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46 Cards in this Set
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- Back
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Mycobacterium bovis
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Found in unpasteurized milk; recent rash of cases in US among immigrants who have favorite cheeses made from unpasteurized milk sent them from home, especially Mexico and Dominican Republic
Almost always resistant to pyrazinamide |
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Mycobacterium tuberculosis
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1. Aerobic, non-motile, non-spore forming bacillus
2. High cell wall content of high molecular weight lipids- mycolic acid 3. Slow growth rate (20 hours) 4. Acid-fast stain 5. Ziehl-Neelsen stain |
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Mycobacterium tuberculosis
Transmission |
-Lungs are the portal of entry except M. bovis in unpasteurized dairy products from other countries
-Inhalation of droplet nuclei (bacillus 5 microns): from infectious person with active pulmonary tuberculosis, NOT just positive PPD -Infectivity: sneeze > coughing > singing > talking -Bacillus remains alive and infectious in air for long period; ventilation key in preventing transmission; isolation of patient and mandated number of air exchanges in hospital rooms |
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Mycobacterium tuberculosis
Primary infection |
Before immune respone:
-Bacillus reaches alveoli and replicates extracellularly in alveolar space and intracellularly in alveolar macrophage -lack of immediate host immune response because MTB prevents insertion of proton-ATPase into phagosome so phagosome never gets acidified and never merges with lysosome -MTB multiplies for weeks, in alveolar macrophages and in cells transported lymphohematogenously throughout body: |
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Mycobacterium tuberculosis
Location of metastatic foci |
Establish in regional nodes (hilar, mediastinal) and then to tissues which retain bacilli and favor multiplication:
apical posterior areas of lungs lymph nodes in neck kidneys epiphyses of long bones vertebral bodies juxtaependymal meningeal areas adjacent to subarachnoid space *These will be areas of reactivation disease in future as organisms seeded remain alive but dormant once immune response occurs |
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Mycobacterium tuberculosis
Development of immune response |
Must of intact cellular immune system including CD4 cells
1. 6-12 weeks after initial infection 2. alveolar macrophage infected with M. tuberculosis releases interleukins 12 and 18 3. These attract and activate T lymphocytes (mainly CD4) 4. When population of activated lymphocytes is large enough, get cutaneous delayed reaction to tuberculin=tissue hypersensitivity: Positive PPD (Implications in AIDS patients with low CD4 cells: Cannot perform this process so no positive PPD response to tuberculin) 5. CD4 cells release IFN-gamma, macrophages release TNFa. TNFa is required to kill MTB and for formation of granuloma Lack of TNF alpha results in inability to control initial TB infection as well as reactivation of latent organisms |
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Mycobacterium tuberculosis
Cells involved in tissue necrosis/granuloma |
-Epithelioid cells= highly stimulated macrophages
-Langhans giant cell=fused macrophages oriented around tuberculosis antigen with multiple nuclei lined up peripherally |
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Mycobacterium tuberculosis
Control of infection |
Small antigen load and high tissue hypersensitivity = Epithelioid cells, giant cells, etc.
Large antigen load and high tissue hypersensitivity = necrosis and caseation Large or small antigen load with no tissue hypersensitivity=few cells. No granulomas & huge #s of bacilli in AIDS patients |
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Ghon complex
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hilar node calcification as a result of resolving of MTB infection
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Mycobacterium tuberculosis
Cavitary disease |
Adolescents/young adults are more likely to develop cavitary disease
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Mycobacterium tuberculosis
Causes of reactivation |
-Iatrogenic immunosuppression (transplant, RA treatment)
-Immunocompromising diseases -Malnutrition -Old Age -Unknown: hormonal? stress? |
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Mycobacterium tuberculosis
Extrapulmonary TB |
-Not very infectious
-Viable organisms remain alive for years -Most common organs disseminated: lymph nodes, spine, kidney |
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Scrofula
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Metastatic focus of TB. Most frequent form of extrapulmonary TB. Ruptured lymph nodes that are infected with TB
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Potts disease
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Metastatic focus in the spine (vertebral body, intervertebral disk, adjacent vertebra)
