Abstract image of a woman sitting on books and studying on a laptop

Non resistant tuberculosis

Download as PPTX, PDF
Dr. Bushra Hasan Khan, profile picture
Dr. Bushra Hasan Khan

This document provides information on pulmonary tuberculosis (TB), including its etiology, diagnosis, treatment and management. Some key points: - TB is caused by the bacterium Mycobacterium tuberculosis and is a global health problem, infecting millions of people annually and causing over a million deaths in 2013. - Diagnosis involves considering symptoms, physical exam, radiology and sputum microscopy. Treatment involves a standard multi-drug regimen administered over 6-9 months and aims to cure the patient and prevent transmission. - India has a high burden of TB cases, with over 2 million estimated in 2012. The Revised National TB Control Programme (RNTCP) implements the WHO-recommended DOTS strategy to improve

1 of 107
Downloaded 67 times
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
Most read
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
105
106
107
PULMONARY TUBERCULOSIS Dr. Bushra Hasan Khan Department of Pharmacology JNMC, AMU, Aligarh.
• Tuberculosis is a global pandemic • TB is second leading cause of death from a single infectious agent, after HIV. • INCIDENCE : 9 million new cases in 2013 • MORTALITY : A total of 1.5 million people died from TB in 2013 (including 360 000 people with HIV) • TB is a leading killer of HIV-positive people causing one fourth of all HIV-related deaths.
• 480 000 people developed MDR-TB in 2013. • In 2012, out of the estimated global annual incidence of 8.6 million TB cases, 2.3 million were estimated to have occurred in India. • The TB mortality rate has decreased 45% since 1990. • About 37 million lives were saved worldwide between 2000 and 2013 through TB diagnosis and treatment
• The world is on track to achieve the global TB target set for 2015 in the Millennium Development Goals • The target for TB in the MDGs is to halt and reverse global incidence. • 86% of people who developed TB and were put on treatment in 2012 were successfully treated. (http://www.tbcindia.nic.in/rntcp.html)
ETIOLOGY • TB is caused by Mycobacterium tuberculosis, a slow-growing obligate aerobe and a facultative intracellular parasite. • Non-spore-forming, rod-shaped, 0.5μm × 3μm • Neutral on Gram's staining • The organism grows in parallel groups called cords  in which acid-fast bacilli are arranged in parallel chains . • Cord formation is correlated with virulence.
• Mycobacteria are rich in lipids – Mycolic acid  prevent attack of cationic proteins, lysozyme, and oxygen radicals in the phagocytic granule – Waxes – Phosphatides • Lipids are bound to proteins and polysaccharides. • Muramyl dipeptide + mycolic acids  granuloma formation; phospholipids  caseous necrosis.
• Once stained, the bacilli cannot be decolorized by acid alcohol  acid-fast bacilli (AFB) • Acid fastness is due mainly to the organisms' – High content of mycolic acids, – Long-chain cross-linked fatty acids， – Other cell-wall lipids.
• Mycolic acids + Arabinogalactan and Peptidoglycan  results in very low permeability of the cell wall  effectiveness of most antibiotics is reduced. • Lipoarabinomannan  involved in the pathogen-host interaction  facilitates the survival of M. tuberculosis within macrophages.
PHARMACOLOGICAL BARRIER:  Cell wall Mainly contains Lipids (Mycolic acid)  Efflux pumps pump out harmful chemicals  Propensity to hide inside the host cells
CLINICAL FEATURES • Fever • Weight loss / anorexia • Cough • Hemoptysis • Chest pain • Night sweats • Fatigue
DIAGNOSIS • History • Physical examination • Radiology • Sputum microscopy
NATURAL HISTORY & SPECTRUM OF DISEASE
AIMS OF TREATMENT • To cure the patient ; restore quality of life & productivity • To prevent death from active TB or its late effects • To prevent relapse of TB • To reduce transmission of TB to others • To prevent the development & transmission of drug resistance
RNTCP • RNTCP ( Revised National Tuberculosis Control Programme) is an application of WHO recommended strategy of DOTS in India. • Objectives: 1- Detecting at least 70% of sputum positive TB patients in the community. 2- Curing at least 85% of the newly detected sputum positive cases.
Five components of DOTS: 1. Political commitment with increased & sustained financing 2. Case detection through quality-assured bacteriology 3. Standardized treatment with supervision & patient support 4. Regular, uninterrupted supply of Anti-TB drugs 5. Monitoring & evaluation system & impact measurement
Stop TB Strategy (WHO, 2006) 1. Pursue high-quality DOTS expansion & enhancement 2. Address TB-HIV, MDR-TB, & the needs of poor & vulnerable populations 3. Contribute to health system strengthening based on primary health care 4. Engage all health care providers 5. Empower people with TB, & communities through partnership 6. Enable & promote research
• Based on the nature/severity of the disease & the patient's exposure to previous ATTs, RNTCP classifies TB patients into 2 t/t categories  – NEW – PREVIOUSLY TREATED
NEW PATIENT CATEGORY • New sputum smear-positive, • New sputum smear-negative, • New extrapulmonary tuberculosis,
PREVIOUSLY TREATED • Sputum smear-positive relapse, • Sputum smear-positive failure, • Sputum smear-positive treatment after default, • Others (patients who are Sputum Smear-Negative or who have Extra-pulmonary disease who can have recurrence)
RECOMMENDED DOSES OF FIRST-LINE ANTITUBERCULOSIS DRUGS FOR ADULTS
DRUGS AND THEIR TARGET SITES
STANDARD REGIMENS FOR NEW TB PATIENTS DOSING FREQUENCY
SETTINGS WITH HIGH LEVELS OF ISONIAZID RESISTANCE IN NEW PATIENTS
SPUTUM MONITORING BY SMEAR MICROSCOPY IN NEW PULMONARY TB PATIENTS
STANDARD REGIMENS FOR PREVIOUSLY TREATED PATIENTS
SPUTUM MONITORING OF PULMONARY TB PATIENTS RECEIVING THE 8-MONTH RETREATMENT REGIMEN WITH FIRST-LINE DRUGS
A POSITIVE SPUTUM SMEAR AT THE END OF THE INTENSIVE PHASE  • Poorly supervised initial phase of t/t & poor patient adherence • Poor quality of anti-TB drugs • Doses of anti-TB drugs  below the recommended range • Slow resolution  extensive cavitation & a heavy initial bacillary load • Co-morbid conditions • MDR-TB that is not responding to first-line treatment • Non-viable bacteria remain visible by microscopy
COHORT ANALYSIS OF TREATMENT OUTCOMES • COHORT  a group of patients diagnosed & registered for t/t during one-quarter of a year • Evaluation of t/t outcome in new pulmonary smear-positive patients  major indicator of programme quality. • Outcomes in other patients (retreatment, pulmonary smear-negative, extrapulmonary) are analysed in separate cohorts.
• Outcomes are routinely evaluated at the beginning of the quarter following the completion of treatment by the last patient in that cohort.
TREATMENT OUTCOMES • CURED • TREATMENT COMPLETED • TREATMENT FAILURE • DIED • DEFAULT • TRANSFER OUT • TREATMENT SUCCESS
Non resistant tuberculosis
MANAGEMENT OF TREATMENT INTERRUPTION • If a patient misses an arranged appointment to receive treatment  the NTP should ensure that the patient is contacted within a day after missing treatment during the initial phase, & within a week during the continuation phase. • Culture and DST should be performed upon return of patients who meet the definition for default
MAJOR ADVERSE EFFECTS OF ATT • The most common ADR is Hepatitis. • Cutaneous reactions • Shock, purpura • Visual impairment • Deafness, dizziness • Acute renal failure
SYMPTOM-BASED APPROACH TO MANAGING SIDE-EFFECTS OF ANTI-TB DRUGS (continued…….)
(continued…….)
Non resistant tuberculosis
IMPORTANT DRUG INTERACTIONS • Rifampicin reduces the conc. & effect of the following drugs  o Anti-infectives (antiretroviral drugs, mefloquine, azole antifungal agents, erythromycin, doxycycline); o Hormone therapy, including ethinylestradiol, norethindrone, tamoxifen, levothyroxine; o CVS drugs including digoxin, digitoxin, verapamil, nifedipine, diltiazem, propranolol, metoprorol, enalapril, losartan; (continued…….)
o Anticonvulsants (including phenytoin); o Haloperidol, quetiapine, benzodiazepines (including diazepam, triazolam), zolpidem, buspirone; o Warfarin; o Cyclosporin; o Corticosteroids; o Theophylline; o Sulfonylurea hypoglycaemics; o Hypolipidaemics including simvastatin and fluvastatin;
T/T REGIMENS IN SPECIAL SITUATIONS • Pregnancy & Lactation • Liver disorders • Renal failure
PREGNANCY AND BREASTFEEDING • Streptomycin  ototoxic to the fetus ; must not be used • Lactation is not a C/I to ATT • After active TB in the baby is ruled out, the baby should be given 6 months of Isoniazid preventive therapy, followed by BCG vaccination • Pyridoxine supplementation is recommended for all pregnant or breastfeeding women taking Isoniazid
LIVER DISORDERS • Patients with the following conditions can receive the usual TB regimens provided that there is no clinical evidence of chronic liver disease: Hepatitis virus carriage, A past history of acute hepatitis, Current excessive alcohol consumption • Hepatotoxic reactions to anti-TB drugs  more common among these patients & should therefore be anticipated
• In patients with unstable or advanced liver disease, LFTs should be done at the start of treatment, if possible. • The more unstable or severe the liver disease is, the fewer hepatotoxic drugs should be used. • If the serum ALT level is more than 3 times normal before the initiation of treatment, the following regimens should be considered. (continued…….)
POSSIBLE REGIMENS INCLUDE: • Two hepatotoxic drugs  9 months of Isoniazid and Rifampicin, plus Ethambutol (until or unless Isoniazid susceptibility is documented);  2 months of Isoniazid, Rifampicin, Streptomycin & Ethambutol, followed by 6 months of Isoniazid & Rifampicin;  6–9 months of Rifampicin, Pyrazinamide and Ethambutol.
• One hepatotoxic drug:  2 months of Isoniazid, Ethambutol & Streptomycin, followed by 10 months of Isoniazid & Ethambutol. • No hepatotoxic drugs:  18–24 months of Streptomycin, Ethambutol & a Fluoroquinolone.
RENAL FAILURE • The recommended initial TB t/t regimen : – 2 months of Isoniazid, Rifampicin, Pyrazinamide & Ethambutol, followed by 4 months of Isoniazid & Rifampicin. • There is significant renal excretion of Ethambutol and metabolites of Pyrazinamide, & doses should therefore be adjusted.
• Three times/week administration of Pyrazinamide (25 mg/kg), & Ethambutol (15 mg/kg) is recommended • While receiving Isoniazid, patients with severe renal insufficiency or failure should also be given Pyridoxine in order to prevent peripheral neuropathy.
• Because of an increased risk of nephrotoxicity & ototoxicity, Streptomycin should be avoided in patients with renal failure. • If Streptomycin must be used, the dosage is 15 mg/kg, two or three times/week, to a maximum of 1 gram per dose, & serum levels of the drug should be monitored.
Non resistant tuberculosis
• MAIN FIRST LINE ANTITUBERCULAR DRUGS – ISONIAZID – RIFAMPICIN – ETHAMBUTOL – PYRAZINAMIDE • OTHER FIRST LINE ANTITUBERCULAR DRUGS – RIFABUTIN – RIFAPENTINE – STREPTOMYCIN
SECOND-LlNE ANTI-TB DRUGS • Fluoroquinolones – Levofloxacin – Moxifloxacin – Gatifloxacin • Injectable Agents – Capreomycin – Amikacin – Kanamycin • Others – Cyclosrine – PAS – Ethionamide – clofazimine
NEWER ANTl-TB DRUGS • Oxazolidinones  Linezolid • Amoxicillin-Clavulanate • Carbapenems • Diarylquinolines  Bedaquiline • Nitroimidazoles  Delamanid • Diamines  SQ109 (an Ethambutol analogue) • Pyrroles  LL3858
DRUGS AND THEIR TARGET SITES
ISONIAZID • MOA  Mycolic acid synthesis inhibitor
 Nicotinoyl-NAD adduct→ inhibits the activities of enoyl-ACP reductase (inhA) & β-ketoacyl acyl carrier protein synthase (KasA)→ interfere with mycolic acid synthesis.  Nicotinoyl-NADP adduct→ inhibit mycobacterial dihydrofolate reductase (DHFRase)→ interfere with nucleic acid synthesis.
MECHANISM OF RESISTANCE: • Mutation or deletion of katG gene (MC). • Mutation in kasA gene. • Over-expression of the inhA & aphC gene (detoxify organic peroxide) PHARMACOKINETICS: • Oral BA ~ 100%. • Only ~10% is protein bound. • Metabolised in liver by Arylamine N-acetyltransferase2 (NAT2). • Excreted in urine as Acetylisoniazid & Isonicotinic acid.
DOSE: • 5mg/kg (4-6 mg/kg) daily, maximum 300 mg • 10 mg/kg (8-12 mg/kg) three times/week; maximum 900 mg • Oral / im / iv ADRs: • Peripheral neuritis : INH binds with Pyridoxal 5-phosphate → decreased neuronal Pyridoxal 5-phosphate • Liver damage : Acetylisoniazid→ Acetylhydralazine  Liver damage • Others : Optic neuritis, Convulsions, Hypersensitivity reactions
DRUG INTERACTIONS: • Al(OH)3 inhibit INH absorption. • With Acetaminophen → Hepatotoxicity • With Carbamazepine, Diazepam, Ethosuximide  Neurological & Psychiatric toxicities by inhibiting CYP3A • With Isoflurane, Enflurane  decrease their effectiveness by inducing CYPE1
RIFAMYCINS MECHANISM OF ACTION: Binds with β-subunit of DNA-dependent RNA Polymerase (rpoB) ↓ Inhibit RNA synthesis MECHANISM OF RESISTANCE: Mutation at codons 526 & 531 site of rpoB gene. PHARMACOKINETICS: • Absorption is variable [Oral bioavailability Rifampicin (68%) & Rifabutin (20%)] • Food- ↓Rifampicin absorbtion but no effect on Rifabutin • High fat diet- ↑Rifapentin absorption
• Half life of Rifampicin→2-5hrs Rifabutin →32-67hrs Rifapentine →14-18hrs • Metabolized by microsomal β-esterases & cholinesterases mainly (deacetylation). • Excretion is mainly through bile. DOSE: • Rifampicin- 10 mg/kg (8-12 mg/kg) daily or 3 times weekly ; 1hr before or 2hrs after meal ; oral or iv • Rifabutin- 5mg/kg/day • Rifapentine- 10mg/kg/week
ADRs: • Rashes, G.I intolerance, Liver damage, Hemolysis, Neutropenia . • Rifampicin  flu-like syndrome → higher dose, schedule ; twice weekly • Rifabutin  Uveitis; arthralgia; polymylgia; orange discoloration of skin, urine, feces, saliva & tears. INTERACTIONS: • Enzyme inducers  Rifampicin> Rifapentin>Rifabutin
PYRAZINAMIDE • Is synthetic pyrazine analog of Nicotinamide. MOA: Pyrazinamide ↓ Passive diffusion Enter M.tuberculosis Deamination ↓ Nicotinamidase/Pyrazinamidase Pyrazinoic acid (POAˉ) Transported to extracellular environment ↓ Protonation HPOA
• HPOA → Inhibit fatty acid synthase-1→ interfere with mycolic acid synthesis. → disruption of membrane transport MECHANISM OF RESISTANCE: • Point mutation in pncA gene (encodes Pyrazinamidase). PHARMACOKINETICS: • Oral bioavailability >90%. • Highly concentrated in lung lining fluid. • T1/2 variable depends upon weight. • Metabolised by microsomal deaminidase. • Excreted in urine.
DOSE: • Orally • 25 mg/kg (20-30 mg/kg) daily • 35 mg/kg (30-40 mg/kg) three times weekly ADRs: • Hepatic damage • Hyperuricemia- inhibit excretion of urate • Others- arthralgia, rashes, g.i upset, dysuria
ETHAMBUTOL • Tuberculostatic drug. MOA: Inhibit Arabinosyl transferase-Ш enzyme ↓ Disrupt the transport of Arabinose sugar ↓ Arbinogalactan biosynthesis impaired ↓ Disruption in mycobacterial cell wall formation
MECHANISM OF RESISTANCE: • Mainly by mutation in codon 306 of embB gene. • KatG 315 mutation Co-occurance of Ethambutol & Isoniazid resistance. PHARMACOKINETICS: • Oral bioavailability ~80%. • ~10-40% bound to plasma proteins. • Half life: 3hrs (1st 12hrs) & 9hrs (next 12hrs) → redistribution. • Rest of drug excreted unchanged in urine.
DOSE: • 15 mg/kg (15-20 mg/kg) daily • 30 mg/kg (25-35 mg/kg) three times weekly ADRs: • Optic neuritis (dose related & daily schedule for >9mnths) • Colour blindness • Hyperuriceamia • Rashes, drug fever, joint pain C/I: • Children <5 years
STREPTOMYCIN MOA: Binds with 30s ribosomal subunit ↓ Misreading of genetic code ↓ Inhibit protein synthesis
MECHANISM OF RESISTANCE: • Mutation in rpsL gene • Mutation in GidB gene PHRAMACOKINETICS: • Very poor oral bioavailability hence given in injectable form. • Distributed extracellularly mainly • Excreted unchanged in urine
DOSE: • 15mg/kg (12-18 mg/kg) daily, or 2 or 3 times weekly; im. ADRs: • Nephrotoxicity • Ototoxicity • Neuromuscular blockade- ↓release of Ach by inhibiting fusion of vesicles with terminal membrane
THANKYOU
Non resistant tuberculosis
Non resistant tuberculosis
ISONIAZID • For treatment of TB disease， isoniazid is used in combination with other agents to ensure killing of both actively dividing M. tuberculosis and slowlygrowing "persister" organisms. Unless the organism is resis tant， the standard regimen includes isoniazid， rifampin， ethambutol， and pyrazinamide (Table 20元-2). 1soniazid is often given together with 25-50 mg of pyridoxine daily to prevent drug-related peripheral neuropathy.
Non resistant tuberculosis
PHARMACOLOGY • 1soniazid is 出e hydrazide of isonicotinic ac此 a small， water-soluble molecule. The usual adult oral daily dose of 300 mg results in peak serum levels of 3-5 吨/mL within 30 min to 2 h after ingestion-well in excess ofthe M1Cs for most susceptible strains ofM. tubercu/osis. Both oral and 1M preparations of isoniazid reach effective levels in the body， although antacids and high-carbohydrate meals may interfere with oral absorption. 1soniazid diffuses well throughout the body， reaching therapeutic concentrations in body cavities and fluids， with concentrations in cerebrospinal fluid (CSF) comparable to those m serum. 1soniazid is metabolized in the liver via acetylation by N-acetyltransferase 2 (NAT2) and hydrolysis. Both fast- and slow acetylation phenotypes occur; patients who are "fast acetylators" may have lower serum levels of ison阳id， whereas "slow acetylators" may have higher levels and experience more toxicity. Satisfactory isoniazid levels are attained in the majority of homozygous fast NAT2 acetylators given a dose of 6 mg/kg and in the majority of homozygous slow acetylators given only 3 mg/kg. Genotyping is increasingly being used to charaιterize isoniazid-related pharmacogenomic responses.
1soniazid's interactions with other drugs • are due primarily to its inhibition of the cytochrome P450 system. Among the drugs with significant isoniazid interactions are warfarin ， carbamazepine， ben zodiazepines， acetaminophen， clopidogrel ， maraviroc， dronedarone， salmeterol， tamoxifen， eplerenone， and phenytoin.
