Mycobacteria, Other AFB, Antimycotic Agents Flashcards

Question

Extrapumonary TB Other Sites

Answer 1

* GI tract * Pericarditis * Peritonitis

Answer 2

* ↑ Prevalence of TB in HIV infection * All pts w/ TB need HIV testing and vice versa * **_Early HIV infection_** ⇒ presentation similar to immunocompetent host * Indolent onset of cough, fever, sweats * **Extrapulmonary manifestations in 10-15%** * CXR shows **upper lobe infiltrates ± cavitation** * **PPD usually ⊕** * **_Advanced HIV infection_** ⇒ atypical presentation * **PPD usually ⊖** * No immune response * CXR shows **lower lobe or diffuse infiltrates** * Cavitation rare * **Extrapulmonary disease in \> 50%** * Often occurs w/o pulmonary disease * **M. avium-intracellulare complex** ⇒ causative agent of **disseminated infection** in AIDS pts

Answer 3

* Grow uninhibited within non-activated MΦ early during infection * **Ingestion by MΦ** ⇒ innate immunity activation * Release IL-12, TNF-α, IL-6, IL-1 * **PMNs, MΦ, and T-cells recruited to site** * Lymphocytes activated in nearby lymph nodes * Can take 6-8 weeks * **T-cell mediated response** ⇒ containment and/or resolution * Releases IFN-𝛾 ⇒ activate MΦ * Activated MΦ can partially inhibit mycobacterial growth * **Activated MΦ ⇒ epithelioid cells ⇒ granuloma ⇒ walls off infected cells ⇒ fibrosis and calcification ⇒ tubercle formation** * Type IV hypersensitivity * **Immune response limits infection but damages lung** * Elimination vs immune injury varies w/ # of organisms present & strength of immune response

Answer 4

* **Hx of compatible sx in pt w/ potential exposure or risk factors** ⇒ high suspicion * Physical exam often nonspecific * Routine labs often nonspecific * May see normocytic anemia * May have elevated ESR * WBC count varies/may be normal

Answer 5

**1° TB ⇒** lower lobe infiltrate ± Ghon complex **2° TB ⇒** upper lobe involvement ± cavity

Answer 6

* **⊕ Acid-fast smears only presumptive e/o TB** * False ⊕ can occur from environmental contamination * ~60% of positive cultures ⇒ ⊕ smears

Answer 7

**Definitive dx by culture isolation only** * Inoculated on _complex media w/ organic substances_ * Egg yolk, animal serum, tissue extracts * Often contain abx or malachite green to inhibit growth of other macteria * **Lowenstein-Jensen** (solid medium) ⇒ slow growth 3-8 wks * **Middlebrook 7H10** (liquid broth) ⇒ 1-3 weeks * Cannot grow all strains * Both cultures must be done

Answer 8

**Production of niacin** Distinguishes M. tuberculosis from atypical mycobacteria.

Answer 9

**Rapid tests that ID M. tuberculosis in clinical specimens within a few hours.** * Sensitivity for smear ⊕ specimens very high * Sensitivity for smear ⊖ specimens ~ 45-75% * Must still perform culture for sensitivity testing * Technically complex and very expensive

Answer 10

**Measure in-vitro IFN-𝛾 response to specific Mtb antigens.** * Ag not present in non-tuberculous mycobaceria or BCG strains * Useful to screen individuals vaccinated with BCG * Blood test ⇒ only 1 visit * Technical complexity limits use

Answer 11

* **Useful for dx and control of TB** * **⊕ Result ⇒ recent or past TB exposure** * _Have T-cells against AFB_ ⇒ Type IV DTH * No info on activity of disease * **Mantoux test** ⇒ most accurate and reliable * Intracutaenous injection of 0.1 ml of purified protein derivative (PPD) * **⊕ Rxn indicated by erythematous indurated area \> 5-10 mm** * See ⊖ results with infection in AIDS or other T-cell deficiencies ⇒ anergic * Requires pt to return for reading in 48-72 hrs * **Two-step TST testing** * See initial false ⊖ result d/t waning cutaneous immunity in remote infections * Can convert to ⊕ if 2^nd TST w/in 2-3 weeks of initial test * Recommended for healthcare workers and elderly pts

