5Mycobacterium tuberculosis complex: Rod shaped, non- pore-forming, thin aerobic bacterium.Important agent for human disease.M. bovisImportant cause of tuberculosis for transmitted by unpasteurised milk.M . africanumWest, central & east africa.M .microtiLess virulent, rarely encountered organism.
6As many as 3000 infectious nuclei per cough. M.tuberculosis transmitted from patient with infectious pulmonary Tb to other personsBy droplet nuclei,Aerosolised by coughing, sneezing orspeaking.As many as 3000 infectious nuclei per cough.
7Tiny droplets dry rapidly. Smallest droplets (<10 um in diameter) Suspended in the air for several hours ,May gain direct access to the terminal air passages when inhaled.
8Risk factors for acquiring infection with M.Tuberculosis: Probability of contact with the case of Tb.Intimacy and duration of that contact.Degree of infectiousness of the case.Shared environment of the contact.
9Risk factor for developing disease after being infected : Individuals innate susceptibility to disease.Level of function of cell mediated immunity.
11Primary TuberculosisResults from initial infection with tubercle bacilli.Children up to 4 yrs of age.Middle, lower lung zone affected mainly.Rapid progression to illness in HIV patients.
12Obstruction & subsequent segmental collapse: Obstructive emphysema: Pleural effusion:due to penetration of bacilli into pleural space from subsequent subpleural area.Lymphadenopathy:due to spread of bacilli from lung parenchyma through lymphatic vessel.Obstruction & subsequent segmental collapse:as enlarged lymph node compress bronchi.Obstructive emphysema:due to partial obstruction.Granulomatous lesions:seen in severe cases as bacilli reach blood stream from pulmonary lesion/lymph nodes
13Secondary Tuberculosis Adult type.Dormant bacilli, may persist for years before reactivating to produce Secondary Tuberculosis- often infectious.Localised to the apical & posterior segments of the upper lobes , where high oxygen concentration favours mycobacterial growth.
14Early symptoms: fever, night sweats, weight loss, malaise, weakness. Secondary Tb.....Early symptoms: fever, night sweats, weight loss, malaise, weakness.Development of Cough : non productive initially, production of purulent sputum.
15Diagnosis of Tuberculosis AFB (Acid Fast Bacilli) microscopyPresumptive diagnosis.Mycobacterial cultureDefinitive diagnosisNucleic acid amplificationUse limited due to low sensitivity.Drug susceptibility testingTo find out drug resistance.Radiographic procedureBased on abnormal chest radiographic findingsTuberculin skin testingLack of mycobacterial specificity limits useCytokine release assayDiagnosis of latent tuberculosis infection.
16Treatment Aim of treating Tuberculosis: To interrupt tuberculosis transmission by rendering patients non-infectious.To prevent morbidity & mortality by curing patients with tuberculosis disease.
17Antitubercular drugs First line drugs : High efficacy & low toxicity. Isoniazid 5mg / kg /d , max of 300 mg / dRifampin 10 mg/kg/d, max of 600 mg / dPyrazinamide mg/kg/d, max of 2g / dEthambutol mg / kg / dStreptomycin 15 mg / kg / d
18Second line agents Either low efficacy or high toxicity or both Slide 76 DrugsDosesAmikacin15 mg/kg/dAminosalicylic acid8-12 g/dCapreomycinCiprofloxacin1500 mg/kg/dClofazimine200 mg/dCycloserinemg/dEthionamidemg/dLevofloxacin500 mg/dRifabutin300 mg/dRifapentine600 mg o.d weekly
19IsoniazidBacteriostatic for resting bacilli but bactericidal for rapidly dividing micro- organisms.Minimal effective conc.: ug/ml.Peak plasma conc. : 1-2 hrs.Good oral & parenteral absorption.
20Metabolismvia acetylation (acetylisoniazid) & via hydrolysis (isonicotinic acid).
21N-acetyltransferase type 2 (NAT 2) Fast acetylatorsSlow acetylatorst½ of INH =1hrt½ of INH =2-5 hrsHepatic insufficiencyIn case of renal impairment, may accumulate to toxic concentration.Dosage reduction recommended
24Resistance Mutation in catalase peroxidase Decreases its activityPrevent conversion of prodrug to active metabolite.Mutation in inh A gene involved in mycolic acid biosynthesis.Resulting in over expression of inh A.
25Tuberculous cavity contains 109 micro- organism. 1 in 106 bacilli genetically resistant to INH.So, resistant mutants selected out in INHmonotherapy.
