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126 Cards in this Set
- Front
- Back
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antibiotics that affect membrane permeability
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the POLYMYXINS: polymyxin B
-cidal agents (cell growth NOT required) -selective against G(-) enteric rods (esp. Pseudomonas) |
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mechanism of bacteriocidal action of Polymyxin antibiotics
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-positively charged polypeptide antibiotic binds first to the negatively charged LPS in outer membrane, then to cytoplasmic membrane phospholipids, causing membrane leakage
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how are polymyxins commonly used?
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-commonly used as topical agents- systemic use largely supplanted by more effecitve and less toxic agents
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what are polymyxins selective against?
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-selective against G(-) enteric rods (esp. Pseudomonas)
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Antibiotics that work as inhibitors of protein synthesis:
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-inhibitors of 30S ribosome {Aminoglycosides (e.g. Streptomycin, Gentamycin)}
-inhibitors of RNA-30S ribosome binding {Tetracyclines: tetrocycline and doxycycline} -Inhibitors of 50S ribosome {eg Erythromycin, Azithromyci} -blocks chain elongation {Chloramphenicol} -inhibits peptidyl transfer {Clindamycin} -INHIBITION OF TRANSLATION: {oxazolidinones: LINEZOLID; Sreptogramins: DALFOPRISTIN and QUINUPRISTIN (SYNERGIN) -Inhibition of translation by other mechanisms: MUPIROCIN |
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problems with streptomycin
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-positively charged at physio pH
-does not penetrate bacteria readily, and some metabolic activity by the bacterium is needed for streptomycin to enter -actin is INHIBITED under anaerobic conditions or acid conditions-- as in urine |
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the 1944 discovery of streptomycin (an aminoglycoside) was important because it extended range of antibiotic to what kind of organisms?
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Mycobacterium tuberculosis and to many gram-negative organisms
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-cidal mechanism of aminoglycosides
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-streptomycin enters cell through membrane imperfections
-binds subunit of 30S ribosome protein, distorting acceptor site-- causing misreading -misreading causes "bad" proteins to be made, membrane leakiness ensues, streptomycin uptake increases -at higher [streptomycin] inhibits formation of initiation complex and of peptide bond formation |
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explain how streptomycin resistant mutants are readily selected for:
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streptomycin "selects" for these mutants by providing an enviro that favors their growth inside, while inhibiting non-resistant bacteria
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how does GENTAMYCIN differ from STREPTOMYCIN
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both in hibit 30S ribosomal protein, but GENTAMYCIN interacts with more than one ribosomal protein on the 30S subunit
hence one cannot obtain resistance to these agents in one step as with streptomycin |
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why is use of aminoglycosides limited to serious infections?
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toxic effects, damaging CN VIII (vestibulocochlear) or renal function
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what type of antibiotics are preferable in those with compromised immune systems? -static or -cidal
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BACTERIOCIDAL antibiotics are often perferred in such patients
why aminoglycosides are often used w/ them |
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broad spectrum antibiotic (including mycoplasma, rickettsia and chlamydia)
well absorbed orally |
tetracyclines: TETRACYCLINE and DOXYCYCLINE
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bacteriostatic effect of tetracycline
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blocks binding of aminoacyl-RNA to 30S ribosomal subunit
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most potent tetracylcine derivative
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TIGECYCLINE (chemical side chain, makes it REFRACTORY to common mechanism of tetracycline RESISTANCE that INVOLVES an EFFLUX PUMP) introduced by Wyeth 2005
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antibiotic that may mottle enamel in children's teeth
and are not to be used in pregancy bc of potential tetrogeneity |
TETRACYCLINES
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antibiotic action of ERYTHROMYCIN
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bacteriostatic inhibitor of 50S ribosomal function, blocks chain elongation
widely used drug spectrum of activity similar to penicillin G (but includes mycoplasma and chlamydia) |
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spectrum of Erythromycin activity
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spectrum of activity similar to penicillin G (but includes mycoplasma and chlamydia)
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an ANTIBIOTIC related to ERYTHROMYCIN, but with higher activity and slightly broader spectrum
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AZITHROMYCIN
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how does AZITHROMYCIN give high tissue concentrations?
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oral drug that gives high and sustained tissue concentrations, which increase at a site of infection (attributable to uptake by phagocytes which migrate to the site)
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antibiotic action of chloramphenicol
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-bacterioSTATIC (but in some species leads to -cidal effect)
-blocks polypeptide chain elongation |
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why is CHLORAMPHENICOL NOT widely used?
