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Outline

General information of first-line anti-TB drugs

Antituberculosis drug-induced adverse reactions(hepatotoxicity, cutaneous) Clinical significant drug interactions

Antituberculosis drugs

First-line drugs Second line drugsIsoniazid CycloserineRifampicin Ethionamide

Pyrazinamide Para-aminosalicylic acidEthambutol Ca reom cinStreptomycin Levofloxacin*Rifapentin Moxifloxacin*Rifabutin Gatifloxacin*

Amikin/kanamycin*

* Not approved by FDA-US

Isoniazid (IsoNicotinic acid Hydrazide)(since year 2495)

()

3-5 mg/kg (max= 300 mg/day)

cerebrospinal, ascitic, pleural fluids, placentabarrier, milk

Metabolized: acetylation (determine by acetylator

status), dehydrazination Excreted in the urine


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Isoniazid (IsoNicotinic acid Hydrazide)(since year 2495)

Pyridoxine deficiency due to its

competition with pyridoxal phosphatefor enzyme apotryptophanase

Pregnancy category C Small concentration of INH in breast milk do not

produce toxicity in nursing newborn

Rifampicin

RNA -subunit RNA polymerase

Metabolized by deacetylation Elimination mainly through the bile, to a much lesser

extent, the urine (dosage adjustment is not necessary)

Pregnancy category C Excreted in breast milk

Rifampicin: warning/precaution

Transient hyperbilirubinemia rifampicin bilirubin bilirubin

ADRs associated with intermittent regimen or higherdose and are caused by rifampicin antibodies- Flu-like syndrome (0.4-0.7%)- Thrombocytopenia , acute hemolytic anemia (0.1%)- Acute renal failure


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Pyrazinamide

The pyrazine analog of nicotinamide

PZA is a prodrug that convert to active form(pyrazinoic acid) by mycobacterial enzymepyrazinamidase

MOA: target an enzyme involved in fatty acidsynthesis

Well absorbed from GI tract

Widely distributed in body tissues and fluids 70% of an oral dose is excreted in urine

Pyrazinamide

Pregnancy category C

Lactation: found in small amounts in breast milk. Hyperuricemia: PZA inhibits renal excretion of

urates, frequently resulting in hyperuricemiausua y asymp oma c

Ethambutol

MOA: inhibition ofarabinosyl transferase

(enzyme that polymerizes arabinose intoarabinan and then arabinogalactan, amycobacterial cell wall constituent )

Approximately 20%of ethambutol is metabolizedby liver

Ethambutol

Excretion:- unchanged drug is excreted

approximately 50% in the urine,20-22% in the feces

Marked accumulation may occur with renalinsufficiency

Patients with decreased renalfunction require reduced dosage


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Ethambutol

Pregnancy category BVisual effects(especially in higher dose; 18% with dose > 30mg/kg/day ) generally reversible when the drug isdiscontinued

Streptomycin

Streptomycin is a protein

synthesis inhibitor Excrete unchanged by the kidney Main ADRs

- hypersensitivity reaction- ototoxicity (especially baby, patients age morethan 40 years)

- nephrotoxicty

Adverse Drug Reactions of anti-TB drugs

Major ADRs

Hepatotoxicity Cutaneous ADRs (skin

Minor ADRs

Anorexia Nausea/vomiting

ras w or w ouitching)

OtotoxicityVisual impairment

A omina pain Joint pains Peripheral neuropathy

(burning, numbness or

tingling sensation inhands or feet) Drowsiness

Adverse Drug Reaction of anti-TB drugs (n=500)

ADR ()

Skin 77 (15.4) 23.3

Hepatitis 46 (9.2) 36.9N/V 42 (8.4) 4.8Dizziness 25 (5.0) 4.0

Thongraung W, et al. Thai Pharm Health Sciences Journal 2009;4(1):46-51

. .Joint pain 16 (3.2) 12.5

Peripheral neuropathy 13 (2.6) 0.0

Visual impairment 10 (2.0) 60.0

Fever 9 (1.8) 0.0Ototoxicity 8 (1.6) 25.0


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ADRs of anti-TB drugs: symptom-based approach