31Hematological reaction: Agranulocytosis, eosinophilia, thrombocytopenia.Sideroblastic anemia (presence of ring sideroblasts in the bone marrow)Reversible .INH deprives ALAS2 (delta-aminolaevulinic acid synthase 2) of pyridoxal phosphate therefore inhibits haem synthesis.Overcome by concomitant administration of pyridoxine(25 to 50 mg/d).
33Hypersensitivity reaction: Fever, rashes, hepatitis , SLE.INH overdose:Tonic - clonic seizure, metabolic acidosis, coma in pregnant women.Pyridoxine – specific antidote.
34Pyridoxine – a necessary co-factor for production of neurotransmitter GABA. In isoniazid overdose, the susceptibility to seizures is induced by isoniazid binding to endogenous pyridoxine, make it inactive and resulting in a depletion of GABA in the brain.Therefore, the administration of exogenous pyridoxine directly counteracts this neurotoxic effect.
35Increase in the generation of lactic acid as a result of muscular activity and recurrent seizures. Generation of acidic INH metabolites.Increase in ketoacids due to enhanced fatty acid oxidation.
37Management : GI decontamination with gastric lavage, Stabilization of vital signs with provision of patent airway and IV sodium bicarbonate,Cardiovascular support with IV fluids and vasopressors.IV pyridoxine – highly effective for INH intoxication and should be administered to all symptomatic patients.
38Uses of INHLatent TbRecent converters: who test positive within 2 years after a documented negative skin test.Immunocompromised patients.Prevention, in close contacts of active cases of pulmonary Tb.
42Mechanism of action: Bactericidal at 3-12 ng/ml for both intracellular & extracellular microorganisms. Kills organisms at poorly accessible sites like abscess, lung cavities.
43Binds to β subunit of bacterial DNA dependent RNA polymerase Binds to β subunit of bacterial DNA dependent RNA polymerase. Suppression of initiation of chain formation but no chain elongation in RNA synthesis. Inhibit RNA synthesis in mammalian mitochondria, viral DNA dependent RNA Polymerase, reverse transcriptase at high concentration.
44Mechanism of resistance Mutation between codons 507 & 533 of polymerase rpo B gene “for β subunit of RNA polymerase.Prevent binding of rifampin to RNA polymerase.Alterations in the target of drug:DNA dependent RNA polymerase.
45Adverse effectsHepatitis from rifampin rarely occurs in patients with normal hepatic function. Chronic liver disease, alcoholism, and old age increase the risk of severe hepatitis when rifampin is given alone or concurrently with isoniazid. < 5% of patients, serum level of aminotransferase, phosphatase, bilirubin increase slightly, but diminish spontaneously despite continuation of treatment.
46Rifampin may potentiate toxic effect of INH, particularly in patients in whom INH is rapidly inactivated. Rifampin induces microsomal enzyme. Facilitate conversion of monoacetylhydrazine, a metabolite of acetylated INH into an acylating agent that could cause hepatic necrosis.
47Light chain proteinuria Light chain proteinuria. Imparts a harmless orange colour to urine, sweat, tears, and contact lenses (soft lenses may be permanently stained)
48GI disturbances – (epigastric distress, nausea, vomiting, abdominal cramps, diarrhea) occasionally required drug discontinuation. Thrombocytopenia, transient leukopenia, and anaemia have occurred during therapy.
49Rifampin × Anticoagulants EFFECT :Decreased anticoagulant effect.MECHANISM:Rifampin induces CYP2C9, CYP2C19, CYP2D6Increases elimination of other drug.MONITORING:Carefully monitor coagulation parameter.Adjust anticoagulant dose.
50EthambutolInhibit mycobacterial arabinosyl transferases, which is involved in polymerization reaction of arabinoglycan …….essential component of mycobacterial cell wall.
51Adv. :Retrobulbar neuritis causing loss of visual acuity and red-green colour blindness. (Serious).Not recommended for children under 5 years of age because of concern about the ability to test their visual acuity.
53Hepatotoxicity (in 1–5% of patients), nausea, vomiting, drug fever, and hyperuricemia. Hyperuricemia may provoke acute gouty arthritis.
54Streptomycin Binds with S12 ribosomal protein. Interfere with initiation of peptide formation.Misreading of mRNA.Breakup of polysomes into nonfunctional monosomes.Irreversible inhibition of mycobacterial protein synthesis.
55Ototoxic and nephrotoxic.(8th cranial nerve involves). Vertigo and hearing loss -most common.may be permanent.
