Standard 8

All patients who have not been treated previously h ld i i t ti ll t d fi t li should receive an internationally accepted first-line

treatment regimen using drugs of known bioavailability The initial phase should consist of two months of

isoniazid, rifampicin, pyrazinamide, and ethambutol The preferred continuation phase consists of

isoniazid and rifampicin given for four monthsisoniazid and rifampicin given for four months

INH + RMP + EMB + PZA 2INH RMP EMB 4INH + RMP + EMB 4

INH + RMP + PZARifater INH+ RMPRifinah

INH + RMP + EMB 9 INH + RMP + EMB 9 pyrazinamide

Risk Groups/Factors for Adverse Antituberculous Drug Reactions

Advanced age Malnutrition Pregnancy Alcoholism Liver failureLiver failure Chronic renal failure HIV infection Disseminated and advanced TBDisseminated and advanced TB Atopy Anaemia Diabetes mellitus Diabetes mellitus Family history of adverse anti-TB drug reactions Patients receiving irregular anti-TB treatment

P ti t i i di ti f th di d Patients receiving medication for other disorders, in addition to anti-TB drugs

A T iti f T b l i P ti t i T iAge Transition of Tuberculosis Patients in Taiwan19572001

2007 >65y/o: 52% J Formos Med Assoc 2006;105:2530

Between July 2002 and December 2003

Male, 69 y/o

Treatment regimen Rifater+ EMB

Skin rash and itching GOT: 75 U/L, GPT:125 U/L Uric acid: 15 7 mg/dlUric acid: 15.7 mg/dl

Rifater Isoniazid Rifampin Pyrazinamide

Ethambutol

AST: 228 ALT: 105

Isoniazid

Asymptomatic elevation of aminotransferasesElevations up to five times the upper limit of normal: 10 20% Elevations up to five times the upper limit of normal: 1020%

Usually return to normal even with continued administration of the drug

Clinical hepatitis: the risk increases Clinical hepatitis: the risk increases Increasing age (< 20 y/o: uncommon; 5064 y/o: 2%) Underlying liver diseaseUnderlying liver disease Heavy alcohol consumption

Fatal hepatitisp Associated with continued administration of INH despite onset of

symptoms of hepatitis

Isoniazid: Peripheral Neurotoxicity

Dose related Uncommon (< 0 2%) at Uncommon (< 0.2%) at

conventional doses The risk is increased

Associated with neuropathy Nutritional deficiency Diabetes Diabetes HIV infection Renal failure

Al h li Alcoholism Pregnant and breastfeeding

women Pyridoxine supplementation

Isoniazid

Central nervous system effects Reported but have not been quantified Such as dysarthria, irritability, seizures, dysphoria, and

i bilit t t tinability to concentrate Lupus-like syndrome Hypersensitivity reactions

Such as fever, rash, Stevens-Johnson syndrome, hemolytic y yanemia, vasculitis, and neutropenia are rare

Isoniazid

10-20%(transaminase)

0 1 0 15% 0.1-0.15%

350.3%35-491.2%50-642.3%

Isoniazid

pyridoxine(pyridoxine)py (py )

(Lupus-like syndrome); 1% Stevens-Johnson syndromey

Rifampin (RIF) Orange Discoloration of Rifampin (RIF): Orange Discoloration of Bodily Fluids (sputum, urine, sweat, tears)y ( p , , , )

Rifampin (RIF)

Hepatotoxicity Transient asymptomatic hyperbilirubinemia

May occur in 0.6% of patients More severe clinical hepatitis

Typically: a cholestatic pattern

Rifampin (RIF)

Cutaneous reactions ( P iti ith ith t ( Pruritis with or without rash): 6% Generally self-limited Continued treatment with

th d b iblthe drug may be possible More severe, occurring in

0 07 0 3% of patients0.070.3% of patients

Rifampin (RIF)

Gastrointestinal reactions (nausea, anorexia, abdominal i )pain)

Rarely severe enough to necessitate discontinuation of the ddrug

Flu-like syndrome More likely to occur with intermittent administration of a

higher dose Severe immunologic reactions: (rare < 0.1%)

Thrombocytopenia, hemolytic anemia, acute renal failure

Rifampin (RIF)

Drug interactions due to induction of hepatic microsomal enzymes Reductions in serum concentrations of common Reductions in serum concentrations of common

drugs Such as oral contraceptives, methadone, and warfarinSuch as oral contraceptives, methadone, and warfarin

Bidirectional interactions between rifamycins and antiretroviral agentsantiretroviral agents

