Term
| Two forms of Resistance and that each means |
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Definition
1. Innate: resistance before exposure to a drug. Inherent R
2. Acquired: antibiotic use driven selection and accumulation of resistant strains |
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Term
| Examples of Innate Resistance |
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Definition
1. G+ bacteria are resistant to polymyxins because they lack LPS _- Charge) on cell surface
2. G- bacteria are resistant to Vancomycin bc too large to cross the outer membrane by diffusion
3. Intracellular bacteria are resistant to Beta-lactams bc the are poorly taken up my animal cells
4. Chlamydia and Mycoplasma are R to B-Lactams bc the don't have peptidoglycan cell walls |
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Term
| Types of acquired Resistance |
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Definition
1. rare point mutations arise in bacteria (vertical transmission only and usually only single drugs resistance)
2. resistance bacteria are in the environment but initially rarely exist in patients |
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Term
| Chromosomal mutations that migrate to plasmid or transposon |
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Definition
1. Horizontal transmission via CONJUGATION (important- most common via R factors), transformation or transductions
2. Plasmid have R factors that may contain multiple transposons- mutidrug resistance and multi-species resistance |
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Term
| Basic Principles of antibiotic resistance |
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Definition
1. R likely to emerge, given enough time and drug use
2. Antibiotic R is progressive- evolves from low levels through intermediate to high levels
3. Organisms Resistant to one drugs are likely to be R to others
4. Once resistance emerges, it is likely to decline slowly, if at all
5. use of antibiotics in one person affects others in the healthcare environment |
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Term
| Bacteriocidal and Bacteriostatic |
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Definition
1. Bacteriocidal drugs cause cell death- drugs of choice for chronic infections or infections known to involve biofilm
2. Bacteriostatic- inhibit cell growth and rely on immune system for clearance. ( Expect for aminogycosides, all inhibitors of protein synthesis are bacteriostatic) |
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Term
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Definition
Minimum Inhibitory Conc. is the lowest that inhibits growth.
1. Kirby-Bauer and E strip tests measure MIC
2. MIC must be abtained for effective treatment
3. Antimicrobial R increases MIC
Minimum Bacteriocidal Con. is the lowest that kills bacteria |
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Term
| Indications for multidrug therapy |
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Definition
1.Probably synergy- more effective in combination
2. Molymicrobial infection- one drugs won't kill all diff. bacteria
3. Uncertain diagnosis
4. REDUCTION IN EMERGENCE OF RESISTANCE
5. reduciton in therapeutic levels of toxis drug
6. organ coverage (access of CSF) |
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Term
| Types of mechanisms of resistance |
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Definition
1. Exclusion
2. Altered target
3. Enxymatic Inactivity
IMP: resistance does not correlate with virulence - a strain sensitive to penicillin isn't actually more pathogenic/dangerous than one resistant |
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Term
| Exclusion (mechanism of resistance) |
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Definition
A. Innate- the cell wall and G- outer membrane act as barriers through size exclusion or lack of specific transport mechanism
B. Acquired
1.altered membrane lipids that reduce drug binding/diffusion
2.altered porin/transport mechanisms
3. more efflux pumps (tetracycline R. this is IMP source of multidrug R. increased expression is often induced in presence of drug) |
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Term
| Altered target (Mechanism as Resistance) |
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Definition
A. amino acid substitutions that reduce the affinity of an antimicrobial for its target
1. PBPs, ribosomes,polymerases
2. alteration must still allow functionality
3. if the target is a single site, R can occur faster (new drugs designed to bind multiple sites)
B. Acquisition of new activity that makes an altered target
1. vancomycin R involves synthesis of D-ala D-lactate instead of D-ala D-ala |
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Term
| Enzymatic inactivation (mechanism of resistance) |
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Definition
A. most robust form of resistance bc no sacrifice in activity needed
B. antimicrobial destruction 0Beta- lactamases)
C. Antimicrobial modification on hydroxyl/ amino acids (acetylation, adenylation, phosphorylation) |
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Term
| Resistance to antimicrobials that target the cell wall |
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Definition
| R to cell wall antimicrobials is mediated my exclusion, altered target and inactivation |
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Term
| Examples of exclusion mechanisms against drugs that target the cell wall |
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Definition
1. innate R in G- acteria to penicillins is a combination of poor uptake and low level expression of efflux pumps
2. G- bacteria innate resistant to glycopeptides (like Vancomycin) bc the outer membrane porins don't allow the larger molecules in
3. Porin proteins in G- may also alter their exclusion properties to acquire Restance to Beta-lactams
4. Staph Aureus G+ intermediate level R to vancomycin (VISA) mediated my thickening the cell wall which excludes the drug from the site of cell wall precursor addition near the cytoplasmic membrane |
