Gina S. de los Reyes, M.D., FPCP, FPCCP TB Treatment Regimen Gina S. de los Reyes, M.D., 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

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 dev’t of drug-resistant T.B (acquired resistance). 6. To protect his/her family and the community from infection.

Anti-TB drugs : Actions & Adverse Effects First line drugs Gastro’nal Cutaneous rxn Hepatitis Bactericidal Rifampicin Peripheral Neuropathy Isoniazid Adverse Effects Action Drug

Anti-TB drugs Ototoxicity Cutaneous Hypersen- sitivity Bactericidal Streptomycin Hepatotoxicity Arthralgia Pyrazinamide Retrobulbar neuritis Bacteriostatic Ethambutol

Second-line drugs Capreomycin Ethionamide Kanamycin Prothionamide Viomycin Amikacin Co-amoxiclav Clarithromycin Rifamycin derivatives- Rifabutin, Rifapentene Ethionamide Prothionamide Sodium para- aminosalicylate (PAS) Cycloserine Ofloxacin Ciprofloxacin

Drug Doses Dosage in mg/kg (range) Drug Daily Thrice/week Isoniazid 5 10 (4-6) (8-12) Rifampicin 8 10 (8-12) (8-12)

Drug Doses Pyrazinamide 25 35 (28-30) (30-40) Ethambutol 15 30 (28-30) (30-40) Ethambutol 15 30 (15-20) (25-35) Streptomycin 15 15 (12-18) (12-18)

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 FDC anti-TB combinations (1) The other key strategy is the use of fixed dose combinations or FDCs. FDC are formulations where 2 or more anti-TB drugs are present in fixed proportion in a single tablet. FDCs have been recommended by the WHO and the IUATLD as the preferred mode of TB treatment, to replace single drug preparations.

FDCs For the patient: simplified drug intake Fewer pills to swallow Pills are identical Correct regimen is followed FDCs (2) For the patient, the ritual of taking the pills is very much simplified For one, the patient, in most cases, will be taking a fewer numbers of pills, Second, all the pills are identical and therefore, there is no confusion what to take first Third, he is assured that he is taking the correct regimen. All in all, these factors should result in better adherence to the treatment.

FIXED DOSE COMBINATION: SIMPLER DOSE COMPUTATION Body Weight (kg) 4-FDC (HRZE) 37 to 54 3 tablets 55 to 70 4 tablets > 70 5 tablets FDC: simple dose computation Using FDC, the number of tablets to take is never more than 5, and only depends on the actual body weight. To make it even simpler, for most Filipinos, the magic number is 55 kgs. 55 kg or more requires 4 tablets while those less than 55 kgs take only 3 tablets. Practical dosing: < 55 kg: 3 tablets daily > 55 kg: 4 tablets daily

Short Course Chemotherapy 6 months regimen which includes Rifampicin and Pyrazinamide Standard Treatment- at least 12 months (w/o Rifampicin)

2 Phases of SCC Intensive phase- 2 months Continuation phase- 4 months

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

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

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) In any population of TB there will be a small number which are naturally resistant. More of them will occur among the millions of TB in any 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

PTB-Smear Positive +/- X-ray abnormalities consistent with active TB At least 2 sputum specimens (+) for AFB +/- X-ray abnormalities consistent with active TB 1 sputum specimen (+) for AFB and with X-ray abnormalities consistent with active TB with sputum culture (+) for M. tuberculosis Normal cxr but with dse-15-20% 18% firbocalcific has smear positive

PTB – Smear Negative At least 3 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 Acceptable to start tx based on cxr findings with a compatible clinical presn even if smear negative

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

Types of TB Cases New Relapse Failure Return after default (RAD) Transfer-in 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, and is diagnosed with ( + ) smear or culture for TB 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 Each standard drug is indicated by a capital letter. H- Isoniazid R- Rifampicin Z- Pyrazinamide E- Ethambutol S- Streptomycin

