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Mechanism of Antimicrobial Resistance

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MIC
Minimum Inhibitory Concentration
Lowest concentration that will prevent detectable growth in a culture over 24hr
MBC
Minimum Bactericidal Concentration
minimum concentration of a drug to kill bacteria
MPC
Mutant Prevention Concentration
inhibitory concentration for the least susceptible (most resistant) mutant in a population
MRSA
HA-MRSA
CA-MRSA
HA-MRSA
Hospital associated MRSA
resistant to beta-lactams, macrolides, aminoglycosides, quinolones, clindamycin
not so communicable
CA-MRSA
Community associated MRSA
resistant to beta-lactams, macrolides
more communicable
PVL toxin causes tissue damage and recurrent infection
Conjugation
Transfer of genes from from bacterium to another
Conjugation: Plasmids
where resistance genes are found
transferred during conjugation
multidrug resistance found in single plasmid
Resistance and Overall fitness
costly to maintain plasmids when antibiotics are gone
competition fades resistance away
cycle antimicrobials for this
some resistance mutations don't have fitness cost
some improve fitness w/wo antimicrobial
MOA of Antimicrobial Resistance
Destroy Antimicrobial Drug
Modify the Target
Efflux Pumps
Change Cell Permeability
Thicken Cell Wall
Others
Destroy Antimicrobial Drug
Beta-lactamase
Aminoglycoside kinase
Beta-lactamase
Hydrolyzes beta-lactam ring
cannot form peptidoglycan crosslink, cell lyses
Beta-lactamase gm+
primarily in staph
Staph. aureus makes narrow spectrum penicillinase
most gm+ don't make beta-lactamase
constitutive (always on)
excreted to environment, lowers EC [antibiotic]
plasmid mediated
Beta-lactamase gm-
constitutive or inducible
plasmid encoded (constitutive)
- generally inhibited by available beta-lactamase inhibitors
Chromosomally encoded beta-lactamase
- not generally inhibited by beta-lactamase inhibitors
found in periplasmic space, lowers intra- but not extracellular [antibiotic]
Beta-lactamases: TEM and SHV
from gm-
hydrolyze penicillins and 1st gen cephalosporins
Beta-lactamase: ESBL
inactivates all penicillins, cephalosporins, and monobactams
in multi drug resistant
use carbapenem
Beta-lactamase: MBL
resistance to carbapenems
use monobactam
Aminoglycoside Modifying Enzymes
encoded on plasmids or transposons
highly transferrable and resistant
In enterococci and Pseudomonas aeruginosa
Acetylate Aminoglycoside: AAC
Adenylate aminoglycoside: ANT
Phosphorylate aminoglycoside: APH
Modification so drug cannot bind: Beta-lactams
Altered PBP-2 in s. areus gives MRSA
Modified PBP in S. Pneumoniae gives penicillin-resistantance
Modification so drug cannot bind: Bacterial Ribosomes: Macrolides
post transcriptionally methylated 23s rRNA in 50s; plasmid or chromosomally encoded
knocks out macrolide, lincosamide, and streptogramin
Modification so drug cannot bind: Bacterial Ribosomes: Tetracycline
mutate 16s rRNA
Modification so drug cannot bind: Bacterial Ribosomes: Aminoglycosides
low level resistance
mutate 30s binding site
decrease streptomycin binding but not all aminoglycosides
Modification so drug cannot bind: Quinolone
Mutations to DNA gyrase, topoisomerase decrease fluoroquinolone binding
Modification so drug cannot bind: Rifamycin
Alter RNA polymerase
Vancomycin Resistance
Horizontal transfer E. fecalis to Staph. Aureus to make VRSA