hematogenous spread, contiguous disease, lymphatic spread from pleural disease -early focus is anterior part of vertebral body; spreads to disk and then to adjacent vertebra; X-ray shows anterior wedging of 2 adjacent vertebral bodies and destruction of disk; tender spine prominence on exam=gibbus |
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Tuberculosis
Symptoms |
-Systemic non-specific: fever, fatigue, night sweats, weight loss
-Pulmonary: cough, productive or dry -Sudden massive hemoptysis= erosion of pulmonary artery=only TB emergency (Rasmussen’s aneurysm) |
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Mycobacterium tuberculosis
Nucleic acid amplification |
Can detect MTB in fresh sputum
-Sensitivity intermediate between acid fast smear and culture -AFB smear negative, nuclei acid amplification=40-77% sensitive -AFB smear positive, nucleic acid amplification=95% &100% specific |
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Mycobacterium tuberculosis
Chest X-ray |
-Upper lobe infiltrate with or without activity
-Hilar adenopathy with or without infiltrates -Pleural effusion, exudative -Lower lobe infiltrate -Miliary pattern |
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Mycobacterium tuberculosis
Upper lobe infiltrate |
-Apical or sub-apical
-Most common in reactivation disease if immune system intact |
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Mycobacterium tuberculosis
Hilar adenopathy |
-Most common chest x-ray in patients with AIDS
-Reflects minimal cellular immune response |
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Mycobacterium Tuberculosis
Treatment |
-Always use at least 2 drugs
-Prolonged length of Rx: 6-9 months -Daily treatment for first 2 months; intermittent with adjusted doses for continuation phase of 4-7 months depending on regimen -Directly observed therapy |
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TB reactivation in meninges
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-rupture of subependymal tubercle into subarachnoid space
-meningitis most severe at base of brain causing thick gelatinous exudate; affects cranial nerves as they exit -CSF exam essential to make diagnosis: low glucose; elevated protein; lymphocytic pleocytosis |
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Mycobacterium Tuberculosis
Diagnostic procedures |
SPUTUM: staining, cultures and molecular diagnostics
Acid fast stain: Acid fast implies mycobacterial species although nocardia is weakly acid fast; many other species besides M. tuberculosis complex will all be AFB positive (Mycobacterium avium, kansasii, abscessus, chelonae ) Culture: Gold Standard. Culture is necessary to determine drug susceptibilities |
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Mycobacterium Tuberculosis
Miliary |
-From description of pathologic lesions as “millet seeds”; chest x-ray shows 0.5-1.0 mm nodules
-following childhood infection and progression as discussed above -immunocompromised: alcoholism, cirrhosis, rheumatologic diseases, treatment with immunosuppressive agents; -diagnosis difficult; may have multiple organ involvement with millet seeds granulomas in tissues -transbronchial bx=highest yield for diagnosis |
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Mycobacterium Tuberculosis
Drugs |
ALL GIVEN ONCE DAILY TOGETHER: NEVER DIVIDE DOSES
1. Isoniazid=INH; bactericidal against dividing organisms -hepatitis: Chemical (20%) vs clinical (age related:<35=0.3%; >65=4%) 2. Rifampin=RMP=bactericidal; Enables short course treatment (6-9 months vs 18-24 months with non-RMP regimens -drug-drug interactions:RMP is potent inducer of hepatic microsomal enzymes: cytochrome p450 3. Pyrazinamide=PZA; Enables shortening of regimen from 9 months to 6 months 4. Ethambutol=EMB: Used in drug resistance and situations where INH or RMP cannot be used (INH hepatotoxicity; RMP drug-drug interactions) |
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Isoniazid
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Tuberculosis treatment-first line
-Bacteriocidal against dividing intracellular and extracellular organisms -Dose = 300mg = one pill = well absorbed -Good CNS penetration -Can be used during pregnancy |
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Isoniazid
Mechanism of action |
INH inhibits synthesis of mycolic acids (essential component of bacterial cell wall)
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Isoniazid
Pharmacology |
-Peak blood levels within 1-2 hours after oral administration
-Peak blood levels decline to 50% within 6 hrs, 50-70% of dose excreted in urine in 24 hrs -Diffuses readily into all body fluids, tissues, organs, excreta -Passes through placenta and into breast milk |
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Isoniazid
Hepatic Toxicity |
Hepatic:
-20% patients have rise in transaminases; resolves without stopping INH; usually occurs within first 1-3 months of RX. -Rise in transaminase >5 times normal is significant and INH should be stopped -Toxicity is age related |
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Isoniazid
Neural Toxicity |
-Uncommon, dose related
-Occurs most often in malnourished and those predisposed to neuropathy (alcoholics, diabetics) -Usually preceded by paresthesias of feet and hands -Pyridoxine indicated for patients with conditions where peripheral neuropathy common: diabetes, uremia, alcoholism, AIDS -Pyridoxine indicated for pregnants women on INH |
