TB Treatment Regimen

Gina S. de los Reyes, M.D., MHPEd, FPCP, FPCCP

Outline

Short Course Treatment; Fixed Dose Combination Classification of TB Cases Treatment Regimens Treatment of TB in Special Situations Symptom-based approach to adverse effects of TB drugs

When to suspect PTB

Cough

of 2 weeks or more +/- night sweats, weight loss, anorexia, unexplained fever & chills, chest pain, fatigue & body malaise

Terminology of TB
ATS Classification 0- No TB Exposure 1- TB Exposure, no evidence of infection 2 - TB infection, no evidence of disease 3 - TB clinically active 4 - TB not clinically active 5 - TB suspect (diagnosis pending) WHO Case Defn. Latent TB Active TB Case Pulmonary or Extrapulmonary Smear (+) or (-)

Who requires treatment for PTB?

1. Active PTB (Class 3) 2. Inactive PTB (Class 4) but with no previous adequate/completed treatment 3. TB suspect (Class 5) when the probability of TB is high, while awaiting confirmation

Aims of Treatment
1. To cure patients with the least interference with their lives 2. To prevent death in seriously ill patients 3. To prevent extensive damage to the lungs with the consequent complications 4. To avoid relapse of the disease 5. To prevent the devt of drug-resistant TB (acquired resistance) 6. To protect his/her family & the community from infection

Characteristics of Mycobacteria
Grow

more slowly than other bacteria Can be dormant Lipid-rich cell wall is impermeable to many agents Intracellular pathogens Notorious for their ability to develop resistance

Drugs used in mycobacteria tuberculosis

Combination

of two or more drugs to prevent emergence of resistance during the course of therapy
must be prolonged

Treatment

Anti-TB drugs : Actions & Adverse Effects

First line drugs
DRUG ACTION Adverse Effects
Hepatitis Peripheral Neuropathy Gastronal Cutaneous rxn Hepatitis

Isoniazid

Bactericidal

Rifampicin

Bactericidal

Anti-TB drugs
DRUG Ethambutol ACTION Bacteriostatic
Adverse Effects

Pyrazinamide Bactericidal

Retrobulbar neuritis Hepatotoxicity Arthralgia Ototoxicity Cutaneous Hypersensitivity

Streptomycin Bactericidal

Second-line drugs

Ethionamide Prothionamide Sodium paraaminosalicylate (PAS) Cycloserine Ofloxacin Ciprofloxacin

Capreomycin Kanamycin Viomycin Amikacin Co-amoxiclav Clarithromycin Rifamycin derivativesRifabutin, Rifapentene

Drug Doses
DRUG Isoniazid Rifampicin Pyrazinamide Ethambutol Streptomycin DAILY (mkd) 5 (4-6) 8 (8-12) 25 (25-30) 15 (15-20) 15 (12-18)

(H) (R) (Z) (E) (S)

FIXED- DOSE COMBINATION (FDC) ANTI-TB DRUGS

Formulation where two or more anti-TB drugs are present in fixed proportions
Advocated by WHO & the International Union Against Tuberculosis & Lung Diseases (IUATLD) to replace single-drug preparations as treatment for TB

FDCs
For

the patient: simplified drug intake

Fewer pills to swallow Pills are identical Correct regimen is followed

FIXED DOSE COMBINATION: SIMPLER DOSE COMPUTATION

Body Weight (kg) 37 to 54 55 to 70 > 70 Practical dosing: 4-FDC (HRZE) (75/150/400/275) 3 tablets 4 tablets 5 tablets

< 55 kg: 3 tablets daily > 55 kg: 4 tablets daily

FIXED DOSE COMBINATION: SIMPLER DOSE COMPUTATION

Body Weight (kg) <50 >50 2-FDC (HR) (400/450) 1 tablet (150/300) 2 tablets Other preparations HRZ HRE

Short Course Chemotherapy

6

months regimen which includes Rifampicin and Pyrazinamide

Treatment- at least 12 months (w/o Rifampicin)

Standard

2 Phases of Short Course Chemotherapy

Intensive phase-

2 months

Continuation ex.

phase- 4 months

2HRZE4HR

Objectives of SCC
To achieve better bactericidal and sterilizing activities To prevent emergence of resistance

Short Course Chemotherapy Advantages

Easy to take Pt feels better quickly Sputum becomes (-) quickly Relapse rate lower If relapse occurs, TB remains sensitive Much cheaper than standard tx

Resistant Mutants
Small number which are naturally resistant More will occur in TB cavity If only one drug is given the sensitive TB are destroyed but the resistant ones multiply NEVER GIVE A SINGLE DRUG (MONOTHERAPY)

Classification of TB Cases
Pulmonary TB
Smear (+) Smear (-)

