MDR-TB

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Journal club:

Dr.Shankar.J Post Graduate Dept of Pharmacology Journal club 1

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EDUCATIONAL FORUM PHARMACOTHERAPY FOR MULTIDRUG RESISTANT TUBERCULOSIS Journal of Pharmacology and Pharmacotherapeutics Year   : 2012  |   Volume  : 3  |   Issue  : 2  |   Page  : 98-104 2

INTRODUCTION (MDR-TB) :

INTRODUCTION (MDR-TB) DEFINITION : Resistance to isoniazid and rifampicin , with or without resistance to other anti-TB drugs. PREVALENCE : 1-3 % - new cases and 12 % - Retreatment cases . REASONS FOR DRUG RESISTANCE: Irregular , incomplete, and inadequate treatment. Poor compliance 3

Classification of ANTI-TB drugs:

Classification of ANTI-TB drugs 4

BIOLOGICAL AND MOLECULAR BASIS OF RESISTANCE:

BIOLOGICAL AND MOLECULAR BASIS OF RESISTANCE Genetic mutations If mutations causing resistance to isoniazid occur in about 1 in 10  8 replication of bacteria , the probability of spontaneous mutation causing resistance to both isoniazid and rifampicin would be 10  8  × 10  8  = 10 16  .  Acquired resistance 5

MECHANISM OF RESISTANCE:

MECHANISM OF RESISTANCE 6

METABOLISM AND ACTIVATION OF ISONIAZID:

METABOLISM AND ACTIVATION OF ISONIAZID 7

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TYPES OF MUTATIONS : CODON 531 of the rpoB  gene (rpoB531) - Rifampicin resistance . CODON 315 of the  katG  gene (katG315) - Isoniazid resistance . SIX CODONS: rpoB531 , rpoB526, rrs513, rpsL43, embB306, and katG315 are the main locations responsible for MDR-TB. 8

TREATMENT REGIMENS:

TREATMENT REGIMENS Should contain at least four drugs with certain effectiveness. MDR-TB suspects Failure of treatment of Category first or third Category second patient who remains smear positive at the end of fourth month treatment . Contacts of MDR-TB cases 9

Category IV Regimen (MDR-TB):

Category IV Regimen (MDR-TB) Intensive Phase (6-9months) Continuation phase (18months) 1.Kanamycin 2. Ofloxacin or Levofloxacin 3. Ethionamide 4. Pyrazinamide 5. Cycloserine 6. Ethambutol + Pyridoxine 100mg/day 1. Ofloxacin or Levofloxacin 2. Ethionamide 3. Cycloserine 4. Ethambutol BACTERICIDAL BACTERIOSTATIC PAS is included – Intolerance to Ofloxacin ( Ofx ) or Levofloxacin ( Lfx ); Kanamycin; Ethionamide ; Pyrazinamide 10

DURATION OF TREATMENT:

DURATION OF TREATMENT Two phases : Initial intensive phase - 6 months and Continuation phase (CP) - 18 months. After 6 months of treatment - Fourth Month Culture -VE +VE Continuation of IPfor 1 month 5 TH and 6 th month culture +VE Continuation of IP for 3more months Total Duration – 9months -VE Start Continuation Phase Irrespective of test results 11

GENERAL GUIDELINES TO TREAT MDR-TB:

GENERAL GUIDELINES TO TREAT MDR-TB At least four drugs with certain effectiveness . Do not use drugs for which there is a possibility of cross resistance. Use drugs from group 1 to 4 in hierarchical basis of their potency and Eliminate drugs with known allergy/high risk of severe adverse drug reactions. 12

MOA of ANTI-TB drugs:

MOA of ANTI-TB drugs 13

MOA OF OFLOXACIN:

MOA OF OFLOXACIN 14

MOA OF KANAMYCIN:

MOA OF KANAMYCIN 15

MOA OF ETHAMBUTOL:

MOA OF ETHAMBUTOL 16

MOA OF D-CYCLOSERINE:

MOA OF D-CYCLOSERINE 17

MOA OF ANTI-TB DRUGS:

MOA OF ANTI-TB DRUGS 18

PK of ANTI-TB Drugs:

PK of ANTI-TB Drugs 19

Formulations of ANTI-TB drugs:

Formulations of ANTI-TB drugs 20

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FORMULATIONS 21

Common ADRs of ANTI-TB drugs:

Common ADRs of ANTI-TB drugs 22

ROLE OF IMMUNOMODULATORS IN MDR-TB:

ROLE OF IMMUNOMODULATORS IN MDR-TB LEVAMISOLE   CYTOKINES/LEUKOTRIENES     MYCOBACTERIUM VACCAE  VACCINE      It works by redirecting host cellular response from a Th-2 dominant to a Th-1 dominant pathway. THALIDOMIDE: MOA – Inhibition of proinflamatory cytokines IL-12 (Interleukin-12) 23

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INTERLEUKIN-2:     Stimulates expansion and enhanced functional capacity of natural killer cells, which can eliminate intracellular M. TB IMMUNOGLOBULINS-IGG Polyclonal Monoclonal Donor lymphocyte infusion Synergic bone marrow transplant 24