Major ADRs Drug (s) probablyresponsible

Management

Skin rash H, R, Z, S Stop anti-TB drugs

Jaundice, hepatitis H, R, Z Stop anti-TB drugsDeafness S Stop streptomycin

,nystagmus)

Confusion (suspectdrug-induced acute

liver failure jaundice)

Most anti-TBdrugs

Stop anti-TB drugs

Visual impairment Ethambutol Stop Ethambutol

World Health Organization (2009) Treatment of tuberculosis:Guidelines-4th ed. WHO/ HTM/TB/2009.420. Geneva: WHO Press.

ADRs of anti-TB drugs: symptom-based approachMinor ADRs Drug

responsibleManagement

Anorexia, nausea,

abdominal pain

H, R, Z Give with small meals or

before bedtimeIf persist, protractedvomiting, sign ofbleeding, refer urgently

Joint pains Z ASA, NSAIDs or paracet.Numbness/tingling H Pyridoxine 50-75 mg/day

Drowsiness H Give before bedtime

Orange/red urine R Tell before startFlu syndrome (fever,chills, malaise,headache, bone pain)

Intermittentdosing of R

Change to daily dose

Anti-TB induced hyperuricemia

10 .. 2528

baseline serum uric acid serum uric acid 2

2532; 10(3): 14-148

Patients No. (%) withincrease

uric acid

Mean serum uric acid

Baseline End of 2month

New case

(n=88)

84 (95.5) 5.5 10.40

Relapse(n=44)

42 (95.) 4.77 10.26

Anti-TB induced hyperuricemia

30 (30/88 = 34.0%) 13 (13/44 = 29.5%) 10-60 ASA NSAIDs

2532; 10(3): 14-148


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Anti- B induced he atotoxicit

Anti-TB induced hepatotoxicity

Definitions

Institute Definitions

WHO 2009 No detailATS 2006 ALT > 3X ULN with jaundice and/or

hepatitis symptoms (abdominal pain,nausea, vom ng, a gue or ALT > 5 X ULN

Thai-NTP208,CDC 2003

AST > 3 XULN AST > 5 X ULN

Hong-Kong2002

Same but include bilirubin > 2 x ULN


1 2 ADR Thailand: ~ 4.0-9.0 %, Other countries: ~ 3-15 % INH alone: 0.1-0.6 %

-

Incidence & Prevalence

. . PZA alone: no data


isoniazid isoniazid

hydrazine (hepatocellular

Mechanism: INH

slow acetylator isoniazid fast acetylators (adjusted oddsratio, 3.66; 95% CI, 1.58-8.49; P =.003)


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Mechanism: INH

Isoniazid(Isonicotinic Acid Hydrazide)

Acetylisoniazid

Acetylation

Hydrolysis

Isonicotinic acid

Acetyhydrazine

Diacetylhydrazine(Non-toxic metabolite)

Hydrazine(Toxic metabolite)

Hydrolysis

Hydrolysis

AcetylationAcetylation


Mechanism: Rifampicin

Rifampicin

hepatocellular injury cholestaticjaundice rifampicin 2

Thongraung W, et al. J Eval Clin Pract. 2011. doi: 10.1111/j.1365-2753.2011.01706.x.

- rifampicin - rifampicin

isoniazid



Rifampicin transient hyperbilirubinemia rifampicin bilirubin

bilirubin bilirubin

single dose serum bilirubin 3

McColl et alrifampicin 600 mg 1 7 4

total bilirubin 1 (10) bilirubin 7



rifampicin isoniazid

rifampicin enzyme inducer isoniazid

toxic metabolite isoniazid


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pyrazinamide pyrazinamide

isoniazid

Mechanism: Pyrazinamide

pyraz no c ac

21 pyrazinamide rifampicin

3 isoniazid


If rechallengeAmong 34 patients who were rechallenged with

anti-TB, 8 patients increased their liver enzymes 2 atient increased liver enz me after PZA

Causative agents

6 patients increased liver enzyme after RMP (5

patients took INH before RMP)

Thongraung W, et al. J Eval Clin Pract. 2011. doi: 10.1111/j.1365-2753.2011.01706.x.