DOSING • The recommended daily dose for the treatment of TB in the United States is 5 mg/kg for adults and 10-20 mg/kg for children， with a maximal daily dose of 300 mg for both. For intermittent therapy in adults (usually twice per week)， the dose is 15 mg/kg， with a maximal daily dose of 900 mg. 1soniazid does not require dosage adjustment in patients with renal disease.
RESISTANCE • Five separate pa出ways for isoniazid resistance have been elucidated. • Most strains have amino acid changes in either the catalase-peroxidase gene (katG) or the mycobacterial ketoenoylreductase gene (inhA). • Less frequently， alterations in kasA， the gene for an enzyme involved in mycolic acid elongation， and loss of NADH dehydrogenase 2 activity confer isoniazid resistance. • 1n 20-30% of isoniazid-resistant M. tuberculosis isolates, increased expression of efflux pump genes， such as efpA， mmpL7， mmr， p55，and the Tap-like gene Rv1258c， has been implicated as the underlying mechanism of resistance.
ADVERSE EFFECTS • Although isoniazid is generally well tolerated， druginduced liver injury and peripheral neuropathy are signi且cant adverse effects associated with this agent. 1soniazid may cause as严nptomatic transient elevation of aminotransferase levels (often termed hepatic adaptation) in up to 20% of recipients. Other adverse reactions include rash (2%)， fever (1.2%)， anemia， acne， arthritic s严nptoms， a systemic lupus erythematosus-like syndrome， optic atrophy， seizures， and psy chiatric symptoms. Symptomatic hepatitis occurs in fewer than 0.1% of persons treated with isoniazid alone for LTB1， and fulminant hepatitis with hepatic failure occurs in fewer than 0.01%. 1soniazid-associated hepatitis is idiosyncratic， but its incidence increases with age， with daily alcohol consumption， and in women who are within 3 months postpartum.
• Guidelines recommend that isoniazid be discontinued in the presence of hepatitis S严nptoms or jaundice and an ALT level three times the upper limit of normal or in the absence of symptoms with an ALT level five times the upper limit ofnormal
• Peripheral neuropathy associated with isoniazid occurs in up to 2% of patients given 5 mg/kg. 1soniazid appears to interfere with P严idoxine (vitamin B 6) metabolism. The risk of isoniazid-related neurotoxicity is greatest for patients with preexisting disorders that also pose a risk of neuropathy， such as H1V infection; for those with diabetes mellitus， alcohol abuse， or malnutrition; and for those simultaneously receiving other potentially neuropathiι medications， such as sta叽ldine. These patients should be given
RIFAMPIN • Rifampin is a semisynthetic derivative of Amycolatopsis rifamycinica (formerly known as Streptomyces mediterranei). The most active antimycobacterial agent available， rifampin is the keystone of first-line treatment for TB. 1ntroduced in 1968， this drug eventually permitted dramatic shortening of the TB treatment course. Rifampin has both sterilizing and bactericidal activity against dividing and nondividing M. tuberculosis.
MOA • Rifampin exerts both intracellular and extracellular bactericidal activity. Like other rifamycins， rifampin specifically binds to and inhibits mycobacterial DNA- dependent RNA polymerase， blocking RNA synthesis.
PHARMACOLOGY • Rifampin is a fat-soluble， complex macrocyclic molecule readily absorbed after oral administration. Serum levels of 10-20 Ilg/mL are achieved 2.5 h after the usual adult oral dose of 10 mg/kg (given without food). Rifampin has a half-life of 1.5-5 h. The drug distributes well throughout most body tissues， includi吨 CSF. Rifampin turns body tluids such as urine， saliva， sputum， and tears a reddish-orange color-an effect that offers a simple means of assessing patients' adherence to this medication. Rifampin is excreted primarily through the bile and enters the enterohepatic circulation; <30% of a dose is renally excreted. As a potent inducer of the hepatic cytochrome P450 system， rifampin can decrease the half-life of some drugs， such as digoxin， warfarin， phenytoin， prednisone， cyclosporine， methadone， oral con traceptives， clarithromycin， azole antifungal agents， quinidine， antiret roviral protease inhibitors， and non-nucleoside reverse transcriptase inhibitors.
DOSING • The daily dosage ofrifampin is 10 mg/kg for adults and 10-20 mg/kg for children， with a maximum of600 mg/d forboth. The drug is given once daily， twice weekly， or three times weekly. No adjustments of dose or frequency are necessary in patients with renal insufficiency
RESISTANCE • Resistance to rifampin in M. tuberculosis， Mycobacterium leprae， and other organisms is the consequence ofspontaneous， mostly missense point mutations in a core region of the bacterial gene coding for the BETA subunit of RNA polymerase (rpoB). RNA polymerase altered in this manner is no longer subject to inhibition by rifampin
ADVERSE EFFECTS • Adverse events associated with rifampin are infrequent and generally mild. • Hepatotoxicity due to rifampin alone is uncommon in the absence of preexisting liver disease and often consists of isolated hyperbilirubinemia rather than aminotransferase elevation. • Other adverse reactions include rash， pruritus， gastrointestinal symptoms， and pancytopenia. • Rarely， a hypersensitivity reaction may occur with intermittent therapy， manifesting as fever， chills ， malaise，rash， and-in some instances-renal and hepatic failure.
ETHAMBUTOL • ME(HANISM OF AaJON Ethambutol is bacteriostatiι against M. tuberculosis. Its prima巧 mechanism ofaction is the inhibition of tlle arabinosyltransferases involved in cell wall s严lthesis， which probably inhibits the formation of arabinogalactan and lipoarabinomannan.
PHARMACOLOGYAND DOSING • From a single dose of etllambutol， 75-80% is absorbedwitllin 2-4 h ofadministration. Serum levels peak at 2-4 Ilg/mL after tlle standard adult da让y dose of 15 mg/kg. Ethambutol is well dis- tributed tllroughout the body except in tlle CSF; a dosage of 25 mg/kg is necessary for attainment of a CSF level half of that in serum. For intermittent tllerapy， tlle dosage is 50 mg/kg twice weekly. To prevent toxicity， tlle dosage must be lowered and the frequency ofadministration reduced for patients with renal insufficiency.
ADVERSE EFFECTS • Ethambutol is usually well tolerated and has no significant interactions with other drugs. Optic neuritis， the most serious adverse effect reported， typically presents as reduced visual acuity， central scotoma， and loss of the ability to see green (or， less commonly， red). The cause of this neuritis is unknown， but it may be due to an effect of ethambutol on the amacrine and bipolar cells of the retina. Symptoms typically develop several months after initiation of therapy， but ocular toxicity soon after initiation of ethambutol has been described. The risk of ocular toxicity is dose dependent， occur ring in 1-5% of patients， and can be increased by renal insufficiency. The routine use of ethambutol in younger children is not recom mended because monitoring for visual complications can be difficult. Ifdrug-resistant TB is suspected， ethambutol can be used for treatment of children
• All patients starting therapywith ethambutol should have a baseline test for visual acuity， visual fields， and color vision and should undergo an examination of the optic fundus. Visual acuity and color vision should be monitored monthly or less often as needed. Cessation of ethambutol in response to early symptoms of ocular toxicity usually results in reversal of the deficit within several months. Recovery of all 叽sual function may take up to 1 year. In the elderly and in patients whose symptoms are not recognized 巳a由， defic山 may be permanent Some experts think that supplementation with hydroxocobalamin (vitamin B 12) is beneficial for patients with etllambutol-related ocular toxicity. Other adverse effects of ethambutol are rare. Peripheral sensory neuropathy occurs in rare instances
RESISTANCE • Ethambutol resistance in M. tuberculosis and NTM is associated primarily with missense mutations in the embB gene that encodes for arabinosyltransferase. Mutations have been found in resistant strains at codon 306 in 50- 70% of cases. Mutations at embB306 can cause slgm且cantly increased MICs of ethambutol， resulting in clinical resistance.
PYRAZINAMIDE • A nicotinamide analog， pyrazinamide is an important bactericidal drug used in the initial phase of TB treatment. Its administration for the first 2 months of therapy with rifampin and isoniazid allows treatment duration to be shortened from 9 months to 6 months and decreases rates of relapse
MOA • Pyrazinamide's antimycobaιterial activity is essentially limited to M. tuberculosis. The drug is more active against slowly replicating organisms than against actively replicating organisms. Pyrazinamide is a prodrug that is converted by the mycobacterial pyrimidase to the active form， pyrazinoic acid (POA). This agent is active only in acidic environments (pH <6.0)， as are found within phagocytes or granulomas. The exact mechanism of action of POA is unclear， but fatty acid synthetase 1 may be the primary target in M. tuberculosis. Susceptible strains of M. tuberculosis are inhibited by pyrazinamide concentrations of 16-50 Ilg/mL at pH 5.5.
PHARMACOLOGY AND DOSING • Pyrazinamide is well absorbed after oral administration， with peak serum concentrations of 20-60 Ilg/mL at 1-2 h after ingestion of the recommended adult daily dose of 15-30 mg/kg (maximum， 2 g/d). It distributes well to various body compartments， including CSF， and is an important component oftreatment for tuberculous meningitis. The serum half-life of the drug is 9-1 1 h with normal renal and hepatic function. Pyrazinamide is metabolized in the liver to POA， 5-hydroxypyrazinamide， and 5-hydroxy-POA. A high proportion of pyrazinamide and its metabolites (-70%) is excreted in the urine. The dosage must be adjusted according to the level of renal function in patients with reduced creatinine clearance
ADVERSE EFFECTS • At the higher dosages used previously， hepatotoxic ity was seen in as many as 15% of patients treated with pyrazinamide However， at the currently recommended dosages， hepatotoxic盯 now occurs less commonly when this drug is administered with isoniazid and rifampin during the treatment of TB. Older age， active liver dis ease， HIV infection， and low albumin levels may increase the risk of hepatotoxicity. The use of pyrazinamide with rifampin for the treatment of LTBI is no longer recommended because of unacceptable rates of hepatotoxicity and death in this setting. Hyperuricemia is a common adverse effect of pyrazinamide therapy that usually can be managed conservatively. Clinical gout is rare Although pyrazinamide is recommended by international TB organizations for routine use in PI吨nancy， it is not recom mended in the United States because of inadequate teratogenicity data.
RESISTANCE • The basis of pyrazinamide resistance in M. tuberculosis is a mutation in the pncA gene coding for pyrazinamidase， the enzyme that converts the prodrug to active POA. Resistance to pyrazinamide is associated with loss of pyrazinamidase activity， which prevents conversion of pyrazinamide to POA. Of pyrazinamide-resistant M. tuberculosis isolates， 72-98% have mutations in pncA. Conventional methods of testing for susceptibility to p严azinamide may produce both false-negative and false-positive results because the high- acidity environment required for the drug's activation also inhibits the growth ofM. tuberculosis. There is some controversy as to the clinical significance of in vitro pyrazinamide resistance
Rifabutin • Rifabutin， a semisynthetic derivative of rifamycin S， inhibits mycobacterial DNA-dependent RNA polymerase. Rifabutin is recommended in place of rifampin for the treatment of HIV-co- infected individuals who are taking protease inhibitors or non- nucleoside reverse transcriptase inhibitors， particularly nevirapine. Rifabutin's effect on hepatic enzyme induction is less pronounced than that of rifampin. Protease inhibitors may cause sign凶cant increases in rifabutin levels through inhibition of hepatic metabolism
PHARMACOLOGY • Like rifampin， rifabutin is lipophilic and is absorbed rapidly after oral administration， reaching peak serum levels 2-4 h after ingestion. Rifabutin distributes best to tissues， reaching levels 5一10 times higher than those in plasma. Unlike rifampin， rifabutin and its metabolites are partially cleared by the hepatic microsomal system. Rifabutin's slow clearance results in a mean serum half-life of 45 h much longer than the 3- to 5-h half-life of rifampin. Clarithromycin (but not azithromycin) and fluconazole appear to increase rifabutin levels by inhibiting hepatic metabolism
ADVERSE EFFECTS • Rifabutin is generallywell tolerated， with adverse effects oιcurring at higher doses. The most common adverse events are gastrointestinal; other reactions include rash， headache， asthenia ， chest pain， myalgia， and insomnia. Less common adverse reactions include fever， chills， a flulike syndrome， anterior uveitis， 1叩atitis， Clostridium d伊cileassociated diarrhea， a diffuse polymyalgia syndrome， and yellow skin discoloration ("pseudo-jaundice"). Laboratory abnormalities include neutropenia， leukopenia， 出rombocytopenia， and increased levels ofliver enzymes. Approximately 80% of patients who develop rifampin- related adverse events are able to complete TB treatment with rifabutin
• RESISTANCE Similar to rifampin resistance， resistance to rifabutin is mediated by some mutations in rpoB
Rifapentine • Rifapentine is a semisynthetic cyclopentyl rifamycin， sharing a mechanism of action with rifampin. Rifapentine is lipophilic and has a prolonged half-life that permits weekly or twice-weekly dosing. Therefore， this drug is the subjeιt ofintensive clinical investigation aimed at determining optimal dosing and frequency ofadministration Currently， rifapentine is an alternative to rifampin in the continuation phase of treatment for noncavitary drug-susceptible pulmonary TB in HIV-seronegative patients who have negative sputum smears at completion of the initial phase of treatment. When administered in these specific circumstances， rifapentine (10 mg/峙， up to 600 mg) is given once weekly with isoniazid. Because of higher rates of relapse， this regimen is not recommended for patients with TB disease and HIV co infection. The regimen is not recommended for preg nant women， for persons with hypersensitivity reactions to isoniazid or rifampin， or for HIV-infected individuals taking ART.
• PHARMACOLOGY Rifapentine's absorption is improved when the drug is taken with food. After oral administration， rifapentine reaches peak serum concentrations in 5-6 h and achieves a steady state in 10 days. The half-life of rifapentine and its active metabolite， 25-desacetyl rifapentine， is -13 h. The administered dose is excreted via the liver (70%). • ADVERSE EFFECTS The adverse-effects profile of rifapentine is similar to that of other rifamycins. Rifapentine is teratogenic in animal models and is relatively contraindicated in pregnancy. • RESISTANCE Rifapentine resistance is mediated by mutations in rpoB Mutations that cause resistance to rifampin also cause resistance to rifapentine
Streptomycin • Streptomycin was the first antimycobacterial agent used for the treatment ofTB. Derived from Streptomyces griseus， streptomycin is bactericidal against dividing M. tuber culosis organisms but has onlylow-level early bactericidal activity. This drug is administered only by the 1M and IV routes. In developed nations， streptomycin is used infrequently because of its toxicity， the inconvenience of injections， and drug resistance. In developing countries， however， streptomycin is used because of its low cost. • MECHANISM OF ACTlON Streptomycin inhibits protein synthesis by binding at a site on the 30S mycobacterial ribosome
Pharmacology and dosing • Serum levels of Streptomycin peak at 25-45 microgram/mL a丘er a l-g dose. This agent penetrates poorly into the CSF， reaching levels that are only 20% ofserum levels. The usual daily dose of streptomycin (given 1M either daily or 5 days per week) is 15 mg/kg for adults and 20-40 mg/kg for children， with a maximum of 1 g/d for both. For patients �60 years of age， 10 mg/kg is the recommended daily dose， with a maximum of 750 mg/d. Because streptomycin is eliminated almost exclu盯ely by the kidneys， 出 use in patients with renal impairment should be avoided or implemented with caution， with lower doses and less frequent administration
ADVERSE EFFECTS • Adverse reactions occur frequently with streptomycin (10-20% of patients). Ototoxicity (primarily vestibulotoxicity)， neuropathy， and renal toxicity are the most common and the most serious. Renal toxicity， usually manifested as nonoliguric renal failure， is less common with streptomycin than with other frequently used aminoglycosides， such as gentamicin. Manifestations of vestibular toxicity include loss of balance， vertigo， and tinnitus. Patients receiving streptomycin must be monitored carefully for these adverse effects， undergoing audiometry at baseline and monthly thereafter.
RESISTANCE • Spontaneous mutations conferring resistance to streptomycin are relatively common， occurring in 1 in 106 organisms. In the two-thirds of streptomycin-resistant M. tuberculosís strains exhibiting high -level resistanιe， mutations have been identified in one of two genes: a 16S rRNA gene (rrs) or the gene encoding ribosomal protein S12 (rpsL). Both targets are believed to be involved in streptomycin ribosomal binding. However， low-level resistance， which is seen in about one-third of resistant isolates， has no associated resistance mutation. A gene (gídB) that confers low-level resistance to streptomycin has recently been identified. Strains ofM. tuberculosis resistant to streptomycin generally are not cross-resistant to capreomycin or amikacin. Streptomycin is not used for the treatment of MDR-TB or XDR-TB because of (1) the high prevalence of streptomycin resistance among strains resistant to isoniazid and (2) the unreliability of drug susceptibility testing

