Treatment of Tuberculosis | Jindal Chest Clinic

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• Treatment
• of TB

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Historical landmarks

• Magical and supernatural treatments
• Tubercle bacillus (Mycobacterium tuberculosis)
  Discovered on March 24, 1882 by Robert Koch
  (Awarded Nobel Prize in 1905)
• Air, Diet, Fish-oils, Minerals etc
• Sanatoria treatment
• Chemotherapy Streptomycin (1944),
• P.A.S., Isoniazid
  (1952)
• Ethambutal,
  Rifampicin (1960s-70s)
• Other new drugs
  (1980s onwards)
• Regimens and Strategies (SCC, Intermittent,
  DOTS)

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Treatment Issues

• Principles of therapy
• Goals
• Scientific Rationale Bacterial Populations
• Drugs and Regimens Efficacy, toxicity, costs
• Strategies Efficacy, compliance
• Surgical Options
• Relapses and sequelae
• Specific situations Comorbidities
• Multi and Extreme Drug Resistance (MDR/XDR)
• TB HIV infection

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Objectives of TB treatment

• To decrease mortality and long term morbidity by
• Ensuring care
• Minimizing relapses
• Preventing development of drug resistance
• To decrease and break the chain of transmission
  of infection
• To achieve the above whilst minimizing side
  effects due to drugs

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Treatment Principles

• Most effective therapy to achieve early negative
  status
• Adequate period of time to ensure complete
  sterilization
• Most effective utilization of available resources
• Ensuring compliance
• Looking after social aspects

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Why is the TB Therapy Long?

• Nature of the disease pathology
• High Load
• Poor drug penetration
• Phenotypic resistance in persisters
• Non-growing mycobacteria
• Stationary phase bacteria
• Residual survivors or persisters not killed
  during antibiotic exposure
• Dormant bacilli
• 3. Poor host immune system for residual bacteria
  (not killed by drugs)

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Bacterial Populations and Chemotherapy

• A. Active growing
• T.b. INH
• Metabolic B. Bacilli with spurts
• Activity of metabolism RIF
• C. Bacilli in acid pH
  PZA
• D. Persisters

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Classification of Anti-TB drugs

• Bacteristatic Ist line vs
• Vs bactericidal Second line
• Anti TB Drugs
• TB specific drugs vs
• Broad spectrum antibiotics

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Anti TB drugs (Stop TB Deptt., WHO)

• Group Drugs
• I Oral H,R,Z,E
• New generation rifamycin-rifabutin
  and rifapentine
• (For HIV-TB)
• II Injectables Kana, Amika,
  Capreo, Strepto
• III Fluoroquinolones Moxi, Gati,
  Levo, Ofloxacin
• IV Oral bacteriostatic, 2nd line
  drugs thioamides, cycloserine, RAS, Terizidone
• V Unclear efficacy Clofazimine,
  Linezolid, High dose H antibiotics

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Drug side-effects/ Toxicities (Ist line drugs)

• INH Neuropathy, skin reactions, hepatitis,
  fever
• RIF Hepatitis, Flu like syndrome, Nephritis
• ETM Retrobulbar/ Optic neuritis, Skin rashes
• PZN Hyperuricaemia, hepatotoxicity, skin rashes
• STM Ototoxicity, vestibular toxicity, skin
  rashes
• PAS GI upset, hypersensitivity, fever, rashes
• Allergic reactions, skin rashes and GI
  intolerance can occur with almost any drug

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Hepatotoxic anti-tuberculous agents
Hepatotoxic Non-hepatotoxic
Isoniazid Ethambutol
Rifampicin Streptomycin
Pyrazinamide Kanamycin
Ethionamide Amikacin
Para-aminosalicylic acid Cycloserine
Capreomycin
Fluoroquinolones
Rare hepatotoxic reactions may occur Rare hepatotoxic reactions may occur
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Treatment strategies (Short Course Chemotherapy

• Use of multiple drugs
• Most effective drugs
• Intensive followed by maintenance phase
• Ensuring compliance and completion

• 4 (Intensive phase)
• 2-3 (Maintenance)
• R, H, Z
• 2 4 months
• DOTS

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Drugs and Regimens

• Daily
• Intensive Phase
• RHZE (2 mths)
• Maintenance
• RH (4 mths)
• RHE (HIV ve Pts)
• Intermittent (Always supervised)
• RNTCP Regimen Category I
• 2 R3 H3 Z3 E3 (24 doses)
• 4 R3 H3 (54 doses)

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Tmt for EPTB
Duration (Mth)
Lymph node 6
Bone joint 6-9
Pleural disease 6
Pericarditis 6
CNS 9-12
Disseminated 6
Genitourinary 6
Peritoneal 6
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Paradoxical Reactions

• Worsening during ATT (e.g. LN, Pl. effusion)
• ? Ongoing inflammation/fibrosis
• ? Immune reconstitution (esp. HIV)
• ? Release of toxins
• Treatment
• Anti-inflammatory drugs
• ? Corticosteroids
• No need for ATT prolongation / 2nd line

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• Revised National TB Control Programme (RNTCP)

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WHY REVISED ?