Extrapulmonary TB

Case Finding
At

least two (2) specimens from a qualityassured laboratory A case of pulmonary TB is already considered as smear (+) if one out of 2 specimens is positive for AFB. TB suspects with 2 negative smears on DSSM shall undergo other diagnostic tests; e.g.CXR, TB culture

Case finding
Specimens

for culture and DST should be obtained from ALL previously treated patients.
settings were rapid molecularbased DST is available, the result should guide the choice of the regimen

In

PTB-Smear Positive

At least 1 sputum specimen (+) for AFB +/- X-ray abnormalities consistent with active TB

PTB Smear Negative

At least 2 sputum specimens (-) for AFB

X-ray abnormalities consistent with active TB No response to a course of antibiotics and/or symptomatic medications Decision by a medical officer to treat with anti-TB drugs

Extrapulmonary TB

At least 1 mycobacterial smear/culture (+) from an extrapulmonary site (organs other than the lungs: pleura, lymph nodes, gut, skin, joints, bones, meninges, intestines, peritoneum, pericardium, etc)
Histological and/ or clinical evidence consistent with active TB & there is decision by a Medical Officer to treat pt with anti-TB drugs

Categories of TB Cases

New Previously Treated: Relapse Failure Return after default (RAD) Transferin Other

Types of TB Cases

New- pt who has never had tx for TB or who has taken anti-TB drugs for < 1month
Relapse - pt. previously treated for TB, has been declared cured or tx completed

Failure- pt while on tx is sputum smear ( + )

at 5 months or later during the course of tx

Types of TB Cases

Return after default A patient who returns to treatment with positive bacteriology (smear or culture), following interruption of treatment for 2 months or more
Transfer-in- pt who has been transferred from another facility with proper referral slip to continue

Types of TB Cases

Other 1. Pt starting treatment again after interrupting

treatment for >2 mos. and has remained smear (-) 2. Pt who was initially registered as new smear-negative case, turned out to be smear (+) during the tx. 3. Chronic case: pt who is sputum(+) at the end of a re-treatment regimen.

Treatment Regimens
Regimen Regimen I 2HRZE/4HR TB Patient
New

pulmonary smear (+)

cases New seriously ill pulmonary smear (-) cases with extensive parenchymal involvement

Treatment Regimens
Regimen TB Patient Regimen II: Failure cases 2HRZES/ Relapse cases 1HRZE/5HRE RAD (smear +) Other (smear +)

Treatment Regimens
Regimen TB Patient
New

Regimen III: 2HRZE/4HR

smear (-) but with minimal PTB on x-ray as confirmed by Medical Officer

Regimen IV:
Refer to specialized facility or DOTS Plus

Chronic

case: Still smear positive after supervised re-treatment

Treatment Regimens
For

New Cases BOTH adult and child: 2HRZE/4HR

Treatment Regimens

Previously Treated Cases:

refer

to Treatment Center /STC for further evaluation Standardized Regimen with 2nd line drugs Individualized treatment regimen depending on drug sensitivity result referred back for CAT II if pansusceptible 2HRZES/ 1HRZE/5HRE

Treatment Regimens
For

extrapulmonary TB (brain,bones,joints):
Treatment

is 9 12 months (2HRZE/710HR)

Sputum follow-up
New

(smear positive)

of 2nd end of 5th end of 6th

end

Previously
end

Treated patients

of 3rd end of 5th end of 8th

Treatment of TB in Special Situations

TB in pregnancy/lactation TB in pts with hepatic disease TB in pts with renal disease TB in the elderly TB in HIV/AIDS

Tuberculosis in Pregnancy
INH, & Rifampicin, PZA & Ethambutol can be used
Take pyridoxine (Vit B6) 25 mg/day since INH may cause demyelination Not recommended:
Streptomycin - Fetal ototoxicity Fluroquinolones - arthropathies
Consensus Statement ( Phil. Practice guidelines Group on Infectious Diseases)

TB treatment in Pregnancy
2HRZE/4HR Supplemental pyridoxine

Consensus Statement ( Phil. Practice guidelines Group on Infectious Diseases)

TB and Lactation
Breast feeding not discouraged Anti-TB drug concentration - low, non-toxic & non-therapeutic in breast milk

Consensus Statement ( Phil. Practice guidelines Group on Infectious Diseases)

TB treatment & Liver Disease

Hepatitis virus carriage or a past hx of acute hepatitis w/o clinical evidence of chronic liver disease Rx- Usual short course chemotherapy established chronic liver disease
2SHRE/6HR or 2HRE/6HE 2SHE/10 HE if extensive liver damage Do liver function tests before initiating tx

TB treatment & Liver Disease

Hepatic failure
Streptomycin & Ethambutol can be given. If a third drug is needed, Isoniazid or Rifampicin can be given cautiously in lowered doses