More Related Content

PPTX
Macrolide antibiotics
andhra university
 
PDF
Pharmacology - Antimycobacterials Drugs
Areej Abu Hanieh
 
PPTX
Tetracyclines, Aminoglycosides, Chloramphenicol, Macrolides
BikashAdhikari26
 
PPTX
Macrolide antibiotics.pptx
Subramani Parasuraman
 
PDF
Antiprotozoal Drugs- Medicinal Chemistry-Pharmacy
Akhil Nagar
 
PPTX
Rational use of Antibiotics
drmainuddin
 
PPT
Urinary Tract Infection
Rahul Kunkulol
 
PPTX
Cephalosporins - Pharmacology
Areej Abu Hanieh
 
Macrolide antibiotics
andhra university
 
Pharmacology - Antimycobacterials Drugs
Areej Abu Hanieh
 
Tetracyclines, Aminoglycosides, Chloramphenicol, Macrolides
BikashAdhikari26
 
Macrolide antibiotics.pptx
Subramani Parasuraman
 
Antiprotozoal Drugs- Medicinal Chemistry-Pharmacy
Akhil Nagar
 
Rational use of Antibiotics
drmainuddin
 
Urinary Tract Infection
Rahul Kunkulol
 
Cephalosporins - Pharmacology
Areej Abu Hanieh
 

What's hot (20)

PPTX
Tetracyclines
abdul waheed
 
PPTX
Pharmacotherapy of malaria
Dr. Ritu Budania
 
PPTX
Oxazolidinones
Chintan Doshi
 
PPTX
Macrolide antibiotics
Narasimha Kumar G V
 
PPTX
Antiprotozoal agents
kencha swathi
 
PPTX
Drugs Used in Urinary Tract Infection
Pravin Prasad
 
PDF
Class oral contraceptives
Raghu Prasada
 
PPTX
Cancer chemotherapy
SuganyaPaulraj
 
PPT
9.ANTIPROTOZOAL DRUGS
Saminathan Kayarohanam
 
PPTX
Cotrimoxazole
Vijay Kevlani
 
PPTX
Antifungal drugs-Antibiotics
Subramani Parasuraman
 
PPTX
Neuraminidase Inhibitors
Jaserah Syed
 
PPT
Betalactam antibiotics
Dr Pralhad Patki
 
PPTX
Sulphonamides Pharmacology For Pharmacy students
Malay Pandya
 
PPT
PROTON PUMP INHIBITORS
Pharmacy Universe
 
PPTX
Anti tubercular drugs
Dr. Koppala R.V.S. Chaitanya
 
PPTX
Penicillins, cephalosporins, amido penicillins
N K
 
PPTX
Antifungal drugs-Synthetic agents
Subramani Parasuraman
 
PPTX
Antiamoebic drugs
Rahul Bhati
 
PPTX
Chemotherapy 1 general principles
Mohamed Bahr
 
Tetracyclines
abdul waheed
 
Pharmacotherapy of malaria
Dr. Ritu Budania
 
Oxazolidinones
Chintan Doshi
 
Macrolide antibiotics
Narasimha Kumar G V
 
Antiprotozoal agents
kencha swathi
 
Drugs Used in Urinary Tract Infection
Pravin Prasad
 
Class oral contraceptives
Raghu Prasada
 
Cancer chemotherapy
SuganyaPaulraj
 
9.ANTIPROTOZOAL DRUGS
Saminathan Kayarohanam
 
Cotrimoxazole
Vijay Kevlani
 
Antifungal drugs-Antibiotics
Subramani Parasuraman
 
Neuraminidase Inhibitors
Jaserah Syed
 
Betalactam antibiotics
Dr Pralhad Patki
 
Sulphonamides Pharmacology For Pharmacy students
Malay Pandya
 
PROTON PUMP INHIBITORS
Pharmacy Universe
 
Anti tubercular drugs
Dr. Koppala R.V.S. Chaitanya
 
Penicillins, cephalosporins, amido penicillins
N K
 
Antifungal drugs-Synthetic agents
Subramani Parasuraman
 
Antiamoebic drugs
Rahul Bhati
 
Chemotherapy 1 general principles
Mohamed Bahr
 
Ad

Viewers also liked (10)

PPTX
Drug prescription in hepatic patients
Mahmoud El-saharty
 
PDF
Blast resistant structures تفجيرات
Dr.Youssef Hammida
 
PPTX
Threatened abortion
Dr. Bushra Hasan Khan
 
PPTX
oxidative stress
shaily mehra
 
PPTX
Obstructive Jaundice and Anesthesia
Dr.S.N.Bhagirath ..
 
PPTX
Dr bushra antiulcer screening
Dr. Bushra Hasan Khan
 
PDF
Threatened miscarriage
Aboubakr Elnashar
 
PPTX
T.B. Special Situations
Pk Doctors
 
PPTX
Drugs used in special age groups like children, elderly and preganancy
Roopali Somani
 
PPTX
Anti tubercular drugs
Sneha Gogineni
 
Drug prescription in hepatic patients
Mahmoud El-saharty
 
Blast resistant structures تفجيرات
Dr.Youssef Hammida
 
Threatened abortion
Dr. Bushra Hasan Khan
 
oxidative stress
shaily mehra
 
Obstructive Jaundice and Anesthesia
Dr.S.N.Bhagirath ..
 