If rechallenge pyrazinamide

0.52 100 person-month isoniazid

Causative agents

0.18 100 person-month

Yee D, et al. Am J Respir Crit Care Med. 2003;167(11):1472-1477


If rechallengeAmong 32 patients who were rechallenged with

anti-TB 20 atient increased liver enz me after PZA

Causative agents

3 patients increased liver enzyme after RMP

. 2010;20(3):221-231.


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If rechallenge

rifampicin ( 1.41) pyrazinamide ( 1.25) isoniazid 0.30

Causative agents

Ormerod LP, Horsfield N. Tuber Lung Dis. 1996;77(1):37-42


Risk factors

Factors Adjusted OR (95% CI)

Age > 35 years 1.61 (1.14 - 3.40)Age > 60 years 1.97 (1.24 - 2.08)Female 1.90 (1.07 - 4.40)

Abnormal pretreatment ALT/AST 2.5 (1.1 - 5.5)Pre-treatment bilirubin > 2mg/dl 9.4 (1.0 85.5)

HIV 3.54 (1.25 10.05)

HBsAg positive 5.5 (2.1 14.3)


Risk factors

Factors Adjusted OR (95% CI)Albumin < 3.5 mg/dl 2.3 (1.1 - 4.8)

Extrapulmonary TB 2.33 (1.16 4.67)NAT2 slow acetylators 4.697 (3.291- 6.705)

Higher dose of rifampicin 2.0 (2.1 14.3)**PZA dose > 30-40 mg/kg/day 3.33 (1.30 8.50)


Initial management

isoniazid, rifampicin

Management

pyrazinami e


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Alternative regimen

???

Management

2

ethambutol streptomycin fluoroquinilones(ofloxacin)

Alternative regimen

Saigal et alofloxacin 31 2

1 (n=15) pyrazinamide


Management

2 (n=16) rifampicin ofloxacin

2HZEO/10HEO 1 26.6% 2

(p=0.043)


Alternative regimen Szklo et alINH,

RMP, PZA 3SEO/9EO 40

Management


Alternative regimen Ho et al

fluoroquinolones 1 (H, R, Z)

Management

, , 134 3

1 () (n=27) ethambutol(with/without streptomycin)

2 () (n=52) ethambutol levofloxacin (with/without streptomycin)


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Alternative regimen

3 () (n=55) ethambutol moxifloxacin (with/without streptomycin)

Management

ADR: (levofloxacin= 4, moxifloxacin = 4)

5 ( 1 , levofloxacin 1 , moxifloxacin 3)

levofloxacin moxifloxacin


Rechallenge

(

transaminase

Management

2


Rechallenge: simultaneous or sequential Tahaoglu et al prospective randomized trial

2 1 (sequential

Management

rec a enge ,PZA

2 (simultaneousrechallenge) PZA

1 recurrent hepatitis 2 recurrent hepatitis 24.0 (p< 0.021)


Rechallenge: simultaneous or sequential Sharma et al prospective randomized trial

(n=237) 3

Management

1 isoniazi ri ampicin pyrazinami e

2 R, H, Z (ATS)

3 H, R, Z (BTS)

recurrent hepatiits 3


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Rechallenge: Which drug should be first?

Lowest incidence of hepatitis WHO, ATS: rifampicin, then INH BTS, Thai-NTP: INH, then rifampicin

Management

rifampicin isoniazid rechallenge PZA ???