Acute Hepatitis defer until hepatitis resolved or

3SE/6HR

TB treatment & renal insufficiency/ renal failure

Isoniazid, Rifampicin & Pyrazinamide can be given in normal dosages
2HRZ/6HR Streptomycin & Ethambutol used with caution (increase dosing intervals); Dose halved if crea cl < 10mL/min Drugs given after HD to avoid drug filtration

Extrapulmonary TB
For

extrapulmonary TB (brain,bones,joints):
Treatment

is 9 12 months (2HRZE/710HR) TB Meningitis Adjunctive therapy with Corticosteroids in TB meningitis & pericarditis

Others
TB in the Elderly
2HRZE/4HR

TB in HIV +
2HRZE/4-7HR Include Rifampicin to hasten sputum conversion ARV should not be started at the same time as anti TB meds to prevent paradoxical reactions (immune reconstitution)

Symptom-based approach to adverse effects of TB drugs

Minor Side-effects 1. Gastrointestinal intolerance 2. Mild skin reactions
3. Orange/red Colored urine

Drugs responsible
Rifampicin

Management
Give meds at bedtime; or with meals Give antihistamine Reassure the patient

Any kind of drugs Rifampicin

Side effects 4. Pain at injection site

Drug(s) responsible Streptomycin

Management Warm compress; Rotate sites of injection Pyridoxine (Vit B6) 100-200 mg for tx; 10mg for prevention

5. Burning sensation of the feet

Isoniazid

Side effects

Drug(s) responsible

Management

6. Arthralgia

Pyrazinamide

Aspirin or NSAID Allopurinol

7. Flu-like symptoms (fever, inflammation of the resp. tract)

Rifampicin

Antipyretics

Major side effects

Drug(s) responsible

Management Discontinue Anti-TB drugs

1. Severe skin Any kind of rash due to drugs (esp hypersensitivity Strep)

2. Jaundice Any kind of due to hepatitis drugs (esp Isoniazid, Rifampicin & Pyrazinamide

D/C anti-TB drugs If sx subside, resume tx & monitor

Major side effects

Drug(s) responsible

Management Discontinue Ethambutol & refer to an opthalmologist

3. Impairment Ethambutol of visual acuity & color vision (optic neuritis)

4. Hearing impairment, tinnitus, vertigo

Streptomycin

Discontinue Streptomycin

Major side effects

Drug(s) responsible

Management

5. Oliguria or Streptomycin Discontinue albuminuria Ethambutol Strep, Ethambutol due to renal disorder

6. Psychosis Isoniazid & convulsion

7.Thrombocytopenia, anemia, shock Rifampicin

Discontinue Isoniazid
Discontinue Rifampicin

Drug interactions
Rifampicin

- potent inducer of the cytochrome P450 enzyme group; metabolism of oral contraceptives, corticosteroids, oral anticoagulants & cyclosporin. Quinolones - inhibit some cytochrome isoenzymes, leading to reduced metabolism of certain drugs.

Directly Observed Treatment (DOT)

All diagnosed TB patients should be offered patient-centered, DOT in health care facilities whenever possible, to monitor adherence & ensure completion of treatment
Self administered ( unsupervised) treatment is not recommended

Thank you for your attention!

2HRZZZZZ ZZZZZZ

Case 1: 27/M, call center agent

Cough for 3 wks, productive of whitish phlegm, low-grade afternoon fever, weight loss (120 lbs decreased to 110 lbs), rightsided chest pain on coughing

3 yrs ago - History of treatment for PTB (NonDOTS); unrecalled meds x 3 wks; lost to follow-up Sputum AFB negative for AFB 2x HbsAg (+); anti-HBs (+); LFTs normal, HIV (+)

Case 2: 18/F pregnant

24

weeks AOG, 52 kg productive cough & sputum AFB smear positive 1x no chest xray was available No previous treatment for PTB

Case 3: 62/M, vendor

Consulted for non-massive hemoptysis previously treated for TB (DOTS) 3 yrs ago, declared cured AFB (+) 1x Weight = 72 kg

Case 4: 37/M construction worker

asymptomatic

with incidental finding of fibro-hazy infiltrates on chest X-ray for pre-employment clearance; AFB (+) Treated for 2 mos. but stopped taking medications 2 mos. ago Heavy alcohol drinker; normal ALT, AST Weight= 75 kg

Case 5: 18/M asthmatic

Diagnosed

with PTB 3, smear positive Hx of blurring of vision after 1 month of treatment with HRZE, stopped meds Wt= 45 kg

Case 4: 52/F diabetic

Diagnosed

with PTB 3, smear positive, started tx 5 months ago Ongoing treatment with INH and Rif Repeat sputum smear (+) Weight = 56 kg Crea clearance = 9 ml/min