Dr bushra antiulcer screening
Dr. Bushra Hasan Khan
 
Threatened miscarriage
Aboubakr Elnashar
 
T.B. Special Situations
Pk Doctors
 
Drugs used in special age groups like children, elderly and preganancy
Roopali Somani
 
Anti tubercular drugs
Sneha Gogineni
 
Ad

Similar to Non resistant tuberculosis (20)

PPTX
Treatment of Tuberculosis | Jindal Chest Clinic
Jindal Chest Clinic
 
PPTX
NTEP GUIDELINES Presentation By Dr Aiswarya Thambi.pptx
AiswaryaT9
 
PPTX
Diagnosis and management of tuberculosis with revised rntcp
DrPrincePrakash
 
PPTX
TUBERCULOSIS. .pptx
CypherArthurArya
 
PPTX
latest pulmonary tuberculosis guidelines.pptx
pramod1203
 
PPTX
RNTCP
Dhileeban Maharajan
 
PPTX
07-Presentation1
manish joya
 
PPTX
Tuberculosis
Suchanda Gadre
 
PPTX
Anti tuberculous Drugs and Patient Counseling
Yamini Shah
 
PPT
MOT
guest8df470
 
PPT
MOT
guest8df470
 
PPTX
Tuberculosis
swathisravani
 
PPTX
Tuberculosis
Krunal Goyani
 
PPTX
Pharmacotherapy Of Tuberculosis infection.pptx
SRIRAM THIRUNAVUKKARASU
 
PPTX
epidemiology of Tuberculosis
Abhishek Agarwal
 
PPTX
Pulmonary TB (Tuberculosis) PPT SlideShare
sonam
 
PPTX
Management of TB 2019
Lifecare Centre
 
PPTX
Pulmonary TB very common now and dys.pptx
MonaAzo
 
PPT
Tuberculosis
Puneet Shukla
 
PPTX
RNTCP
Dr.Sangeeta De
 
Treatment of Tuberculosis | Jindal Chest Clinic
Jindal Chest Clinic
 
NTEP GUIDELINES Presentation By Dr Aiswarya Thambi.pptx
AiswaryaT9
 
Diagnosis and management of tuberculosis with revised rntcp
DrPrincePrakash
 
TUBERCULOSIS. .pptx
CypherArthurArya
 
latest pulmonary tuberculosis guidelines.pptx
pramod1203
 
RNTCP
Dhileeban Maharajan
 
07-Presentation1
manish joya
 
Tuberculosis
Suchanda Gadre
 
Anti tuberculous Drugs and Patient Counseling
Yamini Shah
 
MOT
guest8df470
 
MOT
guest8df470
 
Tuberculosis
swathisravani
 
Tuberculosis
Krunal Goyani
 
Pharmacotherapy Of Tuberculosis infection.pptx
SRIRAM THIRUNAVUKKARASU
 
epidemiology of Tuberculosis
Abhishek Agarwal
 
Pulmonary TB (Tuberculosis) PPT SlideShare
sonam
 
Management of TB 2019
Lifecare Centre
 
Pulmonary TB very common now and dys.pptx
MonaAzo
 
Tuberculosis
Puneet Shukla
 
RNTCP
Dr.Sangeeta De
 

More from Dr. Bushra Hasan Khan (9)