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rarely induces uncommon, but sometimes lethal aplastic anemia
-restricted to infection in which it is vital -useful against some ANaerobes, particularly in bowel (B. fragilis) **sold OTC in many countries |
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antibiotic action of CLINDAMYCIN
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-bacterioSTATIC
-inhibits peptidyl transfer (derivative of linocmycin, has activity against G+ and moderate activity against anaerobes) |
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antibiotic action of OXAZOLIDINONES
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-bacteriostatic
-probably work by inhibiting tRNA translocation -interacts with 16S RNA and 23S rRNA of the 30S and 50S ribosomal subunits |
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OXAZOLIDINONES (ZYVOX/linezolid) are highly active against
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G+ organisms
potential for treating especially VREF, potentially MRSA, VRSA and other multiply resistant bacteria |
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relatively new Antibiotic, first used in april 2000, geared toward multiply resistant bacteria
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ZYVOX (linezolid)
first clinical isolates of linezolid-resistant VREF were isolated by April 2001 |
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antibiotic action of STREOTPGRAMINS:
{DALFOPRISTIN and QUINUPRISTIN}(combination = SYNERGIN) |
-bacterioSTATIC
-binds to the 50S subunit potential for treating MRSA, VREF and other multiply resistant bacteria |
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antibiotic action of MUPIROCIN
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-static at low concentrations
-cidal at high concentrations (topical administration, maybe due to disruption of cell wall synthesis) binds specific tRNA synthetase and prevents its function, resulting in to charged Ile-tRNAs available for protein synthesis -useful from MRSA, esp against nasal carrier state -also for topical treatment of impetigo caused by S. aureus or S pyogenes -weaker effects aginst natural surface flora |
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uses of MUPIROCIN
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-useful from MRSA, esp against nasal carrier state
-also for topical treatment of impetigo caused by S. aureus or S pyogenes -weaker effects aginst natural surface flora |
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antibiotic INHIBITORS of DNA REPLICATION
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QUINOLONES (ciprofloxacin and moxifloxacin)
NITROIMIDAZOLES (metronidazole) |
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the quinolones (CIPROFLAXACIN AND MOXIFLOXACIN) are active against what type of bacteria, what type of infections?
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active vs. G(-) enteric bacilli and some G(+) cocci and P. aeruginosa.
used for a variety of infections: notably UTI, respiratory, and even anaerobic cipro = antibiotic of choice for therapeutic (and even prophylactic) treatment for anthrax (B. anthracis) |
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antibiotic of choice for therapeutic (and even prophylactic) treatment for anthrax (B. anthracis)
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CIPROFLOXACIN (a Quinolone= an inhibitor of DNA replication)
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antibiotic action of quinolones (CIPROFLAXACIN and MOXIFLAXACIN)
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-bacteriocidal
-inhibits the enzyme DNA gyrase necessary for DNA synthesis |
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these antibiotics should not be prescribed for pregnant women or children bc they can damage growing bone
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quinolone derivatives:
CIPROFLOXACIN MOXIFLOXACIN |
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antibiotic action of: Nitroimidazoles (METRONIDAZOLE) {anaerobic drug}
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-bacteriocidal
-active form of drug binds DNA and fragments it -activation requires anaerobic conditions (reduction and activation by an electron transport protein: ferredoxin) |
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antibiotic useful against anaerobic bacteria, especially Bacteroides species
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METRONIDAZOLE (nitroimidazole)
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antibiotic inhibitor of RNA synthesis
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Rifampin
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antibiotic action of Rifampin
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-bactericidal
-inhibits transcription by binding to the BETA subunit of bacterial RNA polymerase, inhibiting specific binding to DNA |
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Rifampin is commonly used to treat what?
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broad spectrum, often used in combination with other antibiotics since resistance develops rapidly when used alone.
