UPDATE IN TUBERCULOSIS 2010

Pornanan Domthong,M.D. 7 January 2011

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New Guideline In TB Case Management Fourth Edition

2010
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Key changes since the third edition

Instead of Diagnostic categories IIV, this edition uses the same patient registration groups used for recording and reporting, which differentiate new patients from those with prior treatment and specify reasons for retreatment.

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NO category, NO 2HRZ/4HR,NO 2HRZE/6HE

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Registration group by outcome of most recent TB treatment

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New guideline
1. New patient regimen : 2 HRZE/4HR Cat I 2. Retreatment regimen with first line Cat II drug : 2SHRZE/HRZE/5HRE 3. Suspect MDR: MDR regimen Cat IV

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Duration of rifampicin in new patients

Should new pulmonary TB patients be treated with the 6-month rifampicin regimen (2HRZE/4HR) or 2-month rifampicin regimen (2HRZE/6HE)?

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 Recommendation 1 New patients with pulmonary TB should receive a regimen containing 6 months of rifampicin: 2HRZE/4HR
Also applies to extrapulmonary TB, except TB of the central nervous system, bone or joint for which some expert groups suggest longer therapy
(Strong/High grade of evidence)

Recommendation 2 The 2HRZE/6HE treatment regimen should be phased out*

(Strong/High grade of evidence)

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Initial regimen in countries with high levels of isoniazid resistance

Recommendation 1
2HRZE/4HRE In populations with known or suspected high levels of isoniazid resistance, new TB patients may receive HRE as therapy in the continuation phase as an acceptable alternative to HR
(Weak/Insufcient evidence, expert opinion) Page 10

levels of isoniazid resistance in thailand

Expert Opinion isoniazid resistance more than 10% may receive HRE as therapy in the continuation phase Thailand < 10% isoniazid resistance

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Standard Regimens For New TB patients

In presumed, or known, to have drug-susceptible TB who no longer recommends omission of ethambutol during the intensive phase of treatment for patients with non-cavitary, smear-negative pTB or epTB who are known to be HiV-negative. in tuberculous meningitis, ethambutol should be replaced by streptomycin.

In settings where the level of isoniazid resistance among new TB cases is high and isoniazid susceptibility testing is not done (or results are not available) before the continuation phase begins)

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Dosing frequency in new patients

Recommendation 1
Wherever feasible, the optimal dosing frequency for new patients with pulmonary TB is daily throughout the course of therapy
(Strong/High grade of evidence) Recommendation 1.1

New patients with pulmonary TB may receive a daily intensive phase followed by a three times weekly continuation phase [2HRZE/4(HR)3]provided that each dose is directly observed
(Conditional/High and moderate grade of evidence) Recommendation 1.2

Three times weekly dosing throughout therapy 2(HRZE)3/4(HR)3] may be used as another alternative to Recommendation 1.1, provided that every dose is directly observed and the patient is NOT living with HIV or living in an HIV-prevalent setting
(Conditional/High and moderate grade of evidence) Page 13

Dosing frequency for new TB patient

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Recommendation 2
New patients with TB should not receive twice weekly dosing for the full course of treatment unless this is done in the context of formal research (Strong/High grade of evidence)

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Tb treatment in persons living with HIV TB patients living in HIV prevalent settings
Recommendation 1
TB patients with known positive HIV status and all TB patients living in HIV prevalent settings should receive daily TB treatment at least during the intensive phase

(Strong/High grade of evidence)

Remark HIV-prevalent settings are defined as countries, subnational administrative units, or selected facilities where the HIV prevalence among adult pregnant women is 1% or among TB patients is 5%

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World health Organization Global Tuberculosis Control A short update to the 2009 report

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Recommendation 2
For the continuation phase, the optimal dosing frequency is also daily for these patients
(Strong/High grade of evidence)

Recommendation 3
If a daily continuation phase is not possible for these patients, three times weekly dosing during the continuation phase is an acceptable alternative
(Conditional/High and moderate grade of evidence)

Recommendation 4
It is recommended that TB patients who are living with HIV should receive at least the same duration of TB treatment as HIVnegative TB patients
(Strong/High grade of evidence)