Anti- B induced cutaneous ADRs

Anti-TB induced cutaneous ADRs

Thailand .. 2536- 2553: 15-45

Other countries

Incidence, prevalence

1.8 42.9


Setting, year Types Causative agents

Korea, 2010 Cutaneous vasculitis RMP, PZA

India 1998 Exfoliative dermatitis Anti-TB

Types of CADR :Case reports (other countries)

2009

Korea, 2008 DRESS Anti-TB, celecoxib

Tunisia, 2005 TEN STR

France, 1996 Erythema Multiforme PZAHong Kong,1995

MP rash Ethambutol


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Setting, year Types Causative agents

, 2009 MP rash RMP, PZA

Types of CADR: Case reports (Thailand)

,2008


Record review in a large hospital 673 CADR 32 ( 19.6) 88.8 61.2

- er thematous a ule 22.8

Types of CADR: prevalence case (Thailand)

- maculopapular rash 18.9- urticaria/angioedema 9.5- erythema multiforme 2.7- 43.2)

Thongraung W, 2010 (unpublished data)


Retrospective study 47 ( 5.7)

- Morbiliform rash 34

Types of CADR: prevalence case (Malaysia)

- Erythema multiform 4 - Urticaria 4 - Exfoliative dermatitis lichenoid eruption 5 )

97.0 CADR 2

Tan WC, et al. Med J Malaysia 2007; 62(2): 143-6.


prospective study (n=269) Cutaneous ADRs 58 ( 21.6)

Mean time since starting treatment 12.7 + 15.8 days,median 8 days (range 0-88 days)

Types of CADR: Incidence case (Thailand)

s- 47 ( 17.5)- 11 ( 4.1)

- Maculopapular rash 7 ( 2.6)

- Urticaria 3 ( 1.1)- Stevens-Johnson syndrome 1 ( 0.4)


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Management of Cutaneous ADR

(, )

Guidelines Types and Severity WHO 2010 Itching without

antihistamines moisturizerClosely monitor

Rash


(ATS/CDC/IDSA 2003)

Types and Severity

Itching without rash Rash (limited area)

antihistamines

Petechial rash(check platelet)

rifampicin platelet baseline

Generalized erythematous

rash especially associatedwith fever, mucousmembrane involvement


(Thai NTP 2008)

Types and Severity

CPM

CPM calamine 0.1% TA cream

(generalizederythematous rash)

prednisolone

2-3 3


(Thai pharmacists)

Severity of cutaneous ADR induced by anti-TB

Severity Clinical presentation

Mild

Moderate

Severe Petichial rash, exfoliative dermatitis, SJS-TEN,DRESS, AGEP, anaphylaxis, ,


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(Thai pharmacists)


Severity Initial managementMild

antihistamine, topicalsteroid, moisturizerClosely monitor


(Thai pharmacists)


Severity Initial managementModerate

antihistamine, topicalsteroid, moisturizerClosely monitor


(Thai pharmacists)


Severity Initial management

Severe


(Evidence from Thai Patients)

Mild cutaneous ADR:

Itch without rash(n=47)

(n = 23, 48.9%)

(n = 21, 44.7%)

(n = 3, 6.4%)

(n = 20, 42.6%)

(n = 3, 6.4%)

(n = 21, 44.7%)

(n = 0, 0.0%)

(n = 0, 0.0%)

(n = 3, 6.4%)


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(Evidence from Thai Patients)

moderate cutaneous ADR:

Itch with rash(n=10)

(n =8, 80.0%)

(n = 1, 10.0%)

(n = 1, 10.0%)

(n = 8, 80.0%)

(n = 0, 0.0%)

(n = 1, 10.0%)

(n = 0, 0.0%)

(n = 0, 0.0%)

(n = 1, 10.0%)


WHO guidelines 2010 (rifampicin

isoniazid) mg

3


ATS/CDC/IDSA 2003

Petechial rash RIF

2-3

INH, ETM PZA 3 4

4


Thai-NTP 2008

2-3 E, R, H, Z

(mg)