{example: combined with ISONIAZID or PYRAZINAMIDE (major Tx against TB)} -drug is efficiently secreted in saliva, useful as a prophylactic against infectious bacteria that enter via nasopharyngeal route (e.g. N. menigitidis) |
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important anti-TB drug (bacteriostatic against tubercle bacilli)
mechanism of action unknown |
ETHAMBUTOL
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important anti-TB drug (bacteriocidal) mechanism unknown
-requires activity of mycobacteria amidase to become activated |
PYRAZINAMIDE
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Pontentially antagonistic antibiotic agents
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an agent that requires growth (eg penicillin) + a bacteriostatic agent (eg tetracycline)
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Potentially synergistic antibiotics
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an agent which damages the cell well/membrane (penicillin/polymyxin) + a cidal agent which is taken up poorly by the bacterium (aminoglycoside)
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more than one antibiotic agent should be used ONLY when:
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1) synergistic action can be expected
2) susceptibility pattern of the most probable pathogens requires the use of more than one agent 3) the likelihood of development of bacterial resistance is reduced 4) the dosage of a toxic drug can be reduced 5) a polymicrobial infection requires use of more than one agent |
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disadvantages of combination antibiotic therapy
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increased risk of side effects and superinfections;
possible drug antagonism; increased cost |
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general reasons for antibiotic inactivity
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1) Antibiotic is inactivated, extracellularly, intracellularly, or both
2) Antibiotic cannot enter the cell, or is actively pumped out 3) Bacterial cell contains an altered enzyme that resists action of antibiotic 4) antibiotic can enter the cell, but the drug-binding target site is replaced |
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Beta-lactamases
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enzymatic inactivation of antibiotics
-cleave beta-lactam ring {penicillins, cephalosporins, etc..} |
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Aminoglycoside modifying enzymes
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generally modify aminoglycosides during transport ax cytoplasmic membrane
acetylation, adenylylation and phosphorylation kanamycin, gentamycin, streptomycin |
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chloramphenicol is inactivated by
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chloramphenicol acetyltranferase
(ACETYLATION) |
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Erythromycin is enzymatically inactivated by:
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erythromycin ESTERASE- hydrolyzes lactone ring
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decreased expression of OUTER MEMBRANE PORINS inhibits what antibiotic actions?
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beta-lactams
nalidixic acid chloramphenicol |
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altering membrane transporters of inner membrane:
-alters activity of what antibiotic? -is relatively rare because? |
aminoglycosides affected
but rare since usually deleterious regarding PMF |
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antibiotics inactivated by efflux mechanisms (that actively pump them out of cell)
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TETRACYCLINE FLUCONAZOLE
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ALTERATION OF RIBOSOMAL TARGET
(methylation of 23S rRNA (comonent of 50S ribosome) is basis for resistance to what antibiotic? |
ERYTHROMYCIN
(tet resistance also via methylation of unknown ribosomal target) |
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ALTERATION OF RIBOSOMAL TARGET
(alteration of S12 (comonent of 30S subunit) is basis for resistance to what antibiotic? |
STREPTOMYCIN
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most common mechanism for Em^r and Sm^r (erythromycin and streptomycin resistances)
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ALTERATION OF RIBOSOMAL TARGETS
methylation of 23S rRNA (for Em) alteration of S12 (for Sm) |
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Alteration of cell wall precursor targets underlies resistance to these antibiotics
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VANCOMYCIN and TEICHOPLANIN
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mechanism for Vancomycin and Teichoplanin resistance by alteration of cell wall precursor targets
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enzyme (related to D-ala-D-ala ligase) makes D-ala-Dala-lactate, which substitutes for D-ala-D-ala in PG precursors and is not recognized by Vm or Tp
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alteration of PBP's affinity is associated with resistance to what antibiotics?
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Methicillin resistance
pen^r (in Neisseria, H. influenzae, and P aeruginosa) |
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altered DIHYDROPTEROATE SYNTHETASE (= altered target/ unerlies resistance to what antibiotic)
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SULFONAMIDE
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altered DHFR (alteration of HOST)
or plasmid encoding DHFR (subs pathway) underlie resistance to what antibiotic? |
TRIMETHOPRIM RESISTANCE
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Polyenes
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-antifungals
-AMPHOTERICIN B and NYSTATIN -axn bind to sterols (esp. ERGOSTEROL) in cell membranes, damaging cell membranes -specificity ([ergosterol] in fungal >> animal cells) -toxicity: poorly absorbed from GI tract |
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prinicipal sterol in fungal membranes
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ERGOSTEROL
(vs. cholesterol in animal membranes) |
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toxic drug used topically and for oral fungal infections "swish and swallow"
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Nystatin
"swish and swallow" method, works bc poorly absorbed from GI tract too toxic for other systemic use |
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anti-fungal action of amphotericin B
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fungicidal (destroys membrane integrity)
binds to ergosterol in cell membranes |
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antifungal action of Nystatin
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fungistatic (except at high, nonphysio dosages)
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Azoles are drugs for what type of infections?