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Dosing frequency

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Treatment extension in new pulmonary Tb patients

Recommendation 1 In patients treated with the regimen containing rifampicin throughout treatment, if a positive sputum smear is found at completion of the intensive phase, the extension of the intensive phase is not recommended (Strong/High grade of evidence)

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Smear status at the end of the intensive phase

1. Poor predictor of which new patients will relapse. 2. However, detection of a positive sputum smear remains important as a trigger for the patient assessment, quality of patients support and supervision and intervention promptly if necessary 3. Continue HR and sputum monitoring on month 3 if specimen obtained at the end of month 3 is smear positive sputum culture and drug susceptibility testing should be performed

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A positive sputum smear at the end of the intensive phase may indicate any of following 1. the initial phase of therapy was poorly supervised and patient adherence was poor 2. poor quality of anti-TB drugs 3. doses of anti-TB drugs are below the recommended range 4. resolution is slow because the patient had extensive cavitation and a heavy initial bacillary load; 5. non-viable bacteria remain visible by microscopy.

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Previously treated patients

Weighted mean of MDR-TB in new and retreatment TB cases from drug resistance surveys, 19942007 MDR in retreatment TB cases from drug resistance surveysand surveillance in 10 countrieS, 19972007

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Previously treated patients

Recommendation 1
Specimens for culture and drug susceptibility testing (DST) should be obtained from all previously treated TB patients at or QUESTION of treatment. DST should be performed for at least before the start 1 isoniazid and rifampicin

Recommendation 2
In settings where rapid molecular-based DST is available, the results should guide the choice of regimen

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Recommendation 3
In settings where rapid molecular-based DST results are not routinely available to guide the management of individual patients, empirical treatment should be started as follows:

Recommendation 3.1
TB patients whose treatment has failed or other patient groups with high likelihood of multidrug-resistant TB (MDR-TB) should be started on an empirical MDR regimen

Recommendation 3.2
TB patients returning after defaulting or relapsing from their first treatment course may receive the retreatment regimen containing first-line drugs 2HRZES/1HRZE/5HRE if country-specific data show low or medium levels of MDR in these patients or if such data are unavailable

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Recommendation 4
In settings where DST results are not yet routinely available to guide the management of individual patients, the empirical regimens will continue through out the course of treatment

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Standard regimens for previously Treated patients depending on the availability of routine DST to guide the therapy of individual retreatment patients

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Multi-drug Resistant Tuberculosis (MDR TB)

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DEFINITIONS
MDR (Multidrug resistant tuberculosis) resisted to at least H, R XDR (Extensive drug resistant tuberuculosis) strain of MDR-TB which also resisted to any one member of fluoroquinolones and one of injected anti-TB drugs : kanamycin, amikacin, capreomycin

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Antituberculosis
First line
Isoniazid ( H ) Rifampicin ( R ) Pyrazinamide ( Z ) Ethambutol ( E ) Streptomycin ( S )

Second line
Aminoglycosides(Inj)
Kanamycin, Amikacin

Fluoroquinolones
Levofloxacin, Moxifloxacin Ofloxacin

Cyclic polypeptides
Capreomycin

Serine analog
Cycloserine,Terazidine

Thioamide
Ethionamide, Prothionamide

Salicylic acid derivatives

PAS Page 30

Surveillance of Drug resistance in Tuberculosis : Thailand 2006

SDRTB Summary of anti tuberculosis resistance as of : 7/6/2007 For : All Males & All females (0 to 99 years of age) New Cases Total tested Fully sensitive Any resistance Mono-resistance H R E S H + R resistance HR HRE HRS HRSE N 1150 970 180 65 10 5 52 (19) 3 3 6 7 Pet 100.0% 84.3% 15.7% 5.7% 0.9% 0.4% 4.5% (1.65%) 0.3% 0.3% 0.5% 0.6% Previously Treated Cases N 194 95 99 10 1 0 11 (67) 12 9 8 38 Pet 100.0% 49.0% 51.0% 5.2% 0.5% 0.0% 5.7% (34.54%) 6.2% 4.6% 4.1% 19.6% 31 Page 31

