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Latent TB Infection
- • TB infection is contained by host’s immune system
- → No symptoms or physical findings suggestive of TB disease
- → Retains potential to develop into active disease
- → Positive reaction to tuberculin skin test (TST) or TB blood test (Interferon Gamma Release Assay (IGRA))
- • Not infectious
- • Chest radiograph is typically normal
- • If done, respiratory specimens are smear and culture negative
- → Replicating intracellularly
- • Should consider treatment for LTBI to prevent TB disease
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Active TB (Pulmonary) Infection
- • Gradual onset
- → Slow growing organism- can take weeks to months to years
- • Symptomatic, actively replicating (≥ 1 of following)
- → Fever, productive cough, chest pain, weight loss, night sweats, hemoptysis (sign of advanced TB), fatigue, and decreased appetite
- • Infectious
- • TST/IGRA result usually positive
- • Atypical presentations may occur in HIV-positive patients and/or elderly patients
- • Chest radiograph is usually abnormal (i.e. infiltrates and cavitary lesions)
- → However, may be normal in persons with advanced immunosuppression or extrapulmonary disease
- • Respiratory specimens are usually smear or culture positive
- → However, may be negative in persons with extrapulmonary disease or minimal or early pulmonary disease
- • Needs treatment for TB disease
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Active TB (Extra-pulmonary) Infection
- • Slowly progressive decline in organ function
- → Has left the lung and has infected other parts of the body
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Clinical Manifestations: Primary Infection
- • Inflammatory response may lead to tissue necrosis and calcification of infected site
- → Caseous necrosis- calcification
- • 90% will have no clinical manifestations
- • 5% may have progressive primary disease
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Clinical Manifestations: Secondary Infection (Reactivation)
- • Organisms within granulomas emerge and begin multiplying extracellularly leading to inflammation and tissue necrosis
- → Aveoli destroyed
- • Pulmonary
- → Coughing, hemoptysis
- • Extrapulmonary
- → Dissemination- infection leaving the lungs
- • Miliary
- → All throughout the body- all organs infected
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Risk Factors for TB Infection
- • Place of birth
- → Mexico, Philippines, Vietnam, India, China
- • Location
- → California, Florida, New York, Texas (highly populated & large number of immigrants)
- → Urban areas
- • Close contacts
- → Family, coworkers, residents in prisons/shelters/nursing homes
- • Age (25 to 64 years)
- • Ethnic minorities (socioeconomic factors)
- → Hispanic, African American, Asian
- • Other
- → Limited access to healthcare
- → Homeless
- → Alcohol and/or drug abuse
- → Coinfection: HIV/AIDS, Hepatitis B
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Purified Protein Derivative (PPD) skin test
- • Becomes positive about 1 to 3 months after infection
- → Cannot screen newly infected patients
- • 0.1 mL of 5-tuburculin-unit PPD dose placed intradermally
- • T-cells in sensitized individuals lead to an inflammatory response causing induration (raised area)
- • Induration diameter read in 48 to 72 hours (need to measure size)
- • Interpretation also depends on TB infection risk and risk of progression to active disease
- • False positives occur in patients who received the Bacillius Calmette Guerin (BCG) Vaccine
- → BCG Vaccine often given in countries with high degree of tuberculosis disease
- • False negatives occur in up to 20% patients
- → No reaction on skin when they actually have the disease
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Induration ≥ 5 mm + Risk Factors
- • HIV-infected persons
- • Recent contact of a person with TB disease
- • Persons with fibrotic changes on chest radiograph consistent with prior TB
- • Patients with organ transplants
- • Persons who are immunosuppressed for other reasons (e.g., taking the equivalent of >15 mg/day of prednisone for 1 month or longer, taking TNF-α antagonists)
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Induration ≥ 10 mm + Risk Factors
- • Recent immigrants (< 5 years) from high-prevalence countries
- • Parenteral drug users (IVDU)
- • Residents & employees of high-risk congregate settings
- • Mycobacteriology laboratory personnel
- • Persons with clinical conditions that place them at high risk
- • Children < 4 years old
- • Infants, children, & adolescents exposed to adults in high-risk categories
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Induration ≥ 15 mm + Risk Factors
- • Any person, including persons with no known risk factors for TB
- • However, targeted skin testing programs should only be conducted among high-risk groups
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Blood Test (Interferon-gamma Release Assays or IGRAs)
- • Preferred in people who have:
- → Received bacille Calmette-Guérin (BCG) vaccine
- → Pts that cannot return for a second appointment to look for a reaction to the skin test
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Other TD Dx
- • AFB sputum smears
- → Daily morning sputum over 3 consecutive days
- • Culture (6 weeks)
- → Slow growing, takes a while
- • Chest X-Ray
- • Other:
- → Elevated WBC count
- → Signs and symptoms
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Steps in TB Disease
- Clinical evaluation for active TB and start therapy
- • Chest X-Ray, AFB sputum smear x 3, sputum culture, HIV test
- • Multi-drug regimen for 6-9 months
- Isolation
- • Negative pressure rooms in hospital
- → Specific requirements for controlled ventilation, negative pressure, and air filtration
- • Home on isolation
- Report to state’s Department of Health
- • Assigned a case number; track patient’s location and DOT (directly observed therapy)
- → Most effective strategy for making sure patients take medications
- • Monitor
- → Adherence
- → Adverse Effects
- → Drug Interactions
- → AFB sputum smears every 1 to 2 weeks until two consecutive smears are negative
- • All places and persons whom patient has been in contact