Answer 12

30-40% of urine cultures may be ⊕ in case of extrapulmonary infections

Answer 13

* **High mutation frequency leads to drug resistance** ⇒ treat w/ multiple drugs simultaneously * Before abx sensitivity results available, treat according to risk for MDR infection * **Initially all pts treated with 4 drugs** * _Susceptibility results w/o MDR disease_ ⇒ change to **3 drugs** * _Susceptibility results with MDR disease_ ⇒ change to **5 drugs based on resistance** * Should have ⊖ sputum cultures in 85% after 2 months & 90-95% after 3 months * If sputum culture remains ⊕ after 3 months ⇒ consider non-adherence vs re-eval for resistance

Answer 14

* _Purpose:_ * Prevent latent infection from progressing to clinical disease * Prevent initial infection * Prevent recurrence of past disease * Usual preventative therapy **⇒ isoniazid for 6 months in non-HIV pts** * May be composed of up to 3 drugs

Answer 15

* **Give Bacillus Calmette-Guerin (BCG)** * Attenuated strain of M. bovis * Used in several European and South American countries * **10-70% success rate in preventing TB infection** * **Effective in ↓ risk of miliary and meningeal forms of TB** * Results in ⊕ PPD test * IGRA preferred screening test

Answer 16

* **Respiratory isolation when TB suspected** * ⊖ Pressure room with doors closed * Providers use N95 masks * **Respiratory isolation during first 2 weeks of treatment for confirmed TB** * Contact tracing and screening programs

Answer 17

**M. avium-intracellulare** Common opportunist in immunocompromised pts esp. AIDS and transplant recipients. * Ubiquitous organism found in soil, fresh and salt water * **Not transmitted person to person** * Difficult to treat * More resistant to abx * Poor host immune status

Answer 18

* _3 species cause human disease_ * **N. asteroides** ⇒ most common * **N. brasiliensis** * **N. cavae** * Found in soil * Transmission * **Inhalation** ⇒ pulmonary infection * **Direct inoculation into skin or subQ tissue** * Infection may disseminate hematogenously ⇒ many organ systems * Predilection for brain abscess formation

Answer 19

* **Gram ⊕** * **Partially acid-fast** * Have shorter myolic acid chains than Mycobacteria * **Filamentous** ⇒ looks like hyphal elements in tissue * Fragments ⇒ **bacillary or coccoid forms**

Answer 20

* Morbidity attack rate ~ 500-1K cases/yr * **Non-communicable** * Inhalation of organisms ⇒ **lobar pneumonia** * Metastatic foci may involve the brain, kidney, or skin * **⊗ Lysosome-phagosome fusion**

Answer 21

* **Multiple abscesses w/ infiltration of PMNs and central necrosis** * Burrowing sinuses and granulomas are not characteristic

Answer 22

* Microscopic exam of sputum, skin lesions, and surgical materials * **Look for gram ⊕ branched filaments** * May mis-diagnose as TB * Grows on **normal media** over wide temp. range * **Incubate @ 40-50°C** ⇒ inhibit most other bacteria * Culture under **aerobic conditions**

Answer 23

Sulfonamides preferred

Answer 24

Part of drug combo for **active and latent TB** _Bactericidal_ against growing bacterial _Bacteriostatic_ against dormant bacteria

Answer 25

* Prodrug activated via oxidation rxn by mycobacteria enzyme **katG** (catalase-peroxidase activity) * Active compound: 1. **Acylates inhA enzyme** * Responsible for mycolic acid synthesis 2. **Acylates NADH dehydrogenase** * Needed to catalyze the rxn