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Term
| Altered target mechanisms (against drugs that target cell walls) |
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Definition
1. PBPs
2. MRSA
3. Streptococci and Neisseria
4. Vancomycin R
5. vanA gene on plasmids in VRSA |
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Term
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Definition
1. Hospital and Community acquired infections
2. mecA gene acquired on transposon and inserted into chromosome
3. mecA encodes an altered PBP that resists binding by ALL b-lactams |
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Term
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Definition
1. some have acquired altered PBPs that are mosaics from other species
2. Both can do transformation, so this plus homologous recombination may explain the mosaicism |
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Term
Vancomycin Resistance
Also, VRE |
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Definition
1. Vanc binds to terminal D-ala D-ala instead of PBPS
2. thus, altered site ISN'T a PBP
3. vanA gene is encoded on a plasmid first described in Vancomycin Resistant Entercoccus
a. van A encodes an enzyme that makes D-ala D-lactate
b. new terminus is still recognized my essential PBPs, but NOT Vancomycin
c. allows continuous cross-linking in presence of vancomycin |
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Term
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Definition
The vanA gene has been found in plasmids in VRSA
a. first described 2002
b. acquired from Anterococcus
c. still rare but can cause treatment problems (treatment of choice of MRSA) |
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Term
| Beta-lactamase inhibitors |
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Definition
Plasmid borne B-lactamases are sensitive to inhibitors
Clavulonic acid and Sulbactam contain B-lactam rings and bind susceptible B-lactamases and inhibit them
(Neither alone functions as an antibiotic, but in combination with B -lactam can restore activity to previously resistant strains
Claculonic acid+ amoxicillin = Augmentin |
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Term
| resistance to antimicrobials that target translation |
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Definition
1. Tetracyclines (resistance common, efflux pumps main mechanism, protection of ribosome target by expression of a new masking protein)
2. Chloramphenicol (acetylation) |
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Term
| Resistance to Fluroquinolones |
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Definition
A. these drugs are completely synthetic so "natural" resistance shouldn't occur
1.used to think that resistance was from amino acids substitutions in the chromosome that changed the DNA gyrase or topoisomerase target
2. Documented plasmid-encoded resistance in G-, enterics ( Qnr gene encodes a protein that binds the drugs and competes w/ DNA. These plasmids encode b-lactamase and/or resistance to aminoglycosides (multirug resistance). Thus should limit use of fluoros in G- enteric infections
In addition to Qnr-mediated and altered target resistance, effux pumps mediate resistance |
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Term
| Keys to control antimicrobial resistance |
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Definition
1.make new antibiotics
2. Prudent use of antibiotics (no antibiotics for viral infections, pain killers for self=limiting infections)
3. more vaccine development to prevent infections in the first place
4. better conrtol of infections in hospitals (many nosocomial infections involve multidrug resistant strains)
5. reduce antibiotic use and animal-to-human infection in agriculture |
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Term
| Enzymatic inactivation mechanisms: Beta lactamases 1/2 |
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Definition
1. First beta lactamase described was plasmid encoded penicillinase from Staph Aureus
a. bc Staph are G+, the enzyme is secreted into the immediate environment
b. needs high density of bacteria to work effectively
c. cleaves penicillin and ampicillin, but not later derivatives like methicillin or cephalosporins |
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Term
| Enzymatic inactivation mechanisms: Beta lactamases 2/2 |
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Definition
A. G- bacteria also have acquired plasmids encoding Beta lactamases
1. Beta lactamases are secreted into the periplasm (Get to higher conc. than G+ exoenzymes. Play an important role in G- resistance and G+ resistance)
2. TEM beta-lactamase (first isolated from E. Coli but then spread fast to other G-)
3. First TEM cleaved Ampicillin
4. Now there are other plasmids that encode for extended spectrum Beta-lactamases (ESBLs) that also cleave cephaosporins- BAD |
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Term
| Enzymatic inactivation mechanisms: Beta lactamases 3/3 |
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Definition
A. Most G- bacteria encode a chromosomal cephalosporinase
1. low level expression fends off poorly absorbed B-lactams
2. High level expression needed to fend off cephalosporins (thus, penicillin resistant strains may be treatable with cephalosporins) |
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Term
| Enzymatic inactivation mechanisms: Beta lactamases 4/4 |
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Definition
A. the existance of b-lactamases has driven the development of b-lactam generations
1. early penicillins and cephalosporins were effective against G+ bacteria, but were bad against G- bc of chromosomal cephalosporinases
2. subsequent generations showed better activity against G- bacteria
3. latest generations have better activity towards Pseudomonas (which make a large amount of b-lactamases and other degenerative enzymes |
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