Mechanisms of Antimicrobial Resistance Flashcards
What are the three broad categories of anti-microbial resistance?
Inactivate or modify the drug (B-lactamase/penicillinase); Alter the antibacterial target (MRSA); Reduce the ability of the drug to get to the target (Block influx, increase efflux)
Where are porins found and how do they mediate antibiotic susceptibility or resistance?
Porins are found in the outer membrane of gram negative bacteria and regulate the selective uptake of essential nutrients and other hydrophilic compounds (including some hydrophilic antibiotics). Changes in their configuration or number may adversely affect the uptake of antibiotics.
Where are efflux pumps found and how do they mediate antibiotic susceptibility or resistance?
Efflux pumps are located in the cell membranes of both gram positive and gram negative bacteria. Function and structure are very similar to P-glycoproteins and remove toxic substances from the bacterial cytoplasm. May be specific for a certain class of drugs or be more general and cause multi-drug resistance.
What is the basic structure of peptidoglycan?
Peptidoglycan precursor subunits consist of a disaccharide backbone (GlcNAc and MurNAc) with a five peptide chain attached to the MurNAc sugar. The 2 distal amino acids are both D-alanine. The precursors are formed in the cytoplasm and then transported across the cell membrane and added to the existing structure by membrane bound penicillin binding proteins. Transglycosylases link the sugar backbone in B-1-4 linkages, and transpeptidases crosslink the peptide chains.
How do B-lactam antibiotics affect the formation of peptidoglycan?
B-lactam antibiotics bind irreversibly to the transpeptidase enzymes and inhibit peptide cross-linking.
How do bacteria become resistant to B-lactams?
1) Modifying the drug - through enzymatic destruction by B-lactamases (penicillinases). 2) Modifying the target - through production of altered penicillin binding proteins that have low affinity for B-lactam binding. 3) Preventing drug-target interaction through porin channel mutations or efflux mechanisms.
What do narrow spectrum B-lactamases affect and what classes of bacteria have them?
Narrow spectrum B-lactamases hydrolyze penicillin type antibiotics (pen, ampicillin, amoxicillin) but NOT cephalosporins. They are found in both gram positive and gram negative organisms, with frequencies ranging from near 95% in S. aureus to less common in E. coli.
What are three narrow B-lactamases and what species carry them?
“bla” gene on plasmid in Staphylococci. TEM-1 on plasmid in E. coli and H. influenzae. SHV-1 in chromosome of Klebsiella pneumoniae. All confer resistance to PCN and ampicillin.
What are ESBLs, what do they act on, and where are they found?
Extended Spectrum B-Lactamases are mutated forms of TEM-1, TEM-2, and SHV-1 that are capable of acting on cephalosporins including 3rd generation cephalosporins - ceftriaxone and ceftazidime. They are usually found on plasmids and nearly exclusively in Gram-negative rods.
What are two ESBLs and what species carry them?
CTX-M is found in E. coli. SHV-type is found in Klebsiella pneumoniae. Both confer resistance to PCN, amp, and cephalosporins. Susceptible to some B-lactamse inhibitors.
What is the ampC B-lactamase, what does it act on, and where is it found?
ampC B-lactamase is capable of hydrolyzing all penicillins and 1st, 2nd, and 3rd generation cephalosporins, is not susceptible to B-lactamase inhibitors, and is found in the chromosomes of certain Gram-negative rods: Enterobacter, Pseudomonas, and a few others.
What determines whether an organism that possesses the ampC B-lactamase is susceptible to 3rd gen cephalosporins?
Whether or not its expression of ampC is induced or constitutive. In its normal, inducible state, the organism will be resistant to ampicillin and cefazolin (1st gen) b/c they induce its production, but susceptible to 3rd gen cephs and PIP-TAZ because they do not. If the organism mutates and ampC becomes constitutively activated, it will be resistant to all of these drugs.
What is the inherent danger in treating an Enterobacter or Pseudomonas infection?
Treatment of a strain that houses inducible ampC with a drug such as ceftriaxone (or PIP-TAZ, or ceftazidime) may select for a constitutive mutant during therapy, resulting in a constitutive ampC, multi drug resistant infection. These must be treated with a carbapenem!!
What are two Carbapenemases?
Carbapenems are B-lactam antibiotics with the broadest spectrum of activity against Gram-negative rods and are used in cases where antibiotic resistance is a concern. Carbapenemases are plasmid mediated enzymes that cleave these and almost all other B-lactam drugs. KPC - Klebsiella Pneumoniae Carbapenemase cleaves all carbs and all B-lactams. NDM-1 - New Dehli Metalo-carbapenemase cleaves all carbs and all B-lactams except aztreonam.
What sorts of PBP alterations may there be and which organisms display what types?
Mutations in PBP may occur through mutation of existing genes or through acquisition of new PBP genes or gene fragments. Staphylococcus (MRSA) produces an inherited (mutation) gene, mecA, which encodes PBP2a and is resistant to all PBP except 5th gen cephs. S. pneumoniae and N. gonorrhea both may “pick up” naked DNA and insert it into their PBP genes, creating mosaic proteins with low affinity for B-lactamases.