Answer 26

Due to mutation in KatG, inhA, or NADH dehydrogenase

Answer 27

Extensively metabolized to inactive compounds: * N-acetyltransferase converts to **N-acetylisoniazide** * Isozymes ⇒ rapid vs slow acetylators * May have to adjust dose for rapid type * N-acetylisoniazide ⇒ **N-acetylhydrazine** * Substrate for CYP-450 ⇒ reactive intermediates * Damages liver proteins ⇒ **hepatotoxicity** * Slow acetylators more prone d/t build-up of metabolites

Answer 28

* **Elevation of serum transaminase** * **Age-dependent hepatitis** * **Peripheral neuritis** * Due to Vit B6 (pyridoxine) depletion * Prevent w/ supplemental Vit B6 * **Drug-induced lupus in slow-acetylators**

Answer 29

* **Phenytoin toxicity in slow-acetylators** * Extra isoniazide inhibits hepatic microsomal enzymes

Answer 30

Used in combo to treat **active TB** & **M. avium-intracellular** _Bacterostatic_ @ low doses _Bactericidal_ @ high doses

Answer 31

**⊗ arabinosyl transferase ⇒ ↓ arabinogalactan synthesis** Enzyme adds arabinose units to arabinogalactan chain

Answer 32

Via over-expression of arabinosyl transferase.

Answer 33

Majority excreted into urine unchanged

Answer 34

* **Optic neuritis** ⇒ blindness and/or vision impairment * Monitor visual acuity and color perception * **Impairs red-green color discrimination** * Eye exam required

Answer 35

* **Shortens duration of treatment when used in combo** * Some e/o activity against **non-replicating persistent mycobacteria** * **Bactericidal against even slow growing TB**

Answer 36

* **Pyrazinamide ⇒ pyrazinoic acid** by deamination by ***pyrazinaminidase*** * Transported to _extracellular compartment_ via **efflux pump** * _Protonated in acidic environment_ of phagolysosome * Protonated lipid soluble compound _re-enters mycobacterium_ * **⊗ fatty acid synthase type I ⇒ ⊗ mycolic acid synthesis** * May also work by **acidifying intracellular environment**

Answer 37

Via mutations of pyrazinaminidase

Answer 38

Mostly hepatic metabolism

Answer 39

* **Hepatotoxicity** * Related to dose and length of treatment * Usu. when given for \> 2 months * **Hyperuricemia** * Due to inhibition of excretion * Monitor uric acid

Answer 40

**Bactericidal** * _Used in combo to treat:_ * **Active TB** * **Mycobacterium leprae (Leprosy)** * **Legionella pneumophilia** (Legionnaire's disease) * _Used for prophylaxis:_ * **When isoniazid resistant** * **Where risk of hepatotoxicity is significant** * Exposure to Neisseria meningitidis * Exposure to Haemophilus influenza type b

Answer 41

* **Binds β subunit of DNA-dependent RNA polymerase (rpoB)** * Forms stable drug-enzyme complex * **↓ chain formation in RNA synthesis** * Good penetration into tissues and TB lesions

Answer 42

**Due to alteration of DNA-dependent RNA polymerase (rpoB)** Resistance develops rapidly if used as a monotherapy.

Answer 43

**Mostly hepatic metabolism** **Undergoes enterohepatic cycling** * Causes significant CYP-450 induction * Repeated admins will ↓ drug concentration

Answer 44

* **Can impair liver function ⇒ hepatitis** * Alcohol ↑ risk * **Red-orange discoloration of urine, tears, and saliva** * **Hypersensitivity reaction common** * See flu-like illness w/ fever, chills, fatigue, and HA * **Multiple drug interactions** * Due to CYP-450 induction * **Can ↓ effectiveness of anticonvulsants, oral contraceptives, and other drugs**