10 mg/kg 10 mg/kg

RMP

RMP RMP RMP

coumadin coumadinRMP

Rifater Isoniazid Rifampin Pyrazinamide

Ethambutol

Pyrazinamide

Hepatotoxicity: about 1%G t i t ti l t Gastrointestinal symptoms: common

Asymptomatic hyperuricemiaA t d ff t f th d An expected effect of the drug

Generally without adverse consequence Nongouty polyarthralgia: may occur in up to 40% of patients Nongouty polyarthralgia: may occur in up to 40% of patients

The pain usually responds to aspirin or other nonsteroidal antiinflammatory agents

Acute gouty arthritis Rare except in patients with preexisting gout

Transient morbilliform rash: usually self-limited

2-20%(3 gm/day) 25 /k 25 mg/kg5%INHRMP

PZA13 mg/dl

(salicylates)( y )

Rifater Isoniazid Rifampin Pyrazinamide

Ethambutol

Ethambutol

Retrobulbar neuritis Decreased visual acuity or red-green color discrimination Dose related

Minimal risk at a daily dose of 15 mg/kg In patients with renal insufficiency

P i h l iti Peripheral neuritis A rare adverse effect

Cutaneous reactions Skin reactions requiring discontinuation of the drug

occur in 0.20.7 % of patients

EMB 15 mg/kg1%1%

Fixed-Dose Combination Preparations

Reducing the risk of thmonotherapy

The ease of administration

The potential for preducing medication errors

Streptomycin

Ototoxicity (vestibular and hearing disturbances) Most important adverse reaction The risk is increased

Age Increasing single doses The cumulative dose (especially above 100 120 g) The cumulative dose (especially above 100120 g)

NeurotoxicityCi l th i i di t l ft i j ti Circumoral parasthesias immediately after injection

Nephrotoxicity

120 gm g

GOT: 777 U/L GPT: 1333 U/L

Baseline Evaluations

Measurements of AST, bilirubin, alkaline phosphatase, and serum creatinine and a platelet count should be obtained for all serum creatinine and a platelet count should be obtained for all adults (uric acid and sugar)

Testing of visual acuity and color vision should be performed Testing of visual acuity and color vision should be performed when EMB is to be used

All patients with tuberculosis have counseling and testing for HIV All patients with tuberculosis have counseling and testing for HIV infection (U.S.)

CBCAST/ALTbilirubinuric acidBUN/Cre Sugarg

Follow-Up Evaluations (1)

It is essential that patients have clinical evaluations at least monthly least monthly To identify possible adverse effects of the anti-TB

medications medications To assess adherence

DOT

Follow-Up Evaluations (2)

It is not necessary to monitor liver or renal function or l t l t t f ti t b i t t d ith fi t li platelet count for patients being treated with first-line

drugs unless there were abnormalities at baseline or th li i l t bt i th t there are clinical reasons to obtain the measurements Patients who have stable abnormalities of hepatic or renal

f ti t b li h ld h t t l function at baseline should have repeat measurements early in the course of treatment, then less frequently to ensure that there has not been worseningthere has not been worsening

2 4 8248

Follow-Up Evaluations (3)

Patients receiving EMB should be Questioned regarding visual disturbances at monthly

intervals Monthly repeat testing of visual acuity and color

vision is recommended for/ Receiving an EMB dose exceeding 15--20 mg/kg

Receiving the drug for more than 2 months

Ethambutol

Tuberculosis ChemotherapypyStill a Double-edged Sword

Am J Respir Crit Care Med 2003; 167: 14612p ;

To Assess the Risk-Benefit of Anti-TB Drugs

Transmission

Anti-TB chemotherapy: Three Basic Principles

Multiple drugs to which the organisms are susceptible The drugs must be taken regularly Therapy must continue for a sufficient period of timepy p

ATS/CDC Am J Respir Crit Care Med 1994; 149: 1359-74

Six-month regimens g 2HERZ/4HR

Nine-month regimen Nine month regimen 2HER/7HR

ATS/CDC/IDSA Am J Respir Crit Care Med 2003; 167: 60362p ;

Alternative Regimens (1)

Alternative Regimens (2A)

Alternative Regimens (2B)

The Management Approach to Adverse Drug Reactions (1)

With regards to the anti-TB treatment regimen f ll i d tifollowing an adverse reaction As many first-line drugs should be tried as possible

More effective and less toxic than the second-line agents Early detection is essential

Clearly affect the associated morbidity and mortality Most adverse reactions are attributable to a single drug