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USES OF IMMUNOMODULATORS Preventing infections to proceed to the disease state; Preventing the occurrence of secondary infections; Early control of infections in conjunction with specific chemotherapy Achieve early clinical response in terms of weight gain and reduction in toxemia . Aerosolized IFN- γ : two million international units inhalation therapy; three times a week for 6 months plus Class I anti- tuberculous chemotherapy.  25

New alternative therapies for MDR TB :

New alternative therapies for MDR TB  Β- lactam antibiotics and β:- lactamase inhibitors.  LINEZOLID ( Lzd )  PHENOTHIAZINES:  Thioridazine , chlorpromazine; NITRIC OXIDE DONORS: DETA-NO  PLANT EXTRACTS: Hexane extract from Lantana hispida .  26

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SNAKE VENOM: Small peptide vgf-1 from Naja-atra , a snake isolated from the Yunnan province of China .  AZOLES: Having Cyp-450 inhibiting activity.  TUBERACTINOMYCIN: It acts by inhibiting protein synthesis  RIMINOPHENAZINES: b 746, b 4157, and CLOFAZIMINE ( Cfz ): Cfz Substituted iminophenazine bright-red dye MOA - Inhibition of transcription of mycobacterial DNA 27

MONITORING THE MDR-TB:

MONITORING THE MDR-TB Monthly Sputum smear and culture should until smear and culture conversion. (*Conversion is defined as two consecutive negative smear and culture taken 30 days apart.) After conversion (Bacteriological monitoring) - Monthly - Smears and Quarterly - Cultures. Weight monitoring - monthly. Monitoring and management of adverse effects caused by second-line drugs. 28

MANAGEMENT OF ADVERSE REACTIONS :

MANAGEMENT OF ADVERSE REACTIONS  Liver disease Causative drugs - Isoniazid , Pyrazinamide and Ethionamide . Weekly LFT - Icterus is present – ATT will be withheld; Normal - treatment will be resumed .. 29

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Arthralgia Causative drugs - Pyrazinamide or Quinolones . Management – Paracetamol or aspirin ; If no improvement then either reduce the doses of offending drugs or withhold temporarily. Monitoring – Serum uric acid level 30

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Hypersensitivity reactions Antihistaminics Severe reactions - Offending drug identified by challenge/ dechallange tests. Generalized erythematous rash associated with fever - then withhold all drugs immediately. Hypothyroidism Causative agents - PAS and ethionamide alone or both combination on prolong duration Monitoring – Thyroid function Hypothyroidism responds to thyroxine . 31

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GIT DISTURBANCES Causative drugs - Ethionamide ,  para -amino salicylic acid, PZA, and ethambutol . Monitoring - Serum bilirubin and Serum aminotransferases levels (AST, ALT) Advise the patients to take drugs embedded in banana . Vomiting – Domperidone or proton pump inhibitor is given 1 h before administration of drugs. If severe vomiting - Drugs can be withheld temporarily. 32

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SEIZURES Offending drugs : Cycloserine , Pyrazinamide, Fluoroquinolones . Temporary withdrawal of the suspected agent Anticonvulsant therapy (e.g ., phenytoin, valproic acid ). Pyridoxine is increased to maximum daily dose (200 mg/day). PSYCHOTIC SYMPTOMS Offending drugs are: Ethionamide / prothionamide , Cycloserine , Isoniazid, and fluoroquinolones . Stop suspected agent for a short-period of time. 33

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PERIPHERAL NEUROPATHY Offending drugs are: Cycloserine , INH, Streptomycin, Kanamycin, Amikacin , Clarithromycin, Viomycin , and Fluoroquinolones . Dose of pyridoxine - increased to 200 mg per day Injectable should be changed to capreomycin . TADs - Amitriptyline and NSAIDs Reduce the dose of the suspected agent. 34

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Management of MDR-TB in pregnancy Started in second/third trimester unless life threatening. Aim - Achieve sputum conversion before delivery . Injectable agents are also avoided, capreomycin is used if it is necessary to administer injectable agent. Teratogenic - Eto , Cycloserine : Limited data Breast feeding   Breast feeding - Sputum microscopy is negative . Chemotherapy - Prevent transmission of tubercle bacilli to baby. Recommendation - Infant formula options. 35

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Diabetes mellitus Potentiate the adverse effects of drugs, renal dysfunction, and peripheral neuropathy. Eto or protionamide - more difficult to control insulin levels . HIV/MDR TB/Drug interactions Nonenteric -coated didanosine contains an aluminum/magnesium-based antacid . Decreased absorption of fluoroquinolone . It should therefore be given 6 h before or 2 h after fluoroquinolone administration . 36

RESISTANCE TO ANTI-TB DRUGS AND TREATMENT:

RESISTANCE TO ANTI-TB DRUGS AND TREATMENT 37

NEWER DRUGS:

NEWER DRUGS 38

CONCLUSION:

CONCLUSION Optimization of treatment regimens along with rapid diagnosis and DST for first- and second-line drugs, greatly improved the clinical outcome. Recent advances in diagnosis of MDR-TB and empirical treatment of patients with several drugs in the initial phase of treatment have further improved the prognosis of MDR-TB. This review has summarized the drugs used to treat MDR-TB, common adverse drug reactions occurring during MDR-TB treatment and their management and has highlighted the importance of preventing the development and dissemination of this man-made disease. 39

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