PPTX
PH 1.19 ANTIEPILEPTIC DRUGS.pptx
Dr. Bushra Hasan Khan
 
PPTX
DR KHAN DENTAL THERAPEUTICS.pptx
Dr. Bushra Hasan Khan
 
PPTX
DR KHAN.pptx
Dr. Bushra Hasan Khan
 
PDF
Sample pdf CBME Practical Pharmacology 2nd Edition.pdf
Dr. Bushra Hasan Khan
 
PPTX
SPECIAL DENTAL PHARMACOLOGY.pptx
Dr. Bushra Hasan Khan
 
PPTX
Heart failure
Dr. Bushra Hasan Khan
 
PPTX
ANTIDEPRESSANTS
Dr. Bushra Hasan Khan
 
PPTX
asthma management
Dr. Bushra Hasan Khan
 
PPTX
Peptic ulcer disease pharmacotherapy
Dr. Bushra Hasan Khan
 
PH 1.19 ANTIEPILEPTIC DRUGS.pptx
Dr. Bushra Hasan Khan
 
DR KHAN DENTAL THERAPEUTICS.pptx
Dr. Bushra Hasan Khan
 
DR KHAN.pptx
Dr. Bushra Hasan Khan
 
Sample pdf CBME Practical Pharmacology 2nd Edition.pdf
Dr. Bushra Hasan Khan
 
SPECIAL DENTAL PHARMACOLOGY.pptx
Dr. Bushra Hasan Khan
 
Heart failure
Dr. Bushra Hasan Khan
 
ANTIDEPRESSANTS
Dr. Bushra Hasan Khan
 
asthma management
Dr. Bushra Hasan Khan
 
Peptic ulcer disease pharmacotherapy
Dr. Bushra Hasan Khan
 

Non resistant tuberculosis

  • 1. PULMONARY TUBERCULOSIS Dr. Bushra Hasan Khan Department of Pharmacology JNMC, AMU, Aligarh.
  • 2. • Tuberculosis is a global pandemic • TB is second leading cause of death from a single infectious agent, after HIV. • INCIDENCE : 9 million new cases in 2013 • MORTALITY : A total of 1.5 million people died from TB in 2013 (including 360 000 people with HIV) • TB is a leading killer of HIV-positive people causing one fourth of all HIV-related deaths.
  • 3. • 480 000 people developed MDR-TB in 2013. • In 2012, out of the estimated global annual incidence of 8.6 million TB cases, 2.3 million were estimated to have occurred in India. • The TB mortality rate has decreased 45% since 1990. • About 37 million lives were saved worldwide between 2000 and 2013 through TB diagnosis and treatment
  • 4. • The world is on track to achieve the global TB target set for 2015 in the Millennium Development Goals • The target for TB in the MDGs is to halt and reverse global incidence. • 86% of people who developed TB and were put on treatment in 2012 were successfully treated. (http://www.tbcindia.nic.in/rntcp.html)
  • 5. ETIOLOGY • TB is caused by Mycobacterium tuberculosis, a slow-growing obligate aerobe and a facultative intracellular parasite. • Non-spore-forming, rod-shaped, 0.5μm × 3μm • Neutral on Gram's staining • The organism grows in parallel groups called cords  in which acid-fast bacilli are arranged in parallel chains . • Cord formation is correlated with virulence.
  • 6. • Mycobacteria are rich in lipids – Mycolic acid  prevent attack of cationic proteins, lysozyme, and oxygen radicals in the phagocytic granule – Waxes – Phosphatides • Lipids are bound to proteins and polysaccharides. • Muramyl dipeptide + mycolic acids  granuloma formation; phospholipids  caseous necrosis.
  • 7. • Once stained, the bacilli cannot be decolorized by acid alcohol  acid-fast bacilli (AFB) • Acid fastness is due mainly to the organisms' – High content of mycolic acids, – Long-chain cross-linked fatty acids， – Other cell-wall lipids.
  • 8. • Mycolic acids + Arabinogalactan and Peptidoglycan  results in very low permeability of the cell wall  effectiveness of most antibiotics is reduced. • Lipoarabinomannan  involved in the pathogen-host interaction  facilitates the survival of M. tuberculosis within macrophages.
  • 9. PHARMACOLOGICAL BARRIER:  Cell wall Mainly contains Lipids (Mycolic acid)  Efflux pumps pump out harmful chemicals  Propensity to hide inside the host cells
  • 10. CLINICAL FEATURES • Fever • Weight loss / anorexia • Cough • Hemoptysis • Chest pain • Night sweats • Fatigue
  • 11. DIAGNOSIS • History • Physical examination • Radiology • Sputum microscopy
  • 12. NATURAL HISTORY & SPECTRUM OF DISEASE
  • 13. AIMS OF TREATMENT • To cure the patient ; restore quality of life & productivity • To prevent death from active TB or its late effects • To prevent relapse of TB • To reduce transmission of TB to others • To prevent the development & transmission of drug resistance
  • 14. RNTCP • RNTCP ( Revised National Tuberculosis Control Programme) is an application of WHO recommended strategy of DOTS in India. • Objectives: 1- Detecting at least 70% of sputum positive TB patients in the community. 2- Curing at least 85% of the newly detected sputum positive cases.
  • 15. Five components of DOTS: 1. Political commitment with increased & sustained financing 2. Case detection through quality-assured bacteriology 3. Standardized treatment with supervision & patient support 4. Regular, uninterrupted supply of Anti-TB drugs 5. Monitoring & evaluation system & impact measurement
  • 16. Stop TB Strategy (WHO, 2006) 1. Pursue high-quality DOTS expansion & enhancement 2. Address TB-HIV, MDR-TB, & the needs of poor & vulnerable populations 3. Contribute to health system strengthening based on primary health care 4. Engage all health care providers 5. Empower people with TB, & communities through partnership 6. Enable & promote research
  • 17. • Based on the nature/severity of the disease & the patient's exposure to previous ATTs, RNTCP classifies TB patients into 2 t/t categories  – NEW – PREVIOUSLY TREATED
  • 18. NEW PATIENT CATEGORY • New sputum smear-positive, • New sputum smear-negative, • New extrapulmonary tuberculosis,
  • 19. PREVIOUSLY TREATED • Sputum smear-positive relapse, • Sputum smear-positive failure, • Sputum smear-positive treatment after default, • Others (patients who are Sputum Smear-Negative or who have Extra-pulmonary disease who can have recurrence)
  • 20. RECOMMENDED DOSES OF FIRST-LINE ANTITUBERCULOSIS DRUGS FOR ADULTS
  • 21. DRUGS AND THEIR TARGET SITES
  • 22. STANDARD REGIMENS FOR NEW TB PATIENTS DOSING FREQUENCY
  • 23. SETTINGS WITH HIGH LEVELS OF ISONIAZID RESISTANCE IN NEW PATIENTS
  • 24. SPUTUM MONITORING BY SMEAR MICROSCOPY IN NEW PULMONARY TB PATIENTS
  • 25. STANDARD REGIMENS FOR PREVIOUSLY TREATED PATIENTS
  • 26. SPUTUM MONITORING OF PULMONARY TB PATIENTS RECEIVING THE 8-MONTH RETREATMENT REGIMEN WITH FIRST-LINE DRUGS
  • 27. A POSITIVE SPUTUM SMEAR AT THE END OF THE INTENSIVE PHASE  • Poorly supervised initial phase of t/t & poor patient adherence • Poor quality of anti-TB drugs • Doses of anti-TB drugs  below the recommended range • Slow resolution  extensive cavitation & a heavy initial bacillary load • Co-morbid conditions • MDR-TB that is not responding to first-line treatment • Non-viable bacteria remain visible by microscopy
  • 28. COHORT ANALYSIS OF TREATMENT OUTCOMES • COHORT  a group of patients diagnosed & registered for t/t during one-quarter of a year • Evaluation of t/t outcome in new pulmonary smear-positive patients  major indicator of programme quality. • Outcomes in other patients (retreatment, pulmonary smear-negative, extrapulmonary) are analysed in separate cohorts.
  • 29. • Outcomes are routinely evaluated at the beginning of the quarter following the completion of treatment by the last patient in that cohort.
  • 30. TREATMENT OUTCOMES • CURED • TREATMENT COMPLETED • TREATMENT FAILURE • DIED • DEFAULT • TRANSFER OUT • TREATMENT SUCCESS
  • 32. MANAGEMENT OF TREATMENT INTERRUPTION • If a patient misses an arranged appointment to receive treatment  the NTP should ensure that the patient is contacted within a day after missing treatment during the initial phase, & within a week during the continuation phase. • Culture and DST should be performed upon return of patients who meet the definition for default
  • 33. MAJOR ADVERSE EFFECTS OF ATT • The most common ADR is Hepatitis. • Cutaneous reactions • Shock, purpura • Visual impairment • Deafness, dizziness • Acute renal failure
  • 34. SYMPTOM-BASED APPROACH TO MANAGING SIDE-EFFECTS OF ANTI-TB DRUGS (continued…….)
  • 37. IMPORTANT DRUG INTERACTIONS • Rifampicin reduces the conc. & effect of the following drugs  o Anti-infectives (antiretroviral drugs, mefloquine, azole antifungal agents, erythromycin, doxycycline); o Hormone therapy, including ethinylestradiol, norethindrone, tamoxifen, levothyroxine; o CVS drugs including digoxin, digitoxin, verapamil, nifedipine, diltiazem, propranolol, metoprorol, enalapril, losartan; (continued…….)
  • 38. o Anticonvulsants (including phenytoin); o Haloperidol, quetiapine, benzodiazepines (including diazepam, triazolam), zolpidem, buspirone; o Warfarin; o Cyclosporin; o Corticosteroids; o Theophylline; o Sulfonylurea hypoglycaemics; o Hypolipidaemics including simvastatin and fluvastatin;
  • 39. T/T REGIMENS IN SPECIAL SITUATIONS • Pregnancy & Lactation • Liver disorders • Renal failure
  • 40. PREGNANCY AND BREASTFEEDING • Streptomycin  ototoxic to the fetus ; must not be used • Lactation is not a C/I to ATT • After active TB in the baby is ruled out, the baby should be given 6 months of Isoniazid preventive therapy, followed by BCG vaccination • Pyridoxine supplementation is recommended for all pregnant or breastfeeding women taking Isoniazid
  • 41. LIVER DISORDERS • Patients with the following conditions can receive the usual TB regimens provided that there is no clinical evidence of chronic liver disease: Hepatitis virus carriage, A past history of acute hepatitis, Current excessive alcohol consumption • Hepatotoxic reactions to anti-TB drugs  more common among these patients & should therefore be anticipated
  • 42. • In patients with unstable or advanced liver disease, LFTs should be done at the start of treatment, if possible. • The more unstable or severe the liver disease is, the fewer hepatotoxic drugs should be used. • If the serum ALT level is more than 3 times normal before the initiation of treatment, the following regimens should be considered. (continued…….)
  • 43. POSSIBLE REGIMENS INCLUDE: • Two hepatotoxic drugs  9 months of Isoniazid and Rifampicin, plus Ethambutol (until or unless Isoniazid susceptibility is documented);  2 months of Isoniazid, Rifampicin, Streptomycin & Ethambutol, followed by 6 months of Isoniazid & Rifampicin;  6–9 months of Rifampicin, Pyrazinamide and Ethambutol.
  • 44. • One hepatotoxic drug:  2 months of Isoniazid, Ethambutol & Streptomycin, followed by 10 months of Isoniazid & Ethambutol. • No hepatotoxic drugs:  18–24 months of Streptomycin, Ethambutol & a Fluoroquinolone.
  • 45. RENAL FAILURE • The recommended initial TB t/t regimen : – 2 months of Isoniazid, Rifampicin, Pyrazinamide & Ethambutol, followed by 4 months of Isoniazid & Rifampicin. • There is significant renal excretion of Ethambutol and metabolites of Pyrazinamide, & doses should therefore be adjusted.
  • 46. • Three times/week administration of Pyrazinamide (25 mg/kg), & Ethambutol (15 mg/kg) is recommended • While receiving Isoniazid, patients with severe renal insufficiency or failure should also be given Pyridoxine in order to prevent peripheral neuropathy.
  • 47. • Because of an increased risk of nephrotoxicity & ototoxicity, Streptomycin should be avoided in patients with renal failure. • If Streptomycin must be used, the dosage is 15 mg/kg, two or three times/week, to a maximum of 1 gram per dose, & serum levels of the drug should be monitored.
  • 49. • MAIN FIRST LINE ANTITUBERCULAR DRUGS – ISONIAZID – RIFAMPICIN – ETHAMBUTOL – PYRAZINAMIDE • OTHER FIRST LINE ANTITUBERCULAR DRUGS – RIFABUTIN – RIFAPENTINE – STREPTOMYCIN
  • 50. SECOND-LlNE ANTI-TB DRUGS • Fluoroquinolones – Levofloxacin – Moxifloxacin – Gatifloxacin • Injectable Agents – Capreomycin – Amikacin – Kanamycin • Others – Cyclosrine – PAS – Ethionamide – clofazimine
  • 51. NEWER ANTl-TB DRUGS • Oxazolidinones  Linezolid • Amoxicillin-Clavulanate • Carbapenems • Diarylquinolines  Bedaquiline • Nitroimidazoles  Delamanid • Diamines  SQ109 (an Ethambutol analogue) • Pyrroles  LL3858
  • 52. DRUGS AND THEIR TARGET SITES
  • 53. ISONIAZID • MOA  Mycolic acid synthesis inhibitor
  • 54.  Nicotinoyl-NAD adduct→ inhibits the activities of enoyl-ACP reductase (inhA) & β-ketoacyl acyl carrier protein synthase (KasA)→ interfere with mycolic acid synthesis.  Nicotinoyl-NADP adduct→ inhibit mycobacterial dihydrofolate reductase (DHFRase)→ interfere with nucleic acid synthesis.
  • 55. MECHANISM OF RESISTANCE: • Mutation or deletion of katG gene (MC). • Mutation in kasA gene. • Over-expression of the inhA & aphC gene (detoxify organic peroxide) PHARMACOKINETICS: • Oral BA ~ 100%. • Only ~10% is protein bound. • Metabolised in liver by Arylamine N-acetyltransferase2 (NAT2). • Excreted in urine as Acetylisoniazid & Isonicotinic acid.
  • 56. DOSE: • 5mg/kg (4-6 mg/kg) daily, maximum 300 mg • 10 mg/kg (8-12 mg/kg) three times/week; maximum 900 mg • Oral / im / iv ADRs: • Peripheral neuritis : INH binds with Pyridoxal 5-phosphate → decreased neuronal Pyridoxal 5-phosphate • Liver damage : Acetylisoniazid→ Acetylhydralazine  Liver damage • Others : Optic neuritis, Convulsions, Hypersensitivity reactions
  • 57. DRUG INTERACTIONS: • Al(OH)3 inhibit INH absorption. • With Acetaminophen → Hepatotoxicity • With Carbamazepine, Diazepam, Ethosuximide  Neurological & Psychiatric toxicities by inhibiting CYP3A • With Isoflurane, Enflurane  decrease their effectiveness by inducing CYPE1
  • 58. RIFAMYCINS MECHANISM OF ACTION: Binds with β-subunit of DNA-dependent RNA Polymerase (rpoB) ↓ Inhibit RNA synthesis MECHANISM OF RESISTANCE: Mutation at codons 526 & 531 site of rpoB gene. PHARMACOKINETICS: • Absorption is variable [Oral bioavailability Rifampicin (68%) & Rifabutin (20%)] • Food- ↓Rifampicin absorbtion but no effect on Rifabutin • High fat diet- ↑Rifapentin absorption
  • 59. • Half life of Rifampicin→2-5hrs Rifabutin →32-67hrs Rifapentine →14-18hrs • Metabolized by microsomal β-esterases & cholinesterases mainly (deacetylation). • Excretion is mainly through bile. DOSE: • Rifampicin- 10 mg/kg (8-12 mg/kg) daily or 3 times weekly ; 1hr before or 2hrs after meal ; oral or iv • Rifabutin- 5mg/kg/day • Rifapentine- 10mg/kg/week
  • 60. ADRs: • Rashes, G.I intolerance, Liver damage, Hemolysis, Neutropenia . • Rifampicin  flu-like syndrome → higher dose, schedule ; twice weekly • Rifabutin  Uveitis; arthralgia; polymylgia; orange discoloration of skin, urine, feces, saliva & tears. INTERACTIONS: • Enzyme inducers  Rifampicin> Rifapentin>Rifabutin
  • 61. PYRAZINAMIDE • Is synthetic pyrazine analog of Nicotinamide. MOA: Pyrazinamide ↓ Passive diffusion Enter M.tuberculosis Deamination ↓ Nicotinamidase/Pyrazinamidase Pyrazinoic acid (POAˉ) Transported to extracellular environment ↓ Protonation HPOA
  • 62. • HPOA → Inhibit fatty acid synthase-1→ interfere with mycolic acid synthesis. → disruption of membrane transport MECHANISM OF RESISTANCE: • Point mutation in pncA gene (encodes Pyrazinamidase). PHARMACOKINETICS: • Oral bioavailability >90%. • Highly concentrated in lung lining fluid. • T1/2 variable depends upon weight. • Metabolised by microsomal deaminidase. • Excreted in urine.
  • 63. DOSE: • Orally • 25 mg/kg (20-30 mg/kg) daily • 35 mg/kg (30-40 mg/kg) three times weekly ADRs: • Hepatic damage • Hyperuricemia- inhibit excretion of urate • Others- arthralgia, rashes, g.i upset, dysuria
  • 64. ETHAMBUTOL • Tuberculostatic drug. MOA: Inhibit Arabinosyl transferase-Ш enzyme ↓ Disrupt the transport of Arabinose sugar ↓ Arbinogalactan biosynthesis impaired ↓ Disruption in mycobacterial cell wall formation
  • 65. MECHANISM OF RESISTANCE: • Mainly by mutation in codon 306 of embB gene. • KatG 315 mutation Co-occurance of Ethambutol & Isoniazid resistance. PHARMACOKINETICS: • Oral bioavailability ~80%. • ~10-40% bound to plasma proteins. • Half life: 3hrs (1st 12hrs) & 9hrs (next 12hrs) → redistribution. • Rest of drug excreted unchanged in urine.
  • 66. DOSE: • 15 mg/kg (15-20 mg/kg) daily • 30 mg/kg (25-35 mg/kg) three times weekly ADRs: • Optic neuritis (dose related & daily schedule for >9mnths) • Colour blindness • Hyperuriceamia • Rashes, drug fever, joint pain C/I: • Children <5 years
  • 67. STREPTOMYCIN MOA: Binds with 30s ribosomal subunit ↓ Misreading of genetic code ↓ Inhibit protein synthesis
  • 68. MECHANISM OF RESISTANCE: • Mutation in rpsL gene • Mutation in GidB gene PHRAMACOKINETICS: • Very poor oral bioavailability hence given in injectable form. • Distributed extracellularly mainly • Excreted unchanged in urine
  • 69. DOSE: • 15mg/kg (12-18 mg/kg) daily, or 2 or 3 times weekly; im. ADRs: • Nephrotoxicity • Ototoxicity • Neuromuscular blockade- ↓release of Ach by inhibiting fusion of vesicles with terminal membrane
  • 73. ISONIAZID • For treatment of TB disease， isoniazid is used in combination with other agents to ensure killing of both actively dividing M. tuberculosis and slowlygrowing "persister" organisms. Unless the organism is resis tant， the standard regimen includes isoniazid， rifampin， ethambutol， and pyrazinamide (Table 20元-2). 1soniazid is often given together with 25-50 mg of pyridoxine daily to prevent drug-related peripheral neuropathy.
  • 75. PHARMACOLOGY • 1soniazid is 出e hydrazide of isonicotinic ac此 a small， water-soluble molecule. The usual adult oral daily dose of 300 mg results in peak serum levels of 3-5 吨/mL within 30 min to 2 h after ingestion-well in excess ofthe M1Cs for most susceptible strains ofM. tubercu/osis. Both oral and 1M preparations of isoniazid reach effective levels in the body， although antacids and high-carbohydrate meals may interfere with oral absorption. 1soniazid diffuses well throughout the body， reaching therapeutic concentrations in body cavities and fluids， with concentrations in cerebrospinal fluid (CSF) comparable to those m serum. 1soniazid is metabolized in the liver via acetylation by N-acetyltransferase 2 (NAT2) and hydrolysis. Both fast- and slow acetylation phenotypes occur; patients who are "fast acetylators" may have lower serum levels of ison阳id， whereas "slow acetylators" may have higher levels and experience more toxicity. Satisfactory isoniazid levels are attained in the majority of homozygous fast NAT2 acetylators given a dose of 6 mg/kg and in the majority of homozygous slow acetylators given only 3 mg/kg. Genotyping is increasingly being used to charaιterize isoniazid-related pharmacogenomic responses.
  • 76. 1soniazid's interactions with other drugs • are due primarily to its inhibition of the cytochrome P450 system. Among the drugs with significant isoniazid interactions are warfarin ， carbamazepine， ben zodiazepines， acetaminophen， clopidogrel ， maraviroc， dronedarone， salmeterol， tamoxifen， eplerenone， and phenytoin.