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Factors to Consider When Starting Therapy
- • Drug-susceptibility results of the presumed source case (if known)
- • Coexisting medical illness
- • Drug-drug interactions
- • Adverse Effects
- • Adherence
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First line drugs for TB
- • Isoniazid (INH)
- • Rifampin
- • Rifapentine
- • Rifabutin*Not FDA-approved for TB
- • Ethambutol
- • Pyrazinamide
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Second line drugs for TB
- • Cycloserine
- • Ethionamide
- • Levofloxacin
- • Moxifloxacin
- • Gatifloxacin
- • p-aminosalicylic acid
- • Streptomycin
- • Amikacin/kanamycin
- • Capreomycin
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Isoniazid (INH)
- • AKA: Iso Nicotinyl Hydrazide
- • First line agent for all forms of TB caused by organisms known or presumed to be susceptible
- • Profound bactericidal activity against rapidly dividing cells (active TB)
- • Tablets, elixer, IV/IM
- • 300 mg Daily 6-9 months
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Isoniazid (INH) ADRs
- • Aminotransferase elevation
- • Clinical or fatal hepatitis
- → Hepatotoxicity
- • Peripheral neurotoxicity
- • CNS effects
- • Lupus-like syndrome
- • Hypersensitivity reactions
- • Diarrhea
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Isoniazid (INH) Monitoring
- • Routine monitoring not necessary
- • LFTs should be measured monthly for those with abnormal liver function
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Rifampin (RIF)
- • First line agent for all forms of TB caused by organisms known or presumed to be susceptible
- • Has activity against organisms that are dividing rapidly (active TB)
- • Has activity against semi-dormant bacterial populations (latent infections)
- • Is an essential component of all short-course regimens
- • Capsule, powder/suspension, IV
- • 600 mg
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Rifampin (RIF) ADR
- • Cutaneous reactions
- • GI reactions
- • Flu-like syndrome
- • Hepatotoxicity
- • Severe immunologic reactions
- • Orange discoloration of bodily fluids
- • Induction of hepatic enzymes / drug interactions
- → Drugs will be metabolized at a faster rate
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Rifampin (RIF) Monitoring
- • No routine monitoring required
- • Evaluate for potential drug interactions
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Rifabutin
- • Used as a substitute for rifampin for all forms of TB caused by organisms known or presumed to be susceptible
- • Commonly used for patients that are having unacceptable drug interactions with rifampin or are intolerant to rifampin
- • Capsule
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Rifabutin ADRs
- • Hematologic toxicity
- • Uveitis
- • GI symptoms
- • Polyarthralgia
- • Hepatotoxicity
- • Pseudojaundice
- • Rash
- • Flu-like syndrome
- • Orange discoloration of bodily fluids
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Rifabutin Monitoring
- • Similar to that of rifampin
- → No predisposition for DIs like rifampin
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Rifapentine
- • May be used once weekly with INH in the continuation phase of treatment for HIV seronegative patients with non-cavitary, drug susceptible pulmonary TB with negative sputum smears at completion of the initial phase of Tx
- • Tablet
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Rifapentine ADRs
- • Similar to those of rifampin
- • Inducer of hepatic enzymes
- → Not to same extent as Rifampin
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Rifapentine Monitoring
- • Similar to that of rifampin
- → Not to same extent as Rifampin
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Pyrazinamide (PZA)
- • First line agent for all forms of TB caused by organisms known or presumed to be susceptible to the drug
- • Believed to exert greatest activity against population of dormant or semidormant organisms contained within macrophages or the acidic environment of caseous foci (necrotic pockets)
- • Tablet
- • 1,500 mg Daily
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Pyrazinamide (PZA) ADRs
- • Hepatotoxicity
- • GI symptoms
- • Polyarthralgia
- • Hyperuricemia
- • Gouty arthritis
- • Photosensitive dermatitis
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Pyrazinamide (PZA) Monitoring
• LFTs should be performed in patients with underlying liver disease, or when used with rifampin
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Ethambutol (EMB)
- • First-line agent included to primarily prevent emergence of RIF resistance when primary resistance to INH may be present
- • Tablet
- • 1,200 mg Daily
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Ethambutol (EMB) ADRs
- • Retrobulbar neuritis
- • Peripheral neuritis
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Ethambutol (EMB) Monitoring
- • Baseline visual acuity testing (monthly)
- • Testing of color discrimination (monthly)
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Use of Second Line Drugs
- • 1st line does not work due to resistance
- • Toxicity
- • ADRs
- • Drug interactions
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Reasons for Resistance (MDR)
- • Slow growing organism
- • Long duration of therapy
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Cycloserine
- • Used for treating patients with drug-resistant TB caused by organisms with known/presumed susceptibility to the drug
- • Capsule
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Cycloserine ADRs
CNS effects
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Cycloserine Monitoring
Neuropsychiatric status should be assessed monthly
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Ethionamide
- • Used for treating patients with drug-resistant TB caused by organisms with known/presumed susceptibility to the drug
- • Tablet
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Ethionamide ADRs
- • GI effects
- • Hepatotoxicity
- • Neurotoxicity
- • Endocrine effects
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Ethionamide Monitoring
LFTs baseline and monthly in patients with liver disease
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Streptomycin (SM)
- • Approximately equal to EMB in initial phase of treatment with 6 month regimens.