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Rifampin
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Enables shorter course of therpay for TB
-Bacteriocidal -Good CNS penetration if meninges inflamed -Can be used in pregnancy |
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Rifampin
Mechanism of Action |
Inhibits DNA-dependent
RNA polymerase in susceptible strains of bacteria |
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Rifampin
Pharmacology |
-Absorption: Almost completely absorbed
-C max is 1 to 4 hr (oral) -Absorption decreased 30% if taken w/food -Distribution: Diffuses well into most body tissues and fluids, including CSF -Crosses placenta & distributes into breast milk -Protein binding is 89%. |
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Rifampin
Toxicity |
-Most common adverse reaction = GI upset
-Can cause cholestatic jaundice -Skin rash -Thrombocytopenia (rare) -Bonded to inactive dye which is excreted in urine, sweat, tears: Colors these fluids orange |
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Rifampin
DDI |
Induces hepatic microsomal enzymes: P450 system; accelerates metabolism of many drugs making them less effective or ineffective when rifampin is being given
ex. methadone (will precipitate withdrawal), coumadin (bleeding disorder), Protease inhibitors (HIV retrovirals are contraindicated) |
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Pyrazinamide
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TB treatment
-Bactericidal in acid environment (macrophages) -Dose = weight dependent = 25-30 mg/kg: PATIENT MUST BE WEIGHED -Main role in sensitive disease is to reduce length of treatment from 9 months to 6 months • Do not use in pregnancy: no teratogenicity data |
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Pyrazinamide
Mechanism of Action |
Unknown
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Pyrazinamide
Pharmacology |
-Well absorbed from GI tract
-Peak plasma concentrations in 2 hours -Widely distributed in body tissues including lungs, liver and CSF when meninges inflamed -10% bound to protein -Half-life (t ½)=9-10 hours in patients with normal renal function but may be prolonged in pts with renal insufficiency -70% of oral dose excreted in urine w/in 24 hours, mainly by GFR |
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Pyrazinamide
Toxicity |
HYPERURICEMIA:
-PZA inhibits renal excretion of urates -All patients have increase in uric acid levels: usually entirely asymptomatic -Occasionally causes arthralgias: Offer patient choice of NSAIDS or D/C PZA and treat longer -Rarely causes acute gouty arthritis, most often in elderly: STOP PZA Hepatic: -Increases in transaminases -Chemically similar to INH |
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Ethambutol
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Treatment for TB
-Most important function is prevention of resistance -Used in drug resistance and when INH or RMP cannot be used (INH hepatotoxicity or RMP drug-drug interactions) -Bacteriostatic -Can use in pregnancy -Primarily excreted by kidney so must adjust dose in renal insufficiency |
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Ethambutol
Dosing |
-Dose = weight dependent
-Toxicity more likely with higher dose |
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Ethambutol
Metabolism |
-Poor CNS penetration
-Excreted in urine -No drug accumulation observed w/ consecutive single daily doses of 25 mg/kg in patients with normal kidney function • BUT marked accumulation in patients with renal insufficiency: TOXICITY |
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Ethambutol
Toxicity |
RETROBULBAR NEURITIS
-Blurred vision=initial symptom • Red-green color blindness common and may be picked up earlier with testing • Dose related: <1% of those receiving 15 mg/kg; recommended dose is 15-25 mg/kg • Check visual acuity & color vision at baseline and monthly: ishihara |
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Tuberculosis Treatment regimen
Normal |
Immunocompetent & Drug sensitive
• 6 Months total: First 2 months=Initiation or intensive phase -2 months H/R/Z/E + 4 months H/R daily for entire 6 months -2 months H/R/Z/E daily + 4 months H/R BIW -TIW for entire 6 months: 2 months H/R/Z/E +4 months H/R • 9 Months total: 9 months H/R without PZA: Pregnant women, Elderly if PZA intolerant, & M.bovis (PZA resistant) • Drop EMB when sensitivities known |
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Tuberculosis Treatment regimen
Extended continuation phase |
Extend continuation phase 3 months if:
-Cavitary disease & positive sputum culture after 2 months initial phase -HIV infected patients with sputum culture still positive at 2 months |
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Multi-drug resistant TB
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Resistance to Both INH & RMP
-NEED 6-9 Month of injectable + 3 oral agents to which organism sensitive for total 24 months treatment after culture conversion • Second line drugs necessary |
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TB treatment
Second line drugs |
Second line drugs have more side effects
Injectables: -Streptomycin -Amikacin -Kanamycin -Capreomycin Oral agents -Quinolones: Levofloxacin or moxifloxacin -Cycloserine -Ethionamide -P-aminosalicyclic acid (PAS) |