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SYSTEMIC ANTIFUNGAL AGENTS
useful for treatment of oral candidiasis (thrush) and other systemic mycoses; important in patients who may require chronic suppression of recurrent fungal infections (eg FLUCONAZOLE, KETOCONAZOLE) |
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antifungal action of AZOLES
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-fungistatic
-inhibition of ergosterol syntehsis, by inhibition of cyt p450 14a-demethylase -membrane and cell properties are disturbed -hyphae synthesis is inhibited, making fungi more easily phagocytosed by PMNs and M0s |
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FLUCANAZOLE (diflucan)
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-fungistatic
-azole (inhibits cell membrane synthesis) -systemic antifungal (thrush, etc..) |
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rare toxicity associated with AZOLE antifungal drugs
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hepatotoxicity in 0.01% of patients
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Antifungal action of the Echinocandins:
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-fungicidal
-inhibitors of glucan synthesis -inhibit the 1,3-beta-D-glucan synthase |
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Caspofungin
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-an ECHINOCANDIN (inhibitor of cell wall (glucan) synthesis)
-fungicidal |
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Antifungal drugs (antimetabolites)
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Flucytosine: inhibits fungal protein synthesis by replacing uracil with 5-flurouracil in fungal RNA
(also inhibits thymidylate synthetase via 5-fluorodeoxy-uridine monophosphate and thus fungal DNA synthesis) |
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antifungal action of FLUCYTOSINE
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-fungicidal or static, depending on fungal isolate
-inhibits fungal protein synthesis by replacing uracil with 5-flurouracil in fungal RNA (also inhibits thymidylate synthetase via 5-fluorodeoxy-uridine monophosphate and thus fungal DNA synthesis) |
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mechanisms of resistance to antifungal compounds
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NO aquired resistance mechanisms that inactivate antifungal drugs have thus far been discovered
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STERILIZATION
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killing of all microorganisms (bacteria, fungi, viruses)
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GERMICIDE (FUNGICIDE, VIROCIDE)
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agent used to kill bacteria (fungi, viruses)
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DISINFECTION
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using a germicide on an inanimate object (does not imply killing all organisms, but only those that are pathogens likely to be encountered in that setting, eg: application of lysol (containing phenol) to floors, or of alcohol to thermometers)
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ANTISEPSIS
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application of chemical agents to the surface of the HUMAN BODY to kill or inhibit pathogenic material
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SEPTIC
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presence of pathogenic bacteria in living tissue
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ASEPTIC
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tissue without pathogenic bacteria
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SANITIZE
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lowering bacterial content on fomites w/o necessarily killing all bacteria (eg: washing dishes in hot soap and water)
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PRESERVATIVE
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agent used in small (non-toxic) concentrations to inhibit the growth of organisms in food, vaccines, etc..
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PHENOL COEFFICIENT
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KILLING CAPACITY OF AN AGENT COMPARED TO PHENOL
PC>1: more effective than phenol PC<1: less effective than phenol (STAPHENE (disinfectant in lab) PC>10) |
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Descending order of resistance
of various biological agents to germicidal chemicals |
Bacterial Spores (most resistant)> MYCOBACTERIA> NONLIPID or SMALL VIRUSES > FUNGI> VEGETATIVE BACTERIA > LIPID or MEDIUM-SIZED VIRUSES
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3 main physical agents of disinfection
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HEAT (wet or dry)
FILTRATION RADIATION |
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what type of heat is most effective in disinfection?
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WET HEAT more effective than dry heat
water molecules speed the denaturation of proteins in abcteria by providing H-bonds to replace those normally present in proteins |
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AUTOCLAVE provides what type of conditions?
for killing of what? |
121 degrees C, 15 pounds
will kill ALL BACTERIA (including spores) within 15 minutes |
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what are the disadvantages of autoclaving?
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complicated, unsuitable for heat-sensitive materials (i.e. most plastics)
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can spores be killed with dry heat? when should dry heat be used?
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-yes, but requires higher temps and longer time (160 C for 1.5-2 hours vs 121 degrees for 15 mins with wet)
-used when materials would be damaged by water: powders, surgical dressings |
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boiling at atmospheric pressure will kill most....
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bacteria (but NOT spores) in 5-10 minutes
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Pasteurization (classical treatment)
-what does it involve? -what does it kill? |
-63 degrees C for 30 minutes
-kills common milk-borne pathogens (tubercle bacillus, Salmonella, Streptococcus and Brucella) and reduces total bacterial count to 1-3% of initial level |
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Pasteurization (HTST)
High Temperature Short Time treatment conditions? yields results similar to what? |
conditions: 71-72 degrees C for 15-17 seconds
yields simlar results to classical treatment |
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test organism historically used to monitor pasteurization
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Coxiella burnetii, agent of Q fever
(a rickettsia, good test organism because it is relatively heat resistant) |
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today milk is deemed pasteurized if it tests negative for what?