- • May have relatively high rate of resistance when TB is acquired in high-incidence countries
- • IV/IM
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Streptomycin (SM) ADRs
- • Ototoxicity
- • Neurotoxicity
- • Nephrotoxicity
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Streptomycin (SM) Monitoring
- • Audiogram, vestibular testing and SCr performed at baseline
- • Monthly SCr and questioning of auditory/vestibular symptoms (balance)
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Amikacin & kanamycin
- • Used for treating patients with drug-resistant TB caused by organisms with known/presumed susceptibility to the drug
- • Frequent cross-resistance to these drugs
- • Most SM-resistant strains are susceptible to these aminoglycosides
- • IV/IM
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Amikacin & kanamycin ADRs
- • Ototoxicity
- • Nephrotoxicity
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Amikacin & kanamycin Monitoring
Nephrotoxicity
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Capreomycin
- • Used for treating patients with drug-resistant TB caused by organisms with known/presumed susceptibility to the drug
- • IV/IM
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Capreomycin ADRs
- • Ototoxicity
- • Nephrotoxicity
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Capreomycin Monitoring
Nephrotoxicity
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p-aminosalicylic acid
- • Used for treating patients with drug-resistant TB caused by organisms with known/presumed susceptibility to the drug
- • Granules, tablets, IV/IM
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p-aminosalicylic acid ADRs
- • Hepatotoxicity
- • GI distress
- • Malabsorption syndrome (decreased folate and steatorrhea)
- → Folate- megaloblastic anemia (RBC does not split)
- → Steatorrhea- inability to secrete pancreatic lipases
- • Hypothyroidism
- • Coagulopathy
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p-aminosalicylic acid Monitoring
- • LFTs
- • Thyroid function tests
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Levofloxacin, Moxifloxacin, Gatifloxacin
- • Levofloxacin is preferred oral agent for treating drug-resistant TB in susceptible patients or when first-line agents can’t be used because of intolerance
- • Tablets, IV
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Levofloxacin, Moxifloxacin, Gatifloxacin ADRs
- • GI distress
- • Neurologic
- • Cutaneous
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Levofloxacin, Moxifloxacin, Gatifloxacin Monitoring
No routine monitoring
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Bedaquiline (Sirturo®)
- First novel TB drug in over 40 years
- • Accelerated approval 12/2012
- • 24 weeks of therapy
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Bedaquiline (Sirturo®) Indication
- • Treatment of MDR pulmonary TB
- • Use with ≥3 active TB drugs
- • Only use if no other effective treatment regimen is available
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Bedaquiline (Sirturo®) ADR (Black Box Warning)
- • Increased risk of death in clinical trials of bedaquiline versus placebo
- • Risk of QT prolongation
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HIV/AIDS in TB
- • Substitute rifabutin in place of rifampin
- • Highly intermittent regimens not recommended
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Hepatic Failure in TB
- • Suspect hepatotoxicity in patients with the following
- → Transaminases > 5 x ULN or Total bilirubin > 3
- → Nausea, vomiting, jaundice
- • Sequential reintroduction with frequent testing of liver enzymes to identify the offending agent
- • Alternative agents selected as needed
- → “liver sparing regimen” – streptomycin, levofloxacin, ethambutol
- ¤ Requires minimum of 18 months duration (longer duration of Tx)
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Pregnancy in TB
- • Isoniazid, rifampin, and ethambutol for 9 months
- → Pyrazinamide not routinely recommended
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Pediatrics in TB
• Ethambutol not routinely recommended
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Extra-pulmonary TB
• Longer duration of therapy
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