  • 77. DOSING • The recommended daily dose for the treatment of TB in the United States is 5 mg/kg for adults and 10-20 mg/kg for children， with a maximal daily dose of 300 mg for both. For intermittent therapy in adults (usually twice per week)， the dose is 15 mg/kg， with a maximal daily dose of 900 mg. 1soniazid does not require dosage adjustment in patients with renal disease.
  • 78. RESISTANCE • Five separate pa出ways for isoniazid resistance have been elucidated. • Most strains have amino acid changes in either the catalase-peroxidase gene (katG) or the mycobacterial ketoenoylreductase gene (inhA). • Less frequently， alterations in kasA， the gene for an enzyme involved in mycolic acid elongation， and loss of NADH dehydrogenase 2 activity confer isoniazid resistance. • 1n 20-30% of isoniazid-resistant M. tuberculosis isolates, increased expression of efflux pump genes， such as efpA， mmpL7， mmr， p55，and the Tap-like gene Rv1258c， has been implicated as the underlying mechanism of resistance.
  • 79. ADVERSE EFFECTS • Although isoniazid is generally well tolerated， druginduced liver injury and peripheral neuropathy are signi且cant adverse effects associated with this agent. 1soniazid may cause as严nptomatic transient elevation of aminotransferase levels (often termed hepatic adaptation) in up to 20% of recipients. Other adverse reactions include rash (2%)， fever (1.2%)， anemia， acne， arthritic s严nptoms， a systemic lupus erythematosus-like syndrome， optic atrophy， seizures， and psy chiatric symptoms. Symptomatic hepatitis occurs in fewer than 0.1% of persons treated with isoniazid alone for LTB1， and fulminant hepatitis with hepatic failure occurs in fewer than 0.01%. 1soniazid-associated hepatitis is idiosyncratic， but its incidence increases with age， with daily alcohol consumption， and in women who are within 3 months postpartum.
  • 80. • Guidelines recommend that isoniazid be discontinued in the presence of hepatitis S严nptoms or jaundice and an ALT level three times the upper limit of normal or in the absence of symptoms with an ALT level five times the upper limit ofnormal
  • 81. • Peripheral neuropathy associated with isoniazid occurs in up to 2% of patients given 5 mg/kg. 1soniazid appears to interfere with P严idoxine (vitamin B 6) metabolism. The risk of isoniazid-related neurotoxicity is greatest for patients with preexisting disorders that also pose a risk of neuropathy， such as H1V infection; for those with diabetes mellitus， alcohol abuse， or malnutrition; and for those simultaneously receiving other potentially neuropathiι medications， such as sta叽ldine. These patients should be given
  • 82. RIFAMPIN • Rifampin is a semisynthetic derivative of Amycolatopsis rifamycinica (formerly known as Streptomyces mediterranei). The most active antimycobacterial agent available， rifampin is the keystone of first-line treatment for TB. 1ntroduced in 1968， this drug eventually permitted dramatic shortening of the TB treatment course. Rifampin has both sterilizing and bactericidal activity against dividing and nondividing M. tuberculosis.
  • 83. MOA • Rifampin exerts both intracellular and extracellular bactericidal activity. Like other rifamycins， rifampin specifically binds to and inhibits mycobacterial DNA- dependent RNA polymerase， blocking RNA synthesis.
  • 84. PHARMACOLOGY • Rifampin is a fat-soluble， complex macrocyclic molecule readily absorbed after oral administration. Serum levels of 10-20 Ilg/mL are achieved 2.5 h after the usual adult oral dose of 10 mg/kg (given without food). Rifampin has a half-life of 1.5-5 h. The drug distributes well throughout most body tissues， includi吨 CSF. Rifampin turns body tluids such as urine， saliva， sputum， and tears a reddish-orange color-an effect that offers a simple means of assessing patients' adherence to this medication. Rifampin is excreted primarily through the bile and enters the enterohepatic circulation; <30% of a dose is renally excreted. As a potent inducer of the hepatic cytochrome P450 system， rifampin can decrease the half-life of some drugs， such as digoxin， warfarin， phenytoin， prednisone， cyclosporine， methadone， oral con traceptives， clarithromycin， azole antifungal agents， quinidine， antiret roviral protease inhibitors， and non-nucleoside reverse transcriptase inhibitors.
  • 85. DOSING • The daily dosage ofrifampin is 10 mg/kg for adults and 10-20 mg/kg for children， with a maximum of600 mg/d forboth. The drug is given once daily， twice weekly， or three times weekly. No adjustments of dose or frequency are necessary in patients with renal insufficiency
  • 86. RESISTANCE • Resistance to rifampin in M. tuberculosis， Mycobacterium leprae， and other organisms is the consequence ofspontaneous， mostly missense point mutations in a core region of the bacterial gene coding for the BETA subunit of RNA polymerase (rpoB). RNA polymerase altered in this manner is no longer subject to inhibition by rifampin
  • 87. ADVERSE EFFECTS • Adverse events associated with rifampin are infrequent and generally mild. • Hepatotoxicity due to rifampin alone is uncommon in the absence of preexisting liver disease and often consists of isolated hyperbilirubinemia rather than aminotransferase elevation. • Other adverse reactions include rash， pruritus， gastrointestinal symptoms， and pancytopenia. • Rarely， a hypersensitivity reaction may occur with intermittent therapy， manifesting as fever， chills ， malaise，rash， and-in some instances-renal and hepatic failure.
  • 88. ETHAMBUTOL • ME(HANISM OF AaJON Ethambutol is bacteriostatiι against M. tuberculosis. Its prima巧 mechanism ofaction is the inhibition of tlle arabinosyltransferases involved in cell wall s严lthesis， which probably inhibits the formation of arabinogalactan and lipoarabinomannan.
  • 89. PHARMACOLOGYAND DOSING • From a single dose of etllambutol， 75-80% is absorbedwitllin 2-4 h ofadministration. Serum levels peak at 2-4 Ilg/mL after tlle standard adult da让y dose of 15 mg/kg. Ethambutol is well dis- tributed tllroughout the body except in tlle CSF; a dosage of 25 mg/kg is necessary for attainment of a CSF level half of that in serum. For intermittent tllerapy， tlle dosage is 50 mg/kg twice weekly. To prevent toxicity， tlle dosage must be lowered and the frequency ofadministration reduced for patients with renal insufficiency.
  • 90. ADVERSE EFFECTS • Ethambutol is usually well tolerated and has no significant interactions with other drugs. Optic neuritis， the most serious adverse effect reported， typically presents as reduced visual acuity， central scotoma， and loss of the ability to see green (or， less commonly， red). The cause of this neuritis is unknown， but it may be due to an effect of ethambutol on the amacrine and bipolar cells of the retina. Symptoms typically develop several months after initiation of therapy， but ocular toxicity soon after initiation of ethambutol has been described. The risk of ocular toxicity is dose dependent， occur ring in 1-5% of patients， and can be increased by renal insufficiency. The routine use of ethambutol in younger children is not recom mended because monitoring for visual complications can be difficult. Ifdrug-resistant TB is suspected， ethambutol can be used for treatment of children
  • 91. • All patients starting therapywith ethambutol should have a baseline test for visual acuity， visual fields， and color vision and should undergo an examination of the optic fundus. Visual acuity and color vision should be monitored monthly or less often as needed. Cessation of ethambutol in response to early symptoms of ocular toxicity usually results in reversal of the deficit within several months. Recovery of all 叽sual function may take up to 1 year. In the elderly and in patients whose symptoms are not recognized 巳a由， defic山 may be permanent Some experts think that supplementation with hydroxocobalamin (vitamin B 12) is beneficial for patients with etllambutol-related ocular toxicity. Other adverse effects of ethambutol are rare. Peripheral sensory neuropathy occurs in rare instances
  • 92. RESISTANCE • Ethambutol resistance in M. tuberculosis and NTM is associated primarily with missense mutations in the embB gene that encodes for arabinosyltransferase. Mutations have been found in resistant strains at codon 306 in 50- 70% of cases. Mutations at embB306 can cause slgm且cantly increased MICs of ethambutol， resulting in clinical resistance.
  • 93. PYRAZINAMIDE • A nicotinamide analog， pyrazinamide is an important bactericidal drug used in the initial phase of TB treatment. Its administration for the first 2 months of therapy with rifampin and isoniazid allows treatment duration to be shortened from 9 months to 6 months and decreases rates of relapse
  • 94. MOA • Pyrazinamide's antimycobaιterial activity is essentially limited to M. tuberculosis. The drug is more active against slowly replicating organisms than against actively replicating organisms. Pyrazinamide is a prodrug that is converted by the mycobacterial pyrimidase to the active form， pyrazinoic acid (POA). This agent is active only in acidic environments (pH <6.0)， as are found within phagocytes or granulomas. The exact mechanism of action of POA is unclear， but fatty acid synthetase 1 may be the primary target in M. tuberculosis. Susceptible strains of M. tuberculosis are inhibited by pyrazinamide concentrations of 16-50 Ilg/mL at pH 5.5.
  • 95. PHARMACOLOGY AND DOSING • Pyrazinamide is well absorbed after oral administration， with peak serum concentrations of 20-60 Ilg/mL at 1-2 h after ingestion of the recommended adult daily dose of 15-30 mg/kg (maximum， 2 g/d). It distributes well to various body compartments， including CSF， and is an important component oftreatment for tuberculous meningitis. The serum half-life of the drug is 9-1 1 h with normal renal and hepatic function. Pyrazinamide is metabolized in the liver to POA， 5-hydroxypyrazinamide， and 5-hydroxy-POA. A high proportion of pyrazinamide and its metabolites (-70%) is excreted in the urine. The dosage must be adjusted according to the level of renal function in patients with reduced creatinine clearance
  • 96. ADVERSE EFFECTS • At the higher dosages used previously， hepatotoxic ity was seen in as many as 15% of patients treated with pyrazinamide However， at the currently recommended dosages， hepatotoxic盯 now occurs less commonly when this drug is administered with isoniazid and rifampin during the treatment of TB. Older age， active liver dis ease， HIV infection， and low albumin levels may increase the risk of hepatotoxicity. The use of pyrazinamide with rifampin for the treatment of LTBI is no longer recommended because of unacceptable rates of hepatotoxicity and death in this setting. Hyperuricemia is a common adverse effect of pyrazinamide therapy that usually can be managed conservatively. Clinical gout is rare Although pyrazinamide is recommended by international TB organizations for routine use in PI吨nancy， it is not recom mended in the United States because of inadequate teratogenicity data.
  • 97. RESISTANCE • The basis of pyrazinamide resistance in M. tuberculosis is a mutation in the pncA gene coding for pyrazinamidase， the enzyme that converts the prodrug to active POA. Resistance to pyrazinamide is associated with loss of pyrazinamidase activity， which prevents conversion of pyrazinamide to POA. Of pyrazinamide-resistant M. tuberculosis isolates， 72-98% have mutations in pncA. Conventional methods of testing for susceptibility to p严azinamide may produce both false-negative and false-positive results because the high- acidity environment required for the drug's activation also inhibits the growth ofM. tuberculosis. There is some controversy as to the clinical significance of in vitro pyrazinamide resistance
  • 98. Rifabutin • Rifabutin， a semisynthetic derivative of rifamycin S， inhibits mycobacterial DNA-dependent RNA polymerase. Rifabutin is recommended in place of rifampin for the treatment of HIV-co- infected individuals who are taking protease inhibitors or non- nucleoside reverse transcriptase inhibitors， particularly nevirapine. Rifabutin's effect on hepatic enzyme induction is less pronounced than that of rifampin. Protease inhibitors may cause sign凶cant increases in rifabutin levels through inhibition of hepatic metabolism
  • 99. PHARMACOLOGY • Like rifampin， rifabutin is lipophilic and is absorbed rapidly after oral administration， reaching peak serum levels 2-4 h after ingestion. Rifabutin distributes best to tissues， reaching levels 5一10 times higher than those in plasma. Unlike rifampin， rifabutin and its metabolites are partially cleared by the hepatic microsomal system. Rifabutin's slow clearance results in a mean serum half-life of 45 h much longer than the 3- to 5-h half-life of rifampin. Clarithromycin (but not azithromycin) and fluconazole appear to increase rifabutin levels by inhibiting hepatic metabolism
  • 100. ADVERSE EFFECTS • Rifabutin is generallywell tolerated， with adverse effects oιcurring at higher doses. The most common adverse events are gastrointestinal; other reactions include rash， headache， asthenia ， chest pain， myalgia， and insomnia. Less common adverse reactions include fever， chills， a flulike syndrome， anterior uveitis， 1叩atitis， Clostridium d伊cileassociated diarrhea， a diffuse polymyalgia syndrome， and yellow skin discoloration ("pseudo-jaundice"). Laboratory abnormalities include neutropenia， leukopenia， 出rombocytopenia， and increased levels ofliver enzymes. Approximately 80% of patients who develop rifampin- related adverse events are able to complete TB treatment with rifabutin
  • 101. • RESISTANCE Similar to rifampin resistance， resistance to rifabutin is mediated by some mutations in rpoB
  • 102. Rifapentine • Rifapentine is a semisynthetic cyclopentyl rifamycin， sharing a mechanism of action with rifampin. Rifapentine is lipophilic and has a prolonged half-life that permits weekly or twice-weekly dosing. Therefore， this drug is the subjeιt ofintensive clinical investigation aimed at determining optimal dosing and frequency ofadministration Currently， rifapentine is an alternative to rifampin in the continuation phase of treatment for noncavitary drug-susceptible pulmonary TB in HIV-seronegative patients who have negative sputum smears at completion of the initial phase of treatment. When administered in these specific circumstances， rifapentine (10 mg/峙， up to 600 mg) is given once weekly with isoniazid. Because of higher rates of relapse， this regimen is not recommended for patients with TB disease and HIV co infection. The regimen is not recommended for preg nant women， for persons with hypersensitivity reactions to isoniazid or rifampin， or for HIV-infected individuals taking ART.
  • 103. • PHARMACOLOGY Rifapentine's absorption is improved when the drug is taken with food. After oral administration， rifapentine reaches peak serum concentrations in 5-6 h and achieves a steady state in 10 days. The half-life of rifapentine and its active metabolite， 25-desacetyl rifapentine， is -13 h. The administered dose is excreted via the liver (70%). • ADVERSE EFFECTS The adverse-effects profile of rifapentine is similar to that of other rifamycins. Rifapentine is teratogenic in animal models and is relatively contraindicated in pregnancy. • RESISTANCE Rifapentine resistance is mediated by mutations in rpoB Mutations that cause resistance to rifampin also cause resistance to rifapentine
  • 104. Streptomycin • Streptomycin was the first antimycobacterial agent used for the treatment ofTB. Derived from Streptomyces griseus， streptomycin is bactericidal against dividing M. tuber culosis organisms but has onlylow-level early bactericidal activity. This drug is administered only by the 1M and IV routes. In developed nations， streptomycin is used infrequently because of its toxicity， the inconvenience of injections， and drug resistance. In developing countries， however， streptomycin is used because of its low cost. • MECHANISM OF ACTlON Streptomycin inhibits protein synthesis by binding at a site on the 30S mycobacterial ribosome
  • 105. Pharmacology and dosing • Serum levels of Streptomycin peak at 25-45 microgram/mL a丘er a l-g dose. This agent penetrates poorly into the CSF， reaching levels that are only 20% ofserum levels. The usual daily dose of streptomycin (given 1M either daily or 5 days per week) is 15 mg/kg for adults and 20-40 mg/kg for children， with a maximum of 1 g/d for both. For patients �60 years of age， 10 mg/kg is the recommended daily dose， with a maximum of 750 mg/d. Because streptomycin is eliminated almost exclu盯ely by the kidneys， 出 use in patients with renal impairment should be avoided or implemented with caution， with lower doses and less frequent administration
  • 106. ADVERSE EFFECTS • Adverse reactions occur frequently with streptomycin (10-20% of patients). Ototoxicity (primarily vestibulotoxicity)， neuropathy， and renal toxicity are the most common and the most serious. Renal toxicity， usually manifested as nonoliguric renal failure， is less common with streptomycin than with other frequently used aminoglycosides， such as gentamicin. Manifestations of vestibular toxicity include loss of balance， vertigo， and tinnitus. Patients receiving streptomycin must be monitored carefully for these adverse effects， undergoing audiometry at baseline and monthly thereafter.
  • 107. RESISTANCE • Spontaneous mutations conferring resistance to streptomycin are relatively common， occurring in 1 in 106 organisms. In the two-thirds of streptomycin-resistant M. tuberculosís strains exhibiting high -level resistanιe， mutations have been identified in one of two genes: a 16S rRNA gene (rrs) or the gene encoding ribosomal protein S12 (rpsL). Both targets are believed to be involved in streptomycin ribosomal binding. However， low-level resistance， which is seen in about one-third of resistant isolates， has no associated resistance mutation. A gene (gídB) that confers low-level resistance to streptomycin has recently been identified. Strains ofM. tuberculosis resistant to streptomycin generally are not cross-resistant to capreomycin or amikacin. Streptomycin is not used for the treatment of MDR-TB or XDR-TB because of (1) the high prevalence of streptomycin resistance among strains resistant to isoniazid and (2) the unreliability of drug susceptibility testing