Can be resolved by designing a treatment regimen to exclude that agent

The Management Approach to Adverse Drug Reactions (2)

Mild or moderate adverse reactions To provide symptomatic treatment for the reaction, adjust the

drug dose, or change the timing of administrationIf th t b f l i f If these measures prove to be unsuccessful, suspension of treatment should then be considered

A i d ti A serious adverse reaction All treatment should be suspended

Management of Common Adverse Effects

Attuned to the potential for adverse effects First-line drugs not be stopped without adequate

justificationj Mild adverse effects

Can generall be managed ith s mptomatic therap Can generally be managed with symptomatic therapy More severe effects

Drugs must be discontinued

Management of Drug-related Hepatitis (1)

The first-line antituberculosis drugs, INH, RIF, and PZA, d i d d li i jcan cause drug-induced liver injury

An asymptomatic increase in AST concentration occurs in nearly 20% of patients treated with the standard four-drug regimen In most patients, asymptomatic aminotransferase elevations

resolve spontaneously In addition to AST elevation, occasionally there are

disproportionate increases in bilirubin and alkaline phosphatase Thi tt i i t t ith if i h t t i it This pattern is more consistent with rifampin hepatotoxicity

Management of Drug-related Hepatitis (2)

If AST levels are more than five times the upper limit of normal (with or without symptoms) or more than three times normal in (with or without symptoms) or more than three times normal in the presence of symptoms hepatotoxic drugs should be stopped immediately and the patient hepatotoxic drugs should be stopped immediately and the patient

evaluated carefully Drug-induced hepatitis is usually a diagnosis of exclusion

Serologic testing for hepatitis A, B, and C should be performed Carefully regarding symptoms suggestive of biliary tract disease

Exposures to other potential hepatotoxins particularly alcohol and Exposures to other potential hepatotoxins, particularly alcohol and hepatotoxic medications

Management of Drug-related Hepatitis (3)

To give at least three nonhepatotoxic anti-TB drugs Until the specific cause of hepatotoxicity can be determined

and an appropriate longer term regimen begun Restarted one at a time

After the AST concentration returns to less than two times the fupper limit of normal

In patients with elevated baseline AST from preexisting liver di d h ld b t t d h th AST t t disease, drugs should be restarted when the AST returns to near baseline levels

RIF: restarted first RIF: restarted first

Management of Drug-related Hepatitis (3)

SMEMBQuinolone

INHRMPPZA

If RIF and INH are tolerated, and hepatitis was severe, a d a e to e ated, a d epat t s as se e e,PZA should be assumed to be responsible and should be discontinued

G t i t ti l U tGastrointestinal UpsetNausea, Vomiting, Poor Appetite, Abdominal Pain

Many of the antituberculosis drugs can cause t i t ti l tgastrointestinal upset

Particularly in the first few weeks of therapy Serum AST and bilirubin should be measured

The initial approach to gastrointestinal intolerance, not associated with hepatic toxicity To change the hour of drug administration and/or to

administer the drugs with food

Drug Administration The first-line anti-TB medications should be administered

together as single dose rather than in divided doses Ingestion with food delays or moderately decreases the

absorption of anti-TB drugs The effects of food are of little clinical significance

The wide therapeutic margin of the first-line agents

Epigastric distress or nausea with the first line drugs Epigastric distress or nausea with the first-line drugs Dosing with food is recommended

Preferable to splitting a dose or changing to a second-line drug p g g g g Antacids have minimal effects on the absorption of the first-line anti-TB

drugs

Rash All drugs used in treating tuberculosis can cause a rash

Th h b i ( ff ti li it d b i The rash may be minor (affecting a limited area or being predominantly manifested as itching)

A tihi t i h ld b i f t ti li f Antihistamines should be given for symptomatic relief All anti-TB medications can be continued

If there is a generalized erythematous rash (especially if If there is a generalized erythematous rash (especially if it is associated with fever and/or mucous membrane involvement)involvement) All drugs should be stopped immediately When the rash is substantially improvedWhen the rash is substantially improved

The medications can be restarted one by one

ASTALT 5

13 mg/dL

i primperan

isoniazidpyridoxinepyridoxine

(1)

AST/ALT 3AST/ALT 5AST/ALT 5

13 mg/dL

Steven-Johnson syndromey

(2)

ethambutol i id pyrazinamide

rechallenge

Male, 56 y/o, Uremia

GOT: 1704 U/L GPT: 1481 U/L

Male, 56 y/o, Uremia