 (MDR-TB)
Pretreatment

1. HIV 2. MDR-TB 3.
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 On treatment (MDR-TB)
1. 2HRZE/4HR intensive 1 (HRZE 3 ) 2. 2HRZE/4HR 3. 2SHRZE/HRZE/5HRE 3 4. 2SHRZE/HRZE/5HRE 5 (high risk) 5. 2

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 (MDR-TB)
Post treatment 6

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1. culture drug susceptibility test 2. 2-4 3. specimen culture/drug susceptibility test 2-3 specimen
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 C/S
CAT I (2HRZE/4HR) failure

1 2 3 DOT

CAT4(1) 6K5OPEZ/12-18 OPEZ

Continue CAT 1 > 5 month HR

***

CAT 2 5 2SHRZE/HRZE/5HRE

4 CXR

C/S
***

NOTE: CAT 2 CAT 1 DOT primary 36 Page

 C/S
CAT 2 (2SHRZE/HRZE/5HRE) failure

1 2 3 DOT

CAT4(2) 6K5O(P) Et Cs (Z)/12-18 O(P) Et Cs (Z)

Continue CAT 2 > 5 month 5 HRE

***

4 CXR

C/S
***
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MDR TB
1 susceptibility empiric CAT4(1) CAT4(2) 2 4 3 6 streptomycin kanamycin Amikacin kanamycin Amikacin 4 quinolone ofloxacin 5 Pyrazinamide 6 18 Page 38

MDR empiric regimen

CAT4(1) 6K5OPEZ/12-18 OPEZ

CAT4(2) ..6K5O(P) Et Cs (Z)/12-18 O(P) Et Cs (Z)

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Retreatmen t

(relapsed)

1 On Cat treatmen t 1,2 5 New PTB & HIV positive Pre treatmen Contact MDR-TB , Health care worker t / / /

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Management Side Effect Of Antituberculosis

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management of cutaneous reactions

itching without a rash and there is no other obvious cause symptomatic treatment with antihistamines and skin moisturizing, and continue TB treatment while observing the patient closely skin rash develop all anti-TB drugs must be stopped. Once the reaction has resolved, anti-TB drugs are reintroduced one by one, starting with the drug least likely to be responsible for the reaction (rifampicin or isoniazid) at a small challenge dose, such as 50 mg isoniazid dose is gradually increased over 3 days. This procedure is repeated, adding in one drug at a time. A reaction after adding in a particular drug identifes that drug as the one responsible for the reaction.
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WHO Treatment of tuberculosis guideline 2010

Rash
response to a patient with a rash depends on its severity. The rash minor

in which case antihistamines should be given for symptomatic relief, but all antituberculosis medications can be continued.

Page 45 American Thoracic Society, CDC, and Infectious Disease Society of America, 2003; 52:43

Rash
The rash major

If there is a generalized erythematous rash, especially if it is associated with fever and/or mucous membrane involvement all drugs should be stoppedimmediately If the patient has severe tuberculosis, three new drugs should be started.(aminoglycoside and 2 oral agent) When the rash is substantially improved the medications can be restarted one by one, at intervals of 23 days. RIF should be restarted first (because it is the least likely to cause rash, CDC, anditInfectious Disease Society of America, 2003; 52:43 and is the most important 46 Page American Thoracic Society, agent), followed by INH and then EMB or PZA.

Management of antituberculosis induce hepatitis

Of the first-line anti-TB drugs, isoniazid, pyrazinamide and rifampicin can all cause liver damage The management of hepatitis induced by TB treatment depends on: whether the patient is in the intensive or continuation phase of TB treatment; the severity of the liver disease; the severity of the TB

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All drugs should be stopped If the patient is severely ill with TB and it is considered unsafe to stop TB treatment, a non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fuoroquinolone should be started. If TB treatment has been stopped, it is necessary to wait for liver function tests to revert to normal and clinical symptoms (nausea, abdominal pain) to resolve before reintroducing the anti-TB drugs.