Editor's Notes

  • #6: ated to a supposed progenitor 时pe). M. tubercu/osis is a rod-shaped， non-spore-forming， thin aerobic bacterium measuring 0.5 阳丑 by 3 f.lm. Mycobacteria， including M. tubercu/osis， are often neutral on Gram's staining. However， once stained， the bacilli cannot be decolorized by acid alcohol; this charac teristic justifies their classification as acid-fast bacilli (AFB; Fig. 202-1). Acid fastness is due mainly to the organisms' high content of mycolic acids， long-chain cross-linked fatty acids， and other cell-wall lipids.
  • #7: Virulent strains of tubercle bacilli form microscopic "serpentine cords" in which acid-fast bacilli are arranged in parallel chains. Cord formation is correlated with virulence. A "cord factor" (trehalose-6,6'-dimycolate) has been extracted from virulent bacilli with petroleum ether. It inhibits migration of leukocytes, causes chronic granulomas, and can serve as an immunologic "adjuvant."
  • #10: This extraordinary shield prevents many pharmacological compounds from getting to the bacterial cell membrane or inside the cytosol. A second layer of defense comes from an abundance of efflux pumps in the cell membrane. These transport proteins pump out potentially harmful chemicals from the bacterial cytoplasm back into the extracellular space and are responsible for the native resistance of mycobacteria to many standard antibiotics. As an example, ATP binding cassette (ABC) permeases comprise a full 2.5% of the genome of Mycobacterium tuberculosis. A third barrier is the propensity of some of the bacilli to hide inside the patient's cells, thereby surrounding themselves with an extra physicochemical barrier that antimicrobial agents must cross to be effective.
  • #11: Chest pain in patients with TB can also result from tuberculous acute pericarditis. Pericardial TB can lead to cardiac tamponade or constriction. Elderly individuals with TB may not display typical signs and symptoms of TB infection, because they may not mount a good immune response. Active TB infection in this age group may manifest as nonresolving pneumonitis. Signs and symptoms of extrapulmonary TB may be nonspecific. They can include leukocytosis, anemia, and hyponatremia due to the release of ADH (antidiuretic hormone)-like hormone from affected lung tissue. Tuberculous meningitis Patients with tuberculous meningitis may present with a headache that has been either intermittent or persistent for 2-3 weeks. Subtle mental status changes may progress to coma over a period of days to weeks. Fever may be low grade or absent. Skeletal TB The most common site of skeletal TB involvement is the spine (Pott disease); symptoms include back pain or stiffness. Lower-extremity paralysis occurs in up to half of patients with undiagnosed Pott disease. Tuberculous arthritis usually involves only 1 joint. Although any joint may be involved, the hips and knees are affected most commonly, followed by the ankle, elbow, wrist, and shoulder. Pain may precede radiographic changes by weeks to months. Genitourinary TB Symptoms of genitourinary TB may include flank pain, dysuria, and frequent urination. In men, genital TB may manifest as a painful scrotal mass, prostatitis, orchitis, or epididymitis. In women, genital TB may mimic pelvic inflammatory disease. TB is the cause of approximately 10% of sterility cases in women worldwide and of approximately 1% in industrialized countries. Go to Tuberculosis of the Genitourinary System and Imaging of Genitourinary Tuberculosis for complete information on these topics. Gastrointestinal TB Any site along the gastrointestinal tract may become infected. Symptoms of gastrointestinal TB are referable to the infected site and include the following: Nonhealing ulcers of the mouth or anus Difficulty swallowing - With esophageal disease Abdominal pain mimicking peptic ulcer disease - With stomach or duodenal infection Malabsorption - With infection of the small intestine Pain, diarrhea, or hematochezia - With infection of the colon MDR-TB is defined as resistance to isoniazid and rifampin, which are the 2 most effective first-line drugs for TB. In 2006, an international survey found that 20% ofM tuberculosis isolates were MDR.[15] A rare type of MDR-TB, called extensively drug-resistant TB (XDR-TB), is resistant to isoniazid, rifampin, any fluoroquinolone, and at least one of 3 injectable second-line drugs (ie, amikacin, kanamycin, or capreomycin)
  • #12: Two sputum samples are collected over two days (as spot-morning/morning-spot) from chest symptomatics (patients with presenting with a history of cough for two weeks or more) to arrive at a diagnosis. In addition to the test's high specificity, the use of two samples ensures that the diagnostic procedure has a high (>99%) test sensitivity as well. As a national health program, RNTCP pays more attention to the sputum-positive pulmonary tuberculosis patients (who are likely to spread the disease in the community) than people with other, non-pulmonary forms of the disease. Clinical monitoring includes at least monthly assessment for symptoms (nausea， vomiting， abdominal discomfort， and unexplained fatigue) and signs (jaundice， dark urine， light stools， diffuse pruritus) of hepatotoxicity， although the latter represent comparatively late manifestations Clinical illness directly following infection is ιlassified as primary TB and is ιommon among ch且dren III 出e first fewyears oflife and among immunocompromised persons. Although primary TB may be severe and disseminated， it generally is not associated with high-level transmissibility. When infection is acquired later in life， the chance is greater that the mature immune system will contain it at least temporarily. Bacilli， however， may persist for years before reactivating to produce secondary (orpos飞primary) TB， which， because of frequent cavitation， is more often infectious than is primary disease. Overall， it is estimated that up to 10% ofinfected persons will eventually develop active TB in their lifetime-half of them during the first 18 months after infection. The risk is much higher among HIV-infeιted persons. Reinfection of a previously infeιted individual， which is common in areas with high rates of TB transmission， may also favor the development of disease. Among infected persons， the incidence of TB is highest during late adolescence and early adulthood; the reasons are unclear. The incidence among women peaks at 25-34 years of age. In this age group， rates among women may be higher than those among men， whereas at older ages the opposite is true. The risk increases in the elderly， possibly because ofwaning immunity and comorbidity. A variety ofdiseases and conditions favor the development of active TB (Table 202-1). In absolute terms， the most potent risk factor for TB among infected individuals is clearly HIV co-infection， which suppresses cellular immunity. The risk that LTBI will proceed to active disease is directly related to the patient's degree of immunosuppression. In a study of HIV-infected， tuberculin skin test (TST)-positive 1 1 05 persons， this risk varied from 2.6 to 13.3 cases/100 person-years and � increased as the CD4+ T cell count decreased.
  • #13: Infection with M tuberculosis results most commonly through exposure of the lungs or mucous membranes to infected aerosols. Droplets in these aerosols are 1-5 μm in diameter; in a person with active pulmonary TB, a single cough can generate 3000 infective droplets, with as few as 10 bacilli needed to initiate infection. When inhaled, droplet nuclei are deposited within the terminal airspaces of the lung. The organisms grow for 2-12 weeks, until they reach 1000-10,000 in number, which is sufficient to elicit a cellular immune response that can be detected by a reaction to the tuberculin skin test. Mycobacteria are highly antigenic, and they promote a vigorous, nonspecific immune response. Their antigenicity is due to multiple cell wall constituents, including glycoproteins, phospholipids, and wax D, which activate Langerhans cells, lymphocytes, and polymorphonuclear leukocytes When a person is infected with M tuberculosis, the infection can take 1 of a variety of paths, most of which do not lead to actual TB. The infection may be cleared by the host immune system or suppressed into an inactive form called latent tuberculosis infection (LTBI), with resistant hosts controlling mycobacterial growth at distant foci before the development of active disease. Patients with LTBI cannot spread TB. The lungs are the most common site for the development of TB; 85% of patients with TB present with pulmonary complaints. Extrapulmonary TB can occur as part of a primary or late, generalized infection. An extrapulmonary location may also serve as a reactivation site; extrapulmonary reactivation may coexist with pulmonary reactivation. The most common sites of extrapulmonary disease are as follows (the pathology of these lesions is similar to that of pulmonary lesions): Mediastinal, retroperitoneal, and cervical (scrofula) lymph nodes - The most common site of tuberculous lymphadenitis (scrofula) is in the neck, along the sternocleidomastoid muscle; it is usually unilateral and causes little or no pain; advanced cases of tuberculous lymphadenitis may suppurate and form a draining sinus Vertebral bodies Adrenals Meninges GI tract Infected end organs typically have high regional oxygen tension (as in the kidneys, bones, meninges, eyes, and choroids, and in the apices of the lungs). The principal cause of tissue destruction from M tuberculosis infection is related to the organism's ability to incite intense host immune reactions to antigenic cell wall proteins. Uveitis caused by TB is the local inflammatory manifestation of a previously acquired primary systemic tubercular infection. There is some debate with regard to whether molecular mimicry, as well as a nonspecific response to noninfectious tubercular antigens, provides a mechanism for active ocular inflammation in the absence of bacterial replication. TB lesions The typical TB lesion is an epithelioid granuloma with central caseation necrosis. The most common site of the primary lesion is within alveolar macrophages in subpleural regions of the lung. Bacilli proliferate locally and spread through the lymphatics to a hilar node, forming the Ghon complex. Early tubercles are spherical, 0.5- to 3-mm nodules with 3 or 4 cellular zones demonstrating the following features: A central caseation necrosis An inner cellular zone of epithelioid macrophages and Langhans giant cells admixed with lymphocytes An outer cellular zone of lymphocytes, plasma cells, and immature macrophages A rim of fibrosis (in healing lesions) Initial lesions may heal and the infection become latent before symptomatic disease occurs. Smaller tubercles may resolve completely. Fibrosis occurs when hydrolytic enzymes dissolve tubercles and larger lesions are surrounded by a fibrous capsule. Such fibrocaseous nodules usually contain viable mycobacteria and are potential lifelong foci for reactivation or cavitation. Some nodules calcify or ossify and are seen easily on chest radiographs. Tissues within areas of caseation necrosis have high levels of fatty acids, low pH, and low oxygen tension, all of which inhibit growth of the tubercle bacillus. If the host is unable to arrest the initial infection, the patient develops progressive, primary TB with tuberculous pneumonia in the lower and middle lobes of the lung. Purulent exudates with large numbers of acid-fast bacilli can be found in sputum and tissue. Subserosal granulomas may rupture into the pleural or pericardial spaces and create serous inflammation and effusions. With the onset of the host immune response, lesions that develop around mycobacterial foci can be either proliferative or exudative. Both types of lesions develop in the same host, since infective dose and local immunity vary from site to site. Proliferative lesions develop where the bacillary load is small and host cellular immune responses dominate. These tubercles are compact, with activated macrophages admixed, and are surrounded by proliferating lymphocytes, plasma cells, and an outer rim of fibrosis. Intracellular killing of mycobacteria is effective, and the bacillary load remains low. Exudative lesions predominate when large numbers of bacilli are present and host defenses are weak. These loose aggregates of immature macrophages, neutrophils, fibrin, and caseation necrosis are sites of mycobacterial growth. Without treatment, these lesions progress and infection spreads. Previous Next Se
  • #14: M. tuberculosis is most commonly transmitted from a person with infectious pulmonary TB by droplet nuclei， which are aerosolized by coughing， sneezing， or speaking. The tiny droplets dry rapidly; the smallest (<5-10 f!m in diameter) may remain suspended in the air for several hours and may reach the terminal air passages when inhaled. There may be as many as 3000 infectious nuclei per cough. Other routes oftransmission oftubercle bacilli (e.g.， through the skin or the placenta) are uncommon and of no epidemiologic significance. The probab山ty of contact with a person who has an infectious form of TB， the inti macy and duration of that contact， the degree of infectiousness of the case， and the shared environment in which the contact takes place are all important determinants of the likelihood of transmission. Several studies of close-contact situations have clearly demonstrated that TB patients whose sputum contains AFB visible by microscopy (sputum smear-positive cases) are the most likely to transmit the infection. The most infectious patients have ca叽tary pulmonary disease or， much less common片， laryngeal TB and produce sputum containing as many as 105-10' AFB/mL. Patients with sputum smear-negative/culturepositive TB are less infectious， although they have been responsible for up to 20% of transmission in some studies in the United States. Those with culture-negative pulmonary TB and extrapulmonary TB are essentially noninfectious. Because persons with both HIV infection and TB are less likely to have cavitations， they may be less infectious than persons without HIV co-infection. Crowding in poorlyventilated rooms is one ofthe most important factors in the transmission oftubercle bacilli because it increases the intensity of contact wi出 a case. The risk ofacquiring M. tuberculosis infection is determined mainly by exogenous factors. Because ofdelays in seeking care and in making a diagnosis， it is generally estimated that， in high-prevalence settings， up to 20 contacts may be infected by each AFB-positive case before the index case is diagnosed. Primary Disease Primary pulmonarγ TB occurs soon after the initial infection with tubercle bacilli. It may be asymptomatic or may present with fever and occasionally pleuritic chest pain. 1n areas of high TB transmission， this form of disease is often seen in children. Because most inspired air is distributed to the middle and lower lung zones， these areas are most commonly involved in primary TB. The lesion forming after initial infection (Ghon focus) is usually peripheral and accompa nied by transient hilar or paratracheal lymphadenopathy， which may or may not be visible on standard chest radiography (Fig. 202-4). Some patients develop erythema nodosum on the legs (see Fig. 25e-40) or phlyctenular conjunctivitis. 1n the majority of cases， the lesion heals spontaneously and becomes ev陆nt only as a small calcified nodule. Pleural reaction overlying a subpleural focus is also common. The Ghon focus， with or without overlying pleural reaction， thickening， and regional l严nphadenopathy， is referred to as the Ghon complex. 1n young children with immature CM1 and in persons with impaired immunity (e.g.， those with malnutrition or H1V infection)， primary pulmonary TB may progress rapidly to clinical illness. The initial lesion increases in size and can evolve in different ways. Pleural effusion， which is found in up to two-thirds of cases， results from the penetration of bacilli into the pleural space from an adjacent subpleural focus. 1n severe cases， the primary site rapidly enlarges， its central portion undergoes necrosis， and cavitation develops (progressive primary TB). TB in young children is almost invariably accompanied by hilar or paratracheal lymphadenopathy due to the spread of bacilli from the lung parenchyma through lymphatic vessels. Enlarged lymph nodes may compress bronchi， causing total obstruction with distal collapse， partial obstruction with large-airway wheezing， or a ball-valve effect with segmental!lobar hyperinflation. Lymph nodes may also rupture into the airway with development of pneumonia， often including areas of necrosis and cavitation， distal to the obstruction. Bronchiectasis (Chap. 312) may develop in any segment/lobe damaged 主 by progressive caseating pneumonia. Occult hematogenous dissemina- � tion commonly follows primary infection. However， in the absence ofa Q' sufficient acquired immune response， which usually contains the infecV; tion， disseminated or miliary disease may result
  • #16: The WHO-recommended Directly Observed Treatment, Short Course (DOTS) strategy was launched formally as Revised National TB Control programme in India in 1997 after pilot testing from 1993-1996. Since then DOTS has been widely advocated and successfully applied.      DOTS is the most effective strategy available for controlling TB. 5.Systematic recording and reporting system that allows assessment of treatment results of each and every patient and of whole TB control programme. RNTCP is already addressing almost all of the components of the stop TB strategy.
  • #17: In 2006, WHO developed a six point Stop TB Strategy which builds on the successes of DOTS while also explicitly addressing the key challenges facing TB. Its goal is to dramatically reduce the global burden of tuberculosis by 2015 by ensuring all TB patients, including for example, those co-infected with HIV and those with drug-resistant TB, benefit from universal access to high-quality diagnosis and patient-centered treatment. The strategy also supports the development of new and effective tools to prevent, detect and treat TB. The Stop TB Strategy underpins the Stop TB Partnership's Global Plan to Stop TB 2006-2015.
  • #18: ,
  • #21: patients aged over 60 years may not be able to tolerate more than 500–750 mg daily, so some guidelines recommend reduction of the dose to 10 mg/kg per day in patients in this age group (2). patients weighing less than 50 kg may not tolerate doses above 500–750 mg daily
  • #23: Sta ndard short-course regimens are divided into an initial， or bac tericidal， phase and a continuation， or sterilizing， phase. During the initial phase， the majority of the tubercle bacilli are killed， symptoms resolve， and usually the patient becomes noninfectious. The continuation phase is required to eliminate persisting mycobacteria and prevent relapse. The treatment regimen of choice for virtually all forms of drug-susceptible TB in adults consists of a 2-month initial (or intensive) phase of isoniazid， rifampin， pyrazi namide， and etham butol followed by a 4-month continuation phase of isoniazid and rifampin (Table 202-3). This regimen can cure TB in more than 90% of patients. ln children， most forms of TB in the absence of HIV infec tion or suspected isoniazid resistance can be safely treated without ethambutol in the intensive phase.