2 E 800

3 R 300

4 R 450

5 H 100

6 H 3007 Z 500

8 Z 1500


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Provocation test, Desensitization, Graded challenge

Pt with suspected drug allergy

Pt with

Pt need immediategoo s a e o ea rea men

Provocation testDesensitization Graded

challenge

Desensitization, Graded challenge

Patients suitable forgraded challenge or desensitization

Patients with HIV infection, cystic fibrosis, ortuberculosis

6666

Patients whom an immediate re-introduction ofantibiotherapy is required

Patients with cancer or rheumatology whoexperienced immediate HSR to their first-linechemotherapy and no alternative drugs are available


Drug desensitization

induction of drug tolerance Drug Tolerance is defined as a

state in which a patient with a drug allergywill tolerate a drug without an adverse

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. Desensitization induces a temporary state oftolerance to the drug, which is maintainedonly as long as the patient continues to takethe specific drug It has to be repeated every time the patientsrequired treatment with the drug or its potentiallycross-reacting drug


Drug desensitization

Starting doses are at 1:1,000,000 to 1:100 of the

target therapeutic dose Dose escalations are doubled at 15-30 min

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n erva s or mme a e reac ons, or a n erva s oup to 24 h for non-immediate reactions.


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Graded challenge

should be performed at the time the patients requiredimmediate treatment with the suspected drug For patient unlikely to be allergic to drug Graded challenge should almost never be performed if

-

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mediated reaction, such as SJS, TEN, interstitialnephritis, hepatitis, or hemolytic anemia. Rare exceptions: treatment with a life-threateningillness in which the benefit of treatment outweighs therisk of a potentially life-threatening reaction


Graded challenge

The starting dose for a graded challenge is higher than

for induction of drug tolerance The number of steps in the procedure may be 2 orseveral

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e interva etween ose are epen ent on t e typeof previous reaction The entire procedure may take hours or days tocomplete

Graded challenge & Desensitization

Graded challenge Diagnosis or therapeuticAt the time whenpatient requiredimmediate treatment with

Desensitization TherapeuticAt the time whenpatient requiredimmediate treatment with

suspected drug No intention to inducetolerance Start 1/100 of dailydose Interval: any

suspected drug Intention to inducetolerance Start 1/100,000 -1/1,000 of daily dose Interval: 15 min anddouble dose

Rechallenge for SJS induced by anti-TB drugs

Methods: 8 pulmonary TB-HIV patients with SJS (all had >

75% BSA involved & mucous membrane affected) Stopped all anti-TB drugs, treated all patients with

Kura MM, Hira SK. Int J dermatol. 2001;40(7):481-4.

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-wksAfter complete resolution of the skin lesions,reintroduction of anti-TB (H, R, Z, E) was started Drugs were started one after another at weekly

intervals, gradually increasing doses and no othersmedications were given during this period


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Rechallenge for SJS induced by anti-TB drugs

Week Day Drug Dose (mg) Clinical signs

1 1 INH 50 None

1 3 INH 100 None

1 5 INH 200 None

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1 7 INH 300 None

2 9 EMB 200 None

2 11 EMB 400 None

2 13 EMB 600 None

2 15 EMB 800 None

Rechallenge for SJS induced by anti-TB drugs (cont.)

Week Day Drug Dose (mg) Clinical signs

3 17 RMP 150 None

3 19 RMP 300 None

3 21 RMP 450 None

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3 23 RMP 600 None

4 25 PZA 250 None

4 27 PZA 500 1 had skinreaction

4 29 PZA 1000 Others none

4 31 PZA 1500 None

Case report:

Oral rapid desensitization to INH & RMF

Case report A 45 year-old pulmonary TB patient was started withPZA (1500), RIF (600), INH (300)After 12 days, she developed a measles-like rash,