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Once drug-induced hepatitis has resolved, the drugs are reintroduced one at a time. If symptoms recur or liver function tests become abnormal as the drugs are reintroduced, the last drug added should be stopped. Some advise starting with rifampicin because it is less likely than isoniazid or pyrazinamide to cause hepatotoxicity and is the most efective agent After 37 days, isoniazid may be reintroduced. In patients who have experienced jaundice but tolerate the reintroduction of rifampicin and isoniazid, it is advisable to avoid pyrazinamide.

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Hepatitis

, AST > 5 INH 50 (1 ) 100 (1 ) 150 (1 ) 200 (1 ) 250 (1 )

AST Rifampicin INH 300 mg/d

RIFAMPCIN 150 (1 ) 300 (2 ) 450 (2 ) AST challenge

Pyrazinamide Pyrazinamide
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Alternative Regimen
If rifampicin cannot be used2SHE/10HE)
regimen without rifampicin is 2 months of isoniazid, ethambutol and streptomycin followed by 10 months of isoniazid and ethambutol.

If isoniazid cannot be used........(6-9RZE)

69 months of rifampicin, pyrazinamide and ethambutol

If pyrazinamide cannot be used..(2HRE/7HR)

before the patient has completed the intensive phase, the total duration of isoniazid and rifampicin therapy may be extended to 9 months

If neither isoniazid nor rifampicin can be used.8-24 EOS)

the non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fuoroquinolone should be continued for a total of 1824 months. Page 51

Treatment of extrapulmonary TB and of TB in special situations

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Treatment of extrapulmonary Tb
Pulmonary and extrapulmonary disease should be treated with the same regimens some experts recommend 912 months of treatment for TB meningitis and 9 months of treatment for TB of bones or joints Unless drug resistance is suspected adjuvant corticosteroid treatment is recommended for TB meningitis and pericarditis In tuberculous meningitis,ethambutol should be replaced by streptomycin. fourth edition no longer includes the option of omitting ethambutol during the intensive phase of treatment(2HRZ/4HR) for patients with extrapulmonary disease who are known to be HIV-negative
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Length Of tuberculosis therapy

Page 54 MMWR 200352:63-64

renal failure and severe renal insuffciency

RIF and INH are metabolized by the liver, so conventional dosing may be used in the setting of renal insufficiency PZA is also metabolized by the liver but its metabolites may accumulate in patients with renal insufficiency EMB is about 80% cleared by the kidneys and may accumulate in patients with renal insufficiency

Page 55 MMWR 2003;52:63-64

Decrease dose or increasing the dosing interval ?

Decreasing the dose of selected antituberculosis drugs may not be the best method of treating tuberculosis because,although toxicity may be avoided, the peak serum concentrations may be too low. Therefore increasing the dosing interval of pyrazinamide and ethambutol are recommended and doses should be adjusted Three times per week

Page 56 MMWR 2003;52:63-64

Page 57 MMWR 2003;52:63-64

pregnancy and breastfeeding

A pregnant woman
The first line anti-TB drugs are safe for use in pregnancy With the exception of streptomycin, streptomycin is ototoxic to the fetus and should not be used during pregnancy.

A breastfeeding woman
should receive a full course of TB treatment. Timely and properly applied chemotherapy is the best way to prevent transmission to the baby. After active TB in the baby is ruled out, the baby should be given 6 months of isoniazid preventive therapy, Pyridoxine supplementation is recommended for all pregnant or breastfeeding women taking isoniazid
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1-2
1 1
40-50% 10-15% 5%

10% 10% 5%
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Nelson LJ. Wells CD,Int J Tuberc Lung Dis 2004;8: 634-47

 //

5
,PE, CXR, +/- Tuberculin test

Tuberculin Test

TB disease

> 15 mm

10-14 mm

< 10 mm

Rx anti TB drug

Rx LTBI INH 6-9 M

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 BCG ?
BCG BCG 50% 64% 78% BCG

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Common pitfall on tuberculin test

BCG tuberuclin test 5 tuberculin test antigen tuberculin Booster effect 2

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Tuberculin test
tuberculin test BCG Tuberculin 10 .

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