  • #24: Patients who weigh 60kg or more receive additional Rifampicin 150mg. Patients who are more than 50 years old receive Streptomycin 500mg. Patients who weigh less than 30kg receive drugs as per Pediatric weight band boxes according to body weight.
  • #25: Key: [========] intensive phase of treatment (HrZe) [------------] continuation phase (Hr) • Sputum smear examination sm + Smear-positive a omit if patient was smear-negative at the start of treatment and at 2 months. b Smear- or culture-positivity at the fifth month or later (or detection of mdr-TB at any point) is defined as treatment failure and necessitates re-registration and change of treatment as described in section 3.7.
  • #26: STANDARD REGIMENS FOR PREVIOUSLY TREATED PATIENTS depending on the availability of routine dST to guide the therapy of individual retreatment patients The assumption that failure patients have a high likelihood of mdr (and relapse or defaulting patients a medium likelihood) may need to be modified according to the level of mdr in these patient registration groups, as well considerations discussed in section 3.8. b And other patients in groups with high levels of mdr. one example is patients who develop active TB after known contact with a patient with documented mdr-TB. patients who are relapsing or returning after defaulting from their second or subsequent course of treatment probably also have a high likelihood of mdr. c regimen may be modified once dST results are available (up to 2–3 months after the start of treatment). Previous TB treatment is a strong determinant of drug resistance (10), and previously treated patients comprise a significant proportion (13%) of the global TB notifications in 2007. Of all the forms of drug resistance, it is most critical to detect multidrug resistance (MDR) because it makes regimens with first-line drugs much less effective (11) and resistance can be further amplified (12). Prompt identification of MDR and initiation of MDR treatment with second-line drugs gives a better chance of cure and prevents the development and spread of further resistance. Because of its clinical significance, MDR (rather than any drug resistance) is used to describe the retreatment patient groups below. At the global level, 15% of previously treated patients have MDR (8), which is five times higher than the global average of 3% in new patients (Figure 3.1). Even in Africa, the WHO region thought to have the lowest level of MDR in retreatment patients, a significant proportion (6%) of retreatment patients have MDR-TB (8).1 If their MDR is not detected and treated with second-line drugs, these patients will suffer poor outcomes and spread MDR in their communities. The Global Plan to Stop TB 2006–2015 sets a target of all previously treated patients having access to DST at the beginning of treatment by 2015. The purpose is to identify MDR as early as possible so that appropriate treatment can be given.
  • #27: Smear- or culture-positivity at the fifth month or later (or detection of mdr-TB at any point) is defined as treatment failure and necessitates reregistration and change of treatment Bacteriologic evaluation through culture and/or smear microscopy is essential in monitoring the response to treatment for TB. In addition， the patient's weight should be monitored regularly and the drug dosage adjusted with any significant weight change. Multidrug-resistant TB (MDR-TB) is defined as disease caused by a strain of M. tuberculosis that is resistant to both isoniazid and rifampin-the most efficacious of the first-line TB drugs. The risk of MDR-TB is elevated in patients presenting from geographic areas in which 三5% of incident cases are MDR-TB and in patients previously treated for TB. Treatment regimens for MDR-TB generally include a late-generation fluoroquinolone and an injectable second-line agent (such as capreomycin， amikacin， or kanamycin). Regimens of at least five drugs are reιommended for the treatment of MDR-TB. Both standardized and optimized/ customized regimens are in use around the world. Extensively drug-resistant TB (XDR-TB) is defined as MDR-TB with additional resistance to any fluoroquinolone and at least one ofthe second-line injectable agents.
  • #28: Patients with pulmonary disease should have their sputum examined monthly until cultures become negative to allow early detection oftreatment failure. With the recommended regimen， more than 80% of patients wil l have negative sputum cultures at the end of the second month of treatment. By the end of the third month， the sputu m of virtually all patients should be culture negative. I n some patients， especially those with extensive cavitary disease and large numbers of organisms， AFB smear conversion may lag behind culture conversion. This phenomenon is presumably due to the expectoration and microscopic visualization of dead bacilli. As noted above， patients with cavitary disease in whom sputum culture conversion does not occur by 2 months require immediate testing for drug resistance. When a patient's sputum cultures remain positive at 二3 months， treatment failure and drug resistance or poor adherence to the regimen are likely， and testing of d rug resista nce should guide the choice of the best treatment option (see below). A sputum specimen should be col lected by the end of treatment to document cure. If mycobacterial cultures are not practical， then monitoring by AFB smear examination should be undertaken at 2， 5， and 6 months. Smears that are positive after 3 months of treatment when the patient is known to be adherent are indicative of treatment failure and possible drug resistance. Therefore, if not done at the start of treatment， drug susceptibility testing is mandatory at this stage. Serial chest radiographs are not recommended because radiog raphic changes may lag behind bacteriologic response and are not hig hly sensitive.
  • #29: Cohort analysis is the key management tool used to evaluate the effectiveness of the national TB control programme. It enables the identification of problems, so that the programme managers and staff can institute appropriate action to overcome them and improve programme performance. Evaluation of the outcomes of treatment and trends must be done at peripheral, district, regional and national levels to allow any necessary corrective action to be taken. It can also identify districts or units that are performing well and allows for positive feedback to be provided to staff; successful practices can then be replicated elsewhere.
  • #32: a These definitions apply to pulmonary smear-positive and smear-negative patients, and to patients with extrapulmonary disease. outcomes in these patients need to be evaluated separately. B The sputum examination may not have been done or the results may not be available. C for smear- or culture-positive patients only.
  • #34: During treatment， patients should be monitored for drug toxicity. The most common adverse reaction of signi白cance is hepatitis. Patients should be carefully educated about the signs and symptoms of drug-induced hepatitis (e.g.， dark urine， loss ofappetite) and should be instructed to discontinue treatment promptly and see their health care provider should these symptoms occur. Although biochemical monitoring is not routinely recommended， all adult patients should undergo baseline assessment of liver function (e.g.， measurement of serum levels of hepatic aminotransferases and bilirubin). Older patients， those with concomitant diseases， those with a history of hepatic disease (especially hepatitis C)， and those using alcohol daily should be monitored especially closely (i.e.， monthly)， with repeated measurements of aminotransferases， during the initial phase of treatment. Up to 20% of patients have small increases in aspa同ate amino transferase (up to three times the upper limit of normal) that are not accompanied by symptoms and are of no consequence. For patients with symptomatic hepatitis and those with marked (five- to sixfold) elevations in serum levels of aspartate aminotransfera妃， treatment should be stopped and drugs reintroduced one at a time after liver function has returned to normal. Hypersensitivity reactions usually require the discontinuation of all drugs and rechallenge to determine which agent is the culprit. Because of the variety of regimens avail able， it usually is not necessary-although it is possible-to desensi tize patients. Hyperuricemia and arthralgia caused by pyrazinamide can usually be managed by the administration of acetylsalicylic acid; however， pyrazinamide treatment should be stopped if the patient develops gouty arthritis. Individuals who develop autoimmune thrombocytopenia secondary to rifampin therapy should not receive the drug thereafter. Similarly， the occurrence of optic neuritis with ethambutol is an indication for permanent discontinuation of - this dr吨. Other common manifestations of d由『阳u呵Jg int川tole阳 p阳r阳川ur川i让tus and ga剖ast引t刚n阳t怡e臼esti引蚓仙stin由加i忖川n叫 up阳5兜划e创t， c曰an gener阳al川lIy忖y be managed with- 主 out the interruption of therapy.
  • #35: The adverse effects of essential anti-TB drugs are described in Annex 1. Table 4.2 shows a symptom-based approach to the management of the most common adverse effects, which effects are classified as major or minor. In general, a patient who develops minor adverse effects should continue the TB treatment and be given symptomatic treatment. If a patient develops a major side-effect, the treatment or the responsible drug is stopped; the patient should be urgently referred to a clinician or health care facility for further assessment and treatment. Patients with major adverse reactions should be managed in a hospital. 4.10.1 management of cutaneous reactions If a patient develops itching without a rash and there is no other obvious cause, the recommended approach is to try symptomatic treatment with antihistamines and skin moisturizing, and continue TB treatment while observing the patient closely. If a skin rash develops, however, all anti-TB drugs must be stopped. Once the reaction has resolved, anti-TB drugs are reintroduced one by one, starting with the drug least likely to be responsible for the reaction (rifampicin or isoniazid) at a small challenge dose, such as 50 mg isoniazid (3). The dose is gradually increased over 3 days. This procedure is repeated, adding in one drug at a time. A reaction after adding in a particular drug identifies that drug as the one responsible for the reaction. The alternative regimens listed in section 4.10.2 below are also applicable when a particular drug cannot be used because it was implicated as the cause of a cutaneous reaction. 4.10.2 management of drug-induced hepatitis This section covers hepatitis presumed to be induced by TB treatment. Of the first-line anti-TB drugs, isoniazid, pyrazinamide and rifampicin can all cause liver damage (drug-induced hepatitis). In addition, rifampicin can cause asymptomatic jaundice without evidence of hepatitis. It is important to try to rule out other possible causes before deciding that the hepatitis is induced by the TB regimen. The management of hepatitis induced by TB treatment depends on: — whether the patient is in the intensive or continuation phase of TB treatment; — the severity of the liver disease; — the severity of the TB; and — the capacity of the health unit to manage the side-effects of TB treatment. If it is thought that the liver disease is caused by the anti-TB drugs, all drugs should be stopped. If the patient is severely ill with TB and it is considered unsafe to stop TB treatment, a non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fluoroquinolone should be started. If TB treatment has been stopped, it is necessary to wait for liver function tests to revert to normal and clinical symptoms (nausea, abdominal pain) to resolve before reintroducing the anti-TB drugs. If it is not possible to perform liver function tests, it is advisable to wait an extra 2 weeks after resolution of jaundice and upper abdominal tenderness before restarting TB treatment. If the signs and symptoms do not resolve and the liver disease is severe, the non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fluoroquinolone should be started (or continued) for a total of 18–24 months (7). Once drug-induced hepatitis has resolved, the drugs are reintroduced one at a time. If symptoms recur or liver function tests become abnormal as the drugs are reintroduced, the last drug added should be stopped. Some advise starting with rifampicin because it is less likely than isoniazid or pyrazinamide to cause hepatotoxicity and is the most effective agent (7, 8). After 3–7 days, isoniazid may be reintroduced. In patients who have experienced jaundice but tolerate the reintroduction of rifampicin and isoniazid, it is advisable to avoid pyrazinamide. Alternative regimens depend on which drug is implicated as the cause of the hepatitis. If rifampicin is implicated, a suggested regimen without rifampicin is 2 months of isoniazid, ethambutol and streptomycin followed by 10 months of isoniazid and ethambutol. If isoniazid cannot be used, 6–9 months of rifampicin, pyrazinamide and ethambutol can be considered. If pyrazinamide is discontinued before the patient has completed the intensive phase, the total duration of isoniazid and rifampicin therapy may be extended to 9 months If neither isoniazid nor rifampicin can be used, the non-hepatotoxic regimen consisting of streptomycin, ethambutol and a fluoroquinolone should be continued for a total of 18–24 months. Reintroducing one drug at a time is the optimal approach, especially if the patient’s hepatitis was severe. National TB control programmes using FDC tablets should therefore stock limited quantities of single anti-TB drugs for use in such cases. However, if the country’s health units do not yet have single anti-TB drugs, clinical experience in resource-limited settings has been successful with the following approach, which depends on whether the hepatitis with jaundice occurred during the intensive or the continuation phase. • When hepatitis with jaundice occurs during the intensive phase of TB treatment with isoniazid, rifampicin, pyrazinamide and ethambutol: once hepatitis has resolved, restart the same drugs EXCEPT replace pyrazinamide with streptomycin to complete the 2-month course of initial therapy, followed by rifampicin and isoniazid for the 6-month continuation phase. • When hepatitis with jaundice occurs during the continuation phase: once hepatitis has resolved, restart isoniazid and rifampicin to complete the 4-month continuation phase of therapy.
  • #38: Many TB patients have concomitant illnesses. At the start of TB treatment, all patients should be asked about medicines they are currently taking. The most important interactions with anti-TB drugs are due to rifampicin. Rifampicin induces pathways that metabolize other drugs, thereby reducing the concentration and effect of those drugs. To maintain a therapeutic effect, dosages of the other drug(s) may need to be increased. When rifampicin is discontinued, its metabolism-inducing effect resolves within about 2 weeks, and dosages of the other drug(s) will need to be reduced Rifampicin interacts with oral contraceptive medications leading to lowered protective efficacy. A woman receiving oral contraception may choose between two options while receiving treatment with rifampicin: following consultation with a clinician, an oral contraceptive pill containing a higher estrogen dose (50 µg), or another form of contraception.
  • #41: and rifampin supplemented by ethambutol for the first 2 months. Although the WHO has recom mended routine use of pyrazinamide for preg nant women， this drug has not been recom mended in the United States because of insufficient data documenting its safety in pregnancy. Streptomycin is contraindicated because it is known to cause eig hth-cranial-nerve damage in the fetus. Treatment for TB is not a contraindication to breast-feeding; most of the drugs administered wil l be present in small quantities in breast milk， albeit at concentrations far too low to provide any therapeutic or prophylactic benefjt to the child. Women of childbearing age should be asked about current or planned pregnancy before starting TB treatment. A pregnant woman should be advised that successful treatment of TB with the standard regimen is important for successful outcome of pregnancy. A breastfeeding woman who has TB should receive a full course of TB treatment. Timely and properly applied chemotherapy is the best way to prevent transmission of tubercle bacilli to the baby. Mother and baby should stay together and the baby should continue to breastfeed. After active TB in the baby is ruled out, the baby should be given 6 months of isoniazid preventive therapy, followed by BCG vaccination
  • #43: Note that TB itself may involve the liver and cause abnormal liver function. 2 In some cases of concurrent acute (i.e. viral) hepatitis not related to TB or TB treatment, it may be possible to defer TB treatment until the acute hepatitis has resolved. In patients with unstable or advanced liver disease, liver function tests should be done at the start of treatment, if possible. If the serum alanine aminotransferase level (6) is more than 3 times normal before the initiation of treatment,1 the following regimens should be considered (also discussed in section 4.10.2).2 The more unstable or severe the liver disease is, the fewer hepatotoxic drugs should be used.
  • #44: Expert consultation is advisable in treating patients with advanced or unstable liver disease. Clinical monitoring (and liver function tests, if possible) of all patients with preexisting liver disease should be performed during treatment.
  • #46: As a rule， patients with chronic renal failure should not receive aminoglycosides and should receive etha m butol only if seru m d rug l evels can be mon itored . Isoniazid， rifampin， and pyrazinamide may be given in the usual doses in cases of mild to moderate renal failure， but the dosages of isoniazid and pyrazinamide should be reduced for all patients with severe renal failure except those undergoing hemodialysis.
  • #75: MECHANISM OFACTlON 1soniazid is a prodrug activated by the mycobacterial KatG catalase-peroxidase; isoniazid is coupled with reduced nicotinamide adenine dinucleotide (NADH). The resulting isonicotinic acyl-NADH complex blocks the mycobacterial ketoenoylreductase known as 1nhA， binding to its substrate and inhibiting fatty acid syn thase and ultimately mycolic acid synthesis. Mycolic acids are essential components ofthe mycobacterial cell wall. KatG activation ofisoniazid also results in the release of free radicals that have antimycobacterial activity， including nitric oxide.