 79. • 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) EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  80. 80. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  81. 81. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  82. 82. • 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. EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  83. 83. • Relatively uncommon • Rash occurred in 0.15% in one large study • Reactions include: • Hair loss • Urticaria • Erythema multiforme • Angioedema • Hyperhydrosis • Skin striae EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  84. 84. • Reactions include: • Bullous eruption • Exfoliative dermatitis • PruritisLichenoid eruption • Erythema multiforme with eosinophilia and elevated liver enzymes EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  85. 85. • Macular toxicity • Cholestasis with jaundice • Aplastic anaemia • Neutropenia • Thrombocytopenia • Pulmonary infiltrates with eosinophilia • Exacerbation of lupus • Hyperuricemia EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  86. 86. • Headache dependant on intracranial pressure • Relieved by CSF removal • Tubulointerstitial nephritis with anuric renal failure EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  87. 87. • Isolated from Streptomyces griseus in 1944 • Most common adverse effects are • Ototoxicity, • Rash • Nephrotoxicity EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  88. 88. • Dose-dependant • Vestibulocochlear toxicity, with vestibular damage • Vertigo • Cochlear toxicity • Present as hearing loss • Might not be clinically significant EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  89. 89. • Morbiliform rash • Maculopapular rash • Erythematous rash • Urticarial lesions • Pruritis • Scaling • Lichenoid eosinophilia • Mouth ulcers • Purpura • Exfoliative dermatitis • Stevens-Johnson • DRESS EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  90. 90. • 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 EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  91. 91. • Nephrotoxicity: • Renal damage in 0.1 – 1% • Transient Cr elevation • Hematological reactions: • Neutropenia • Hemolytic anemia • Eosinophilia • Thrombocytopenia • Granulocytopenia • Pancytopenia • Aplastic anaemia EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  92. 92. • Neurotoxicity: • Transient giddiness • Perioral numbness • Neuromuscular blockade (rare) • Lupoid reactions EJ Forget, et al., Expert Opin. Drug Saf. (2006) 5(2):231-249
  93. 93. • 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
  94. 94. • Used as salvage drugs in the treatment of tuberculosis since 1985 •Essential structure Ciprofloxacin Levofloxacin Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  95. 95. • 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 Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  96. 96. • 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 Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  97. 97. • 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 Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  98. 98. • 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 Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  99. 99. • 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 Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  100. 100. • Synthesized in 1952, • Cycloserine • Structural analogue of D-alanine amino acid • Terizidone • Combination of 2 cycloserine molecules Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  101. 101. • 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 Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  102. 102. • Used as a 2nd line drug in the treatment of TB since 1956 • Its structure is analogous to INH Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  103. 103. • 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 Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  104. 104. • Cardiovascular effects: • Postural hypotension • Endocrine effects: • Gynecomastia, alopecia, hypothyroidism, impotence, or menorrhagia • Disturb patient’s glycemic control • Cutaneous reactions: • Acne, photosensitivity, and exanthema • Hematologic reactions: • Thrombocytopenia and purpura Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  105. 105. • A polypeptide antibiotic • Obtained from Streptomyces capreolus • Used as an antituberculosis drug since 1959 Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  106. 106. • 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 Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  107. 107. • Used as an anti-TB drug since 1946 • Used to be 1st line drug in a combination regimen with INH and streptomycin Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  108. 108. • GI effects: • Anorexia, diarrhea, N/V • Hepatitis: 0.3-0.5% • Malabsorption syndrome • Endocrine effects: • Hypothyroidism • Especially when administered with ethionamide • Allergic reactions • Fever, rash, and pruritus Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  109. 109. • 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 Arbex MA, et al., J Bras Pneumol. 2010;36(5):641-656
  110. 110. •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
  111. 111. • 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
  112. 112. • 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
  113. 113. Anil M. et al., Drug Safety 12 (1): 1-25,1995
  114. 114. • 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
  115. 115. • Management of hepatitis • 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
  116. 116. • Management of hepatitis • 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
  117. 117. • Management of hepatitis • 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
  118. 118. สานักโรคเอดส์ วัณโรค และโรคติดต่อทางเพศสัมพันธ์ กรมควบคุมโรค กระทรวงสาธารณสุข, แนวทางเวชปฏิบติการรักษาวัณโรคในผู้ใหญ่ พ.ศ.2554 ั
  119. 119. สานักโรคเอดส์ วัณโรค และโรคติดต่อทางเพศสัมพันธ์ กรมควบคุมโรค กระทรวงสาธารณสุข, แนวทางเวชปฏิบติการรักษาวัณโรคในผู้ใหญ่ พ.ศ.2554 ั
  120. 120. สานักโรคเอดส์ วัณโรค และโรคติดต่อทางเพศสัมพันธ์ กรมควบคุมโรค กระทรวงสาธารณสุข, แนวทางเวชปฏิบติการรักษาวัณโรคในผู้ใหญ่ พ.ศ.2554 ั
  121. 121. สานักโรคเอดส์ วัณโรค และโรคติดต่อทางเพศสัมพันธ์ กรมควบคุมโรค กระทรวงสาธารณสุข, แนวทางเวชปฏิบติการรักษาวัณโรคในผู้ใหญ่ พ.ศ.2554 ั
  122. 122. สานักโรคเอดส์ วัณโรค และโรคติดต่อทางเพศสัมพันธ์ กรมควบคุมโรค กระทรวงสาธารณสุข, แนวทางเวชปฏิบติการรักษาวัณโรคในผู้ใหญ่ พ.ศ.2554 ั
  123. 123. สานักโรคเอดส์ วัณโรค และโรคติดต่อทางเพศสัมพันธ์ กรมควบคุมโรค กระทรวงสาธารณสุข, แนวทางเวชปฏิบติการรักษาวัณโรคในผู้ใหญ่ พ.ศ.2554 ั
  124. 124. สานักโรคเอดส์ วัณโรค และโรคติดต่อทางเพศสัมพันธ์ กรมควบคุมโรค กระทรวงสาธารณสุข, แนวทางเวชปฏิบติการรักษาวัณโรคในผู้ใหญ่ พ.ศ.2554 ั
  125. 125. • 1st Rapid oral INH desensitization protocol CL Holland, et al., Chest 1990; 98:1518-19)
  126. 126. • 1st Rapid oral RFP desensitization protocol CL Holland, et al., Chest 1990; 98:1518-19)
  127. 127. •Single day protocol J Matz, et al. Am J Respir Crit Care Med Vol 149. pp 815-817, 1994
  128. 128. •Single day protocol: Patient characteristics J Matz, et al. Am J Respir Crit Care Med Vol 149. pp 815-817, 1994
  129. 129. •Single day protocol: Outcome J Matz, et al. Am J Respir Crit Care Med Vol 149. pp 815-817, 1994
  130. 130. • A successful oral 7days desensitization protocol in immediate-type reaction to RFP S Buergin, et al., Int Arch Allergy Immunol 2006;140:20–26
  131. 131. S Buergin, et al., Int Arch Allergy Immunol 2006;140:20–26
  132. 132. • A rapid oral desnsitization protocol S Bavbek, et al., Int Arch Allergy Immunol 2012;157:209–212
  133. 133. Latest accessible desensitization protocol specific to streptomycin …..1963!!! S Lal, et, al., Tubercle, Lond., (1963), 44, 360-362
  134. 134. • 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
  135. 135. • 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)

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