• National Tuberculosis Programme
• Started in 1962
• Domiciliary treatment at District TB centers
• Over dependence on chest X-ray for diagnosis
• Self administered drug regimens
• Poor funding
• Poor treatment completion rates
• RNTCP
• Started in 1997
• Presently covers the entire country

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Directly Observed Treatment, Short course (DOTS)

• Principle strategy of RNTCP
• Components
• Sustained political commitment
• Access to quality-assured TB sputum microscopy
• Standardized short-course chemotherapy
• Uninterrupted supply of quality assured drugs
• Recording and reporting system enabling outcome
  assessment

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Diagnosis of pulmonary tuberculosis

• Patients with TB feel ill and seek care promptly
• Active case finding is unnecessary and
  unproductive
• Microscopy is appropriate technology, indicating
  infectiousness, risk of death, and priority for
  treatment
• X-ray is non-specific for TB diagnosis
• Serological and amplification technologies (PCR,
  etc.) currently of no proven value in TB control

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Diagnosis of Pulmonary Tuberculosis

• Two specimens optimal
• Spot specimen on first visit sputum container
  given to patient
• Early morning collection by patient on next day
• Spot specimen during second visit

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Patient categorization

• New patients (Cat. I and III merged)
• Previously treated / Retreatment cases/
  Defaulters (Cat. II)
• Other specific categories
• Multi-drug resistant TB (Cat IV)
• TB and HIV

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What is DOTS ?

• A strategy (Directly Observed Therapy, Short
  Course) to ensure treatment completion in which
• Treatment observer (DOT provider) must be
  accessible and acceptable to the patient and
  accountable to the health system
• DOT provider administers the drugs in intensive
  phase.
• Ensures that the patient takes medicines
  correctly in continuation phase.
• Provides the necessary information and
  encouragement for completion of treatment.
• Direct observation ensures treatment for the
  entire course with the right drugs in the right
  doses at the right intervals

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Why DOTS?

1. To ensure compliance
2. To render early non-infectiousness
3. To standardize treatment regimen and avoid drug
   resistance
4. Provide free and affordable treatment
5. Control TB nationally and globally

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Treatment schedules (RNTCP)

• New cases 2 H3R3Z3E3 /
• 4 H3R3
• Previously treated 2 H3R3Z3E3S3/
• 1
  H3R3Z3E3 /
• 5 H3R3E3
• Treatment under Direct Supervision (DOTS)

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RNTCP What should be the duration?

• New patients should receive a 6 month regimen
• 2HRZE/ 4HR (Thrice weekly)
• Intensive Phase 2 months
• Maintenance Phase 4 months

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Can steroids help early resolution?

• No. Steroids have proven benefit in only
• TB Meninigitis
• TB Pericarditis
• Other uses of steroids in TB.
• (Tuberculous) Addisons disease
• Acute hypersensitivity reaction to ATT
• Severe, unresolving IRS (Immune Reconstitution
  Syndrome)

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Do anti TB drugs have interactions with other
drugs?

• Yes. Rifampicin induces pathways that metabolize
  other drugs.
• It reduces the concentrations and effects of
  following drugs
• Anti infective (macrolides, doxicycline, azole
  antifungals, mefloquine, antiretroviral)
• Hormones (tamoxifen, levothyroxine,
  ethinylestradiol, norethindrone)
• Cardiovascular agents digoxin, nifedipine,
  diltiazem, propranolol, hypo lipidaemics, etc.
• Others Methadone, warfarin, cyclosporin,
  corticosteroids, anti convulsants, theophylline,
  sulphoxylurla

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Can ATT be used safely during pregnancy?

• Yes, except streptomycin (Ototoxic to the fetus)
• Breast feeding should continue on ATT
• Treatment / Chemoprophylaxis for the babies of
  mothers with active TB

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ATT in patients with liver disease?

• No chronic liver disease Hepatitis virus
  carriers Past H/o hepatitis Excessive alcohol
  use
• Usual TB regimens
• More common hepatotoxic reactions
• Unstable / Advanced liver disease
• LFT before starting tmt. (ALT gt 3 times)
• Two hepatotoxic drugs
• 9 RHE
• 2 RHES 6 HR
• 6-9 RZE
• One hepatotoxic drug 2HES 10 HE
• No hepatotoxic drug 18-24 SE Flouro

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Latent MTB Infection

• A. Diagnosis
• Positive tuberculin test
• Exclude active disease
• B. Regimens
• INH for 12 mths For both
• HIV and cases
• R Z for 2 mths For HIV ve
• H R for 3 mths HIV ve
• R for 4 mths HIV ve

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• TB and HIV
• Co-infection

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Mechanisms of Coinfection

• Impairment of immune response
• Progressive depletion dysfunction of CD4
  lymphocytes
• Impaired macrophage function
• Invasion of inflamed bronchial walls the
  breeding sites

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Augmented Effects

• HIV on TB
• Rapid progression
• Active disease (40)
• Higher morbidity
• Mortality 4 times higher (than HIV ve), 20-35
• Increased ADRs to ATT
• Increased drug resistance (MDR and XDR)
• TB on HIV
• Increased viral replication, load, immune
  suppression, infections, morbidity and mortality

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How does TB occur?

