Journal club: Dr.Shankar.J Post Graduate Dept of Pharmacology Journal club 1
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 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
PowerPoint Presentation: 40