56EthionamideInhibits mycobacterial growth by inhibiting the activity of the enoyl-ACP reductase of fatty acid synthase II. Thus inhibit mycolic acid biosynthesis with consequent impairment of cell-wall synthesis.
57Neurologic symptoms – depression, drowsiness, and asthenia Neurologic symptoms – depression, drowsiness, and asthenia. olfactory disturbances, blurred vision, diplopia, dizziness, paresthesias, headache, restlessness, and tremors. Pyridoxine relieves.
58ChemoprophylaxisTo prevent development of active TB in patients who are at risk.Tuberculin skin testȳ interferon testMantoux testT-Spot.TbHeaf testQuantiFeron Tb GoldTine test
59Indications for chemoprophylaxis: New born of a mother with active TB.Young children (<6 yrs.) with positive TB.Household contacts of patients with TB.Patients with positive tuberculin test with additional risk factors such as diabetes mellitus, malignancy, AIDS.
60Isoniazid prophylaxis, continued for 12 months Isoniazid prophylaxis, continued for 12 months. Pyridoxine co-administered.HIV infected, exposed to MDRTb –rifampin + pyrazinamide (with close monitoring for hepatic toxicity) or high-dose ethambutol +pyrazinamide, with or without a fluoroquinolone.
62Known to exposed to drug resistant organisms. Recent immigrants.Pts with extrapulmonary TB.Pts with meningitis.HIV pts.
63Continued for atleast 6 months after three negative cultures obtained.
64MDTObjectives:To make patient non-infectious as early as possible by rapidly killing the dividing bacilli by using 3 to 4 bactericidal drugs.To prevent the development of drug-resistant bacilli.To prevent relapse by killing the persisters (dormant bacilli).To reduce the total duration of effective therapy.
65Recommended by WHO. Choice of treatment regimen based on: Their efficacy, effectiveness, availability of financial recourses.
66Long course regimens: INH alone with one or two bacteriostatic drugs for 18 months. Poor patient compliance, high failure rate.
67Short course regimen: 6-9 months duration. Highly effective. Less toxic.
68Intensive phase: tuberculocidal drugs daily or thrice weekly for a period of 2-3 months. - To render the patient non-contagious. INH 300mg + Rifampicin 600 mg + Pyrazinamide 1500 mg + Ethambutol 1000 mg/Streptomycin 1000 mg + Pyridoxine 10 mg daily for 2 months.
69Continuous phase: drugs usually INH & Rifampicin daily or thrice weekly for a period of 4-6 months. - Helps to eliminate persisters & prevents relapse. - INH 300mg +Pyridoxine 10 mg + Rifampicin 600 mg daily for 4 months.
71RNTCP: Revised National Tuberculosis Control Programme, launched in 1997 DOTS: Directly observed treatment short course.
72Patient is administered drugs under the supervision of a health worker to ensure that drugs are actually consumed. Supervised and monitored by bacteriological examinations. Aimed at ensuring patient compliance thus preventing the emergence of drug resistant tuberculosis.
77Sustained political and administrative commitment Recording and reporting systemUninterrupted supply of quality assured anti-TB drugsAppropriate treatment strategiesDiagnosis of MDR-TB through culture and drug susceptibility testing.Sustained political and administrative commitment
78Sustained political and administrative commitment A well functioning DOTS programme.Long term investment of staff and resources.Coordination efforts between community, local governments, and international agencies.Addressing the factors leading to the emergence of MDR-TB
79Diagnosis of MDR-TB through quality- assured culture and drug susceptibility testing. Proper triage of patients for Culture & testing and management under DOTS-Plus.Co-ordination with National and Supra-National Reference Laboratories
80Appropriate treatment strategies that utilize second-line drugs under proper management conditions Rational standardized treatment design (evidence- based)Directly observed therapy (DOT) ensuring long-term adherence.Monitoring and management of adverse drug reactions.Adequate human resources.
81TB treatment in HIV patients: Rifabutin preferred over rifampicin in HIV patients on antiretroviral drugs as it doesn’t interact with PI’s.
83Tuberculosis is a relative CI for use of glucocorticoids.
84TB of serum membrane like pleura, peritonium, pericardium, meninges, to prevent fibrous tissue formation.To treat hypersensitivity reactions to antiTB drugs.Tuberculosis of eye, larynx, genitourinary tract to prevent fibrosis & scar tissue formation.Once patients general condition improves, steroid is tapered to avoid HPA axis suppression.