• Endogenous reactivation
• HIV is most potent risk factor
• Exogenous (Re) infection
• Increased chances of TB exposure in hospitals

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Clinical Features

• Early stage (CD4 gt 200/mm3)
• Typical reactivation TB
• (Upper lobes infiltrates/cavities)
• Advanced stage (CD4 lt 200/mm3)
• Atypical disease
• Disseminated/extrapulmonary TB

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Clinical Presentation, Symptoms

• Fever, cough, chest pain, weight loss
• Chronic diarrhoea
• Generalized lymphadenopathy
• Organ specific symptoms and signs

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Atypical Manifestations (Pulmonary)

• Lower lobe/diffuse involvement
• Absence of cavity formation
• Endobronchial involvement
• Prominent hilar/mediastinal
• Pleural effusion common
• Miliary TB
• Chest wall abscess/cutaneous sinuses

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Extra Pulmonary TB

• LYMPH NODE
• - Commonest EP site
• - Peripheral
• - Intrathoracic
• -Intra-abdominal
• (accompanying visceral involvement)
• DISSEMINATED
• - Miliary or more than
• - one XP site
• - Mycobacteremia

• SKIN
• - May co-exist with pulmonary TB
• Erythematous papules, purpura, subcutaneous
  nodules, pustules
• Biopsy- little granuloma, AFB
• HEPATOSPLENIC
• Round, hypoechoic, multiple lesions lt1 cm
• TB MENINGITIS
• CSF findings may be normal
• LARYNGEAL

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Tuberculin skin testing

• Tuberculin reactivity four fold less in HIV
  infection
• Reactivity declines with increasing immune
  suppression
• early HIV 40-70
• advanced HIV 10-30
• Annual tuberculin testing for HIV infection to
  detect latent infection
• Tuberculin anergy assoc. with risk of active TB
  is controversial

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Treatment of HIV-TB dual infection

• Both ATT and ART (Anti retroviral treatment)
• HAART (Highly Active Anti-Retroviral Therapy)
• At least 3 drugs from amongst
• - Protease inhibitors
• - Reverse transcriptase inhibitors
• - Viral integrase enzyme inhibitors
• - Viral entry inhibitors
• Combined ATT and ATT is more toxic drug-drug
  interaction (Rif causes decrease in conc. of
  ARV),
• Rifabutin is an alternate choice.

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Tuberculosis and ARV Therapy
Status When to Start ARV Therapy
CD4 less than 200/mm3 Start TB Therapy Start ARV as soon as TB therapy can be tolerated
CD4 between 200 and 350/mm3 Start TB therapy Start ARV therapy after 2 mo. Of TB therapy with EFV
CD4 greater than 350/mm3 Treat TB, start ARV therapy according to general indications
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Why MDR/ XDR TB in HIV?

• Poor immune response leads to increased rapidly
  dividing bacilli and spontaneous mutations
• Noncompliance due to frequent ADR
• Large pill burden
• Malabsorption of ATT

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Adverse drug reactions

• More frequently in HIV infected, 20-25
• Related to level of immune activation and immune
  suppression
• Thiacetazone induced exfoliative dermatitis, TEN,
  Steven Johnson syndrome can be fatal
  (contraindicated with HIV)
• ATT induced hepatitis four fold higher than in
  seronegative patient
• Risk factors- anergy , lymphopenia, Elevated
  Neopterin levels

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Do anti TB drugs have interactions with other
drugs?

• Yes. Rifampicin induces pathways that metabolize
  other drugs.
• It reduces the concentrations and effects of
  following drugs
• Anti infective (macrolides, doxicycline, azole
  antifungals, mefloquine, antiretroviral)
• Hormones (tamoxifen, levothyroxine,
  ethinylestradiol, norethindrone)
• Cardiovascular agents digoxin, nifedipine,
  diltiazem, propranolol, hypo lipidaemics, etc.
• Others Methadone, warfarin, cyclosporin,
  corticosteroids, anti convulsants, theophylline,
  sulphoxylurla

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Paradoxical reaction

• Defined as temporary worsening of clinical
  condition, appearance of new radiologic
  manifestations after initiation of Tt ,and are
  not due to Tt failure or a second process
• Due to recovery of immunological Th 1 response to
  mycobacterial antigen
• Heightened granulomatous response may clear the
  organism but itself may cause tissue damage

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