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alkaline phosphatase
(enzyme that denatures underconditions simlar to those that kill C. burnetti, and its loss of activity is quicker and easier to assay than monitoring the presence of viable C. burnetti) |
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Filtration:
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-Used for heat-sensitive liquids
-Allows retention of high quality, no effects of heat treatment -Can be performed very quickly for small samples -Used for vaccines and a number of drug formulations |
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Filtration Pore Sizes:
to exclude most bacteria? to exclude ALL bacteria? |
0.45 micron- excludes most bacteria
0.22 micron- excludes ALL bacteria |
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drawbacks of disinfection by FILTRATION
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-- Many viruses pass through all common filters
-- Filters tend to clog - sometimes need series progressing from large to small pore size -- Expense- |
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most commmon application of RADIATION (in sterilization)
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UV light emitted by mercury vapor lamps (non-ionizing)
-used to decrease bacterial content of air in ORs, barracks, nurseries, restaurants, etc.. |
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antibacterial action of UV radiation
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UV wavelengths absorbed by nucleic acids and proteins,
-cross-links thymine dimers (interferes with DNA replication, not lethal) -causes toxic intracellular peroxide formation |
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advantages/disadvantages of UV radation as disinfectant
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simple, can be left on for long time w/o monitoring
-poor capacity to penetrate anything, but air, irritation and damage to human tissue, should not be viewed directly, intensity should be regulated |
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miscellaneous physical methods of sterilzation
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drying (lowers water levels below that needed for bacterial growth)
high osmotic pressure (salt/sugar |
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ionizing radation as disinfectant
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xray, gamma rays, high energy radiation
not widely used disadvantage: containment, changes tastes? |
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chemical methods of disinfection target what?
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Lipids, proteins and DNA
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examples of chemical methods of disinfection
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GASEOUS STERILIZATION
ETHYL ALCOHOL HALOGENS CATIONIC DETERGENTS OXIDIZING AGENTS PHENOLS SOAPS/DETERGENTS HEAVY METALS ALDEHDES PRESERVATIVES |
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ethylene glycol is used in what kind of sterilization?
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GASEOUS STERILIZATION,
alkylating agent, toxic to humans, suitable only for dry materials, used in presence of CO2 (bc of explosivity) |
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optimal effective concentration of ethyl alcohol
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60-70 precent
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how does ethanol work as a sterilizing agent?
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denatures proteins, not reliable against all organisms, subject to legal restrictions, where as isopropyl alcohol has NO restrictions, is slightly more potent, less volatile, but more $$$
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commonly used as sterilizing agent on skin before injections, in tinctures of antisepectics and germicides or in jars where thermometers are stored
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ethanol
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does ethanol kill spores?
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NO
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halogens used as antisepctics
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iodine (KI): reliable skin antiseptic; chlorine: widely used as a gas in water supplies and surface cleaner in hypochlorite soln in food industry
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cationic detergents are active against bacteria by what axn
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disrupting cell membranes and dissolving lipid films that may protect bacteria
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why are anionic detergents less effective than cationic detergents
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molecules are repelled by the negative charge of the bacterial surface
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disadvantages of cationic detergents
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not active against Pseudomonas (most common agent in burn infection), poorly active against tubercle bacilli
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these agents leave a tenacious bactericidal film on surfaces of treated objects
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cationic detergents
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what kind of anticeptic agent is Hydrogen peroxide
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oxidizing agent,3% soln used to treat some wound infections, particularly deep wounds that contain anaerobes. (eg in gingiva) axn is somewhat antagonized by catalase containing cells/tissues/bacteria
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Potassium permanganate is used as what kind of antiseptic
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in dilute soln
another oxidizing agent used as an urethral antiseptic |
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antiseptic axn of phenols
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effectively denatures proteins, therefore kills a wide variety of bacteria, but requires high concentrations
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ordinary soap
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anionic detergents, only weakly bacteriocidal, mostly just move bacteria around
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antibacterial soaps include this antibacterial agent
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TRICLOSAN (INHIBITS a specific step in LIPID BIOSYNTEHSIS) resistant mutants can be isolated
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how is silver nitrate (1%) used to treat newborns?
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drop placed in eyes, kills gonococcal organisms.
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mercurial compounds in organic form, commonly used on minor skin wounds, how do these heavy metals work as antiseptic agents?
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heavy metals bind to SH groups in protein
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formaldehyde is often used in what?
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vaccines
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glutaraldehyde is sometimes used to treat areas where...
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blood samples and used syringes are present and may be contaminated with hep. virus.
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cidex is a buffered 2% soln of:
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GLUTARALDEHYDE
sometimes used to treat areas where... blood samples and used syringes are present and may be contaminated with hep. virus. |
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Preservatives used in food
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short chain fatty acids and organic acids. examples: lactic acid, propionic acid, benzoic acid, natural phenolics
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