Treatment Regimens Regimen TB Patient Regimen I 2HRZE/4HRE New pulmonary smear (+ ) cases New seriously ill pulmonary smear (-) cases with extensive parenchymal involvement New severely ill extra- pulmonary TB cases

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

Treatment Regimens Regimen TB Patient Regimen III: 2HRZ/4HR New smear (-) but with minimal PTB on x-ray as confirmed by Medical Officer New extra-pulmonary TB (not serious) High resis if inh resis is > 4%; in phil-14.9% to 16.9% inh reis

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, Ethambutol & Rifampicin can be used Not recommended: Pyrazinamide, Streptomycin, Kanamycin, Capreomycin Strep hazardous throughout- ototoxixity and fetal malformation Consensus Statement ( Phil. Practice guidelines Group on Infectious Diseases)

TB treatment in Pregnancy Non-cavitary Disease -9HRE Cavitary Disease- 12HRE Treat if symptomatic; If resistant to HR, may use Z after 1st trim; inadeq data on teratogenicity TB prophy - <35 yo, N cxr, (+)ppd, asx-delay until 3-6months postpartum except ppd>15 and no prev tx, >10 with high prev, with cxr inactive ptb; >5 mm in immunocomp; HIV+, recent converters, close contacts >35, ppd<15 – no tx unless immunocomp or close contacts; H hepatitis higher esp >35yo 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 Supplemental pyridoxine to baby; if mother and baby both taking antiTB meds- do not breastfeed; 25MG/D VIT B6 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 2SHE/10 HE

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 Etham 5-23mkd; pza-12-20 mkd

Others TB in the Elderly TB in HIV + with susceptibility testing 9HR TB in HIV + with susceptibility testing 2HRZE/4-7HR w/o susceptibility testing Non-cavitary- 9HRZE Cavitary -12HRZE Tb in elderly- harbor few bacilli that are resistant

Symptom-based approach to adverse effects of TB drugs Reassure the patient Rifampicin 3. Orange/red Colored urine Give anti- histamine Any kind of drugs 2. Mild skin reactions Give medication at bedtime 1. Gastro- intestinal intolerance Management Drugs responsible Side-effects (Minor)

Pyridoxine (Vit B6) 100-200 mg for tx; 10mg for prevention Isoniazid 5. Burning sensation of the feet Warm compress; Rotate sites of injection Streptomycin 4. Pain at injection site Management Drug(s) responsible Side effects

Antipyretics Rifampicin 7. Flu-like symptoms (fever, inflammation of the resp. tract) Aspirin or NSAID Allopurinol Pyrazinamide 6. Arthralgia Management Drug(s) responsible Side effects

Discontinue Anti-TB drugs Any kind of drugs (esp Strep) 1. Severe skin rash due to hypersensitivity D/C anti-TB drugs If sx subside, resume tx and monitor Any kind of drugs (esp Isoniazid, Rifampicin and Pyrazinamide 2. Jaundice due to hepatitis Management Drug(s) responsible Major side effects

Discontinue Ethambutol & refer to an opthalmologist 3. Impairment of visual acuity & color vision (optic neuritis) Discontinue Streptomycin Streptomycin 4. Hearing impairment, tinnitus, vertigo Management Drug(s) responsible Major side effects

Major side effects Drug(s) responsible Management 5. Oliguria or albuminuria due to renal disorder Streptomycin Rifampicin Discontinue Strep, Rifampicin 6. Psychosis & convulsion Isoniazid Discontinue Isoniazid 7.Thrombo- cytopenia, anemia, shock Discontinue Rifampicin

Thank You for your kind attention!

2HRZE/4HR 2H3R3Z3E3/4H3R3

Challenge doses for detecting cutaneous or hypersensitivity to anti-TB drugs Day 1 Day 2 Challenge Doses Isoniazid 50mg 300mg Rifampicin 75mg 300mg Pyrazinamide 250mg 1.0g Ethambutol 100mg 500mg Streptomycin 125mg 500mg Drug