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All anti-TB were stopped First rechallenge with PZA (500 mg), no reaction Then, rechallenge with RIF (150 mg)After 3 hrs later after RIF, pruritis, urticaria,

angioedema, chest heaviness, shortness of breathdeveloped RIF was stopped & treated with EPI, DIP

Case report:


Case report Several hrs later, she developed a fever to 40oC, chill,

arthralgia 5 days later, INH (300), PZA (1500), ETM (700), STR


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was s ar e , m n a er e rs ose prur s,urticaria, angioedema developed, then all drugs werestopped INH (100) was restarted, generalized pruritis wasdeveloped

She was referred for evaluation and possibledesensitization

Case report

C p t


20/22

Case report:


Case report


Skin Prick Test (wheal/flare) Intradermal test(Wheal/flare)

0.9 NSS - 0.9 NSS 0.05 ml -

Histamine 1/1,000 + 9/16 Histamine 1/10,000

+15/29

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.

Sorbital 70% - Sorbital 70% ND

INH 0.1 mg/ml 0.9 NS - INH 0.1 mg/ml 0.9 NS(0.05 ml)

-

INH 1.0 mg/ml 0.9 NS - INH 1.0 mg/ml 0.9 NS(0.05 ml) -

RIF 0.1 mg/ml sorbital - RIF ND

RIF 1.0mg/ml sorbital - RIF ND

1st desensitization (INH elixir (50mg/5 ml) diluted with sorbital)


Case report:


Time Drug Dose, mg

7.00 INH 0.1

7878

. .

7.30 INH 1.0

7.45 INH 2.0

8.00 INH 4.08.30 INH 8.0

9.00 INH 16.0


Case report:


Time Drug Dose, mg

9.30 INH 32.0

10.30 INH 50

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.

14.30 INH 150

15.00 INH 150

24.30 INH 150

Continue INH 150 mg q 12 hrs

Case report:


Case report 9 hrs into desensitization, a fever of 38.8oC, mildchest heaviness developed (tx with DIP,

metaproterenol inhalation) She was able to continue desensitization without


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further symptoms except for persistent fever Prednisolone 40 mg was given, patients defervesced6 hrs later Prednisolone was maintained to suppress fever There was no later development of fever, rash,

athralgias, angioedema or chest complaints The next day, RIF was restarted

Case report: Case report:


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Case report:


Time Drug Dose, mg

7.00 RMF 0.17.15 RMF 0.5

8181

. .

7.45 RMF 2.0

8.00 RMF 4.0

8.15 RMF 8.08.30 RMF 16.0


Case report:


Time Drug Dose, mg

8.45 RMF 32.09.15 RMF 50

8282

.

12.15 RMF 100

16.15 RMF 150

24.15 RMF 300

Continue RMF 300 mg q 12 hrs

There was no adverse reaction on RIF desensitization

Desensitization Therapy

for allergic reactions to antituberculosis Drug

Setting: Japan Methods: retrospective Study subjects: All 46 TB patients shown allergicreactions ( 23 pts with skin eruption, 16 pts with fever, 7ts with fever & skin reactions

Kobashi Y, et al Med. 2010; 49(21): 2297-301

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Causative drugs (based on the clinical course judged byattending physicians and/or drug lymphocyte stimulationtest (DLST)): RFM 30 cases (15 clinical & DLST, 15clinical), INH 16 cases (9 clinical & DLST, 7 clinical) Desensitization protocol: Japanese Society fortuberculosis (JST) 1997

Desensitization protocol




Day INH (mg) RIF (mg)

1 25 252 25 25

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3 25 25

4 50 50

5 50 50

6 50 50

7 100 100

8 100 100



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Day INH RIF

9 100 10010 200 200

11 200 200

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12 200 200

13 300 300

14 300 300

15 300 30016 400 450

RESULTS Failed (7/30) Failed (3/16)

Alternative Tuberculosis Regimens

Causative drug Alternative TB regimen

Isoniazid 6-9 RZERifampicin 2HES/10HE

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Isoniazid & Rifampicin 18-24 SEFx

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