Answer 45

* Similar indications and MOA as rifampin * Less potent inducer to CYP-450 * **Used instead of rifampin to treat TB in HIV pts** * **Used for prevention and treatment of M. avium complex**

Answer 46

**Streptomycin and Amikacin** (aminoglycosides) • Given parenterally, not as convenient

Answer 47

* Replicate more slowly * Can exist in a dormant state * Intracellular organisms

Answer 48

* Drug combos always given to minimize development of resistance * Also shortens duration of therapy * Meds must be taken regularly * Therapy must continue for a period sufficient to resolve the illness

Answer 49

* Confirm dx by culture and test for susceptibility * _Standard initial phase treatment_ ⇒ daily doses of "RIPE" 1. **Rifampin** 2. **Isoniazid** 3. **Pyrazinamide** 4. **Ethambutol or streptomycin** * _Once susceptibility shown_ ⇒ **ethambutol/streptomycin can be discontinued** * _After 2 months_ ⇒ **pyrazinamide stopped** * **Isoniazid and rifampin continued for 4 more months** * 2-3 times per week * **Rifabutin used in HIV pts for entire 6 month period** * Normal course of treatment lasts 6 months * Pts with other comorbidities will require prolonged treatment * **Sputum monitored weekly until no e/o TB**

Answer 50

~10% develop active TB over lifetime s/p infection Must exclude active disease before treatment for latent TB * _Candidates for prophylaxis_ * **Known exposure to someone with active TB until ⊖ TST** * **Pts who recently converted to ⊕ TST** * **⊕ TST w/ risk for progression from latent to active TB** * _Possible drug regimens_ * **Isoniazid (INH) 300 mg/d x 6-9 months** * **Rifampin (RIF) daily for 3-4 months** * **Weekly isoniazid + rifapentine for 3 months** * Only with directly observed treatment (DOT)

Answer 51

* Improper drug use ⇒ resistance * **17% of newly dx TB cases resistant to 1 or more first-line agents** * Isoniazide most common (10%) * Treat longer with drugs that are active * **Multidrug-resistant TB (MDR-TB)** ⇒ caused by organism that is resistant to at least isoniazid and rifampin * **Extensively drug resistant TB (XDR-TB)** ⇒ caused by organism resistant to isnoiazid, rifampin, and other drugs * Fluoroquinolones and one of Amikacin, Kanamycin, Capreomycin

Answer 52

* Must determine if disease actually present or part of environmental contamination * _Triple therapy for newly dx patients_ ⇒ administered 3x/week and 12 months after last negative culture (Put your MAC to REM sleep) 1. **Rifampin** 2. **Ethambutol** 3. **Macrolide ⇒ charithromycin or azithromycin** * **Azithromycin used for prophylaxis in immunocompromised pts**

Answer 53

* ↓ Prevalence worldwide since WHO provided free multidrug therapy * _Therapy depends on severity of disease_ * **Tuberculoid leprosy (paucibacillary)** * Bacterial burden low * Only 2 drugs recommended 1. **Dapsone** 2. **Rifampin** * **Lepromatous leprosy** * Most severe form * Requires 3 drugs 1. **Dapsone** 2. **Rifampin** 3. **Clofazimine (orphan drug)** * Treatment is for 2-5 years

Answer 54

**Used primarily to treat leprosy.** May be used for other indications.

Answer 55

* **Competitive ⊗ of dihydropteroate synthase** * Analogue of para-aminobenzoic acid * Similar to sulphonamides ⇒ wide spectrum of activities * Antibacterial * Antiprotozoal * Antifungal

Answer 56

* Retained up to 3 weeks in skin, muscle, and esp. liver & kidney * **Primarily metabolized in the liver** * **70-85% slowly excreted in urine** * **Enterohepatic recirculation** of free drug prolongs half-life

Answer 57

* **Severe hemolysis in pts with G6PD deficiency** * Skin rashes * Reversible peripheral neuropathy * Blurred vision