Antibiotic Resistance Flashcards
What are the two fundamental forms of antibiotic resistance?
innate (or intrinsic) and acquired
What is innate resistance?
Innate resistance exists prior to drug exposure, and is the result of structural or growth properties of the microbe.
Which are more resistance to B-lactams, gram-positive and gram-negative? Why?
gram negative bacteria tend to be more resistant to beta-lactams than Gram positive bacteria because the outer membrane of Gram negative bacteria acts as a barrier to access to the cell wall found in the periplasmic space.
Similarly, intracellular bacteria are resistant to beta-lactams because beta-lactams are poorly taken up by animal cells.
What is acquired resistance?
occurs through the exposure of bacteria to antibiotics, resulting in the selection and accumulation of resistant strains.
Upon exposure to antibiotics in the clinical setting, the resistant strain is selected in favor of antibiotic-sensitive strains, and the resistant strain soon becomes the predominant microbe.
Acquired resistance most commonly arises through what processes?
chromosomal mutations, the acquisition of a transposon that imparts antibiotic resistance, or the acquisition of a plasmid (R factor) that may encode resistance to multiple antibiotics and contain multiple transposons.
Because R factors can encode multidrug resistance (MDR), it is possible for a patient to be infected by a microbe that is resistant to an antibiotic never used to treat the patient.
T or F. Transduction and transformation can also lead to the horizontal transfer of antibiotic resistance, but this occurs far less frequently than plasmid-mediated horizontal transfer.
T
Basic tenets of drug resistance:
Resistance is likely to emerge, given sufficient time and drug use
Antibiotic resistance is progressive, evolving from low levels through intermediate to high levels
Organisms that are resistant to one drug are likely to become resistant to other antibiotics
Once resistance appears, it is likely to decline slowly, if at all
The use of antibiotics by one person affects others in the extended as well as the immediate healthcare environment
Bactericidal antibiotics are the drugs of choice for what kinds of infections?
potentially lethal or chronic infections, or infections known to involve a biofilm.
In contrast, bacteriostatic antibiotics can be used when the immune response can be relied upon to assist in clearance.
What is the main measurement of antibiotic efficacy?
determination of the minimum inhibitory concentration (MIC), the lowest concentration that inhibits growth.
How can the MIC be measured?
(MIC), the lowest concentration that inhibits growth. Automated methods determine the MIC for specific bacterial isolates, but the MIC can also be determined by the Kirby-Bauer method used in the Basic Microbiology Laboratory of this course or by the E strip test
How does E strip test work?
serial dilutions of the antibiotic are spread across a paper strip and the strip is then placed on an agar plate spread with the bacterial isolate. As the bacterial “lawn” grows during incubation, growth will be inhibited where the concentration of antibiotic is high as it diffuses from the strip into the agar. Consequently, a “halo” of no growth will form in those areas; however, the lawn will intersect with the strip at the MIC because the antibiotic concentration in the agar below that point will no longer inhibit growth.
What is the minimum bactericidal concentration (MBC)?
the lowest concentration that kills bacteria, can also be determined. The MHC and MBC are basically the same for bactericidal antibiotics.
T or F. The MIC must be reached in tissues or blood for efficacious treatment.
T. Antibiotic resistance raises the MIC.
While antibiotic resistance raises the MIC needed for treatment, antibiotic resistance does not increase the virulence of a microbe. Virulence is determined by the pathogenic potential of a microbe, which remains the same in the presence or absence of antibiotics. Antibiotics simply assist the immune response in clearing the infection.
What is the breakpoint?
the relative concentration needed for susceptibility instead of resistance, and is an empirically-determined measure of attained MIC in tissues or blood.
The combined use of two or more antibiotics simultaneously is one way to reduce the occurrence of resistance as long as ____.
the two antibiotics do not have the same mechanism of action
consider that the spontaneous mutation frequency in bacteria is about 1 x 10-7 for a specific mutation that would lead to antibiotic resistance. If an infection is treated simultaneously with two antibiotics, the frequency with which resistance to both antibiotics would occur is 1 x 10-7 multiplied by 1 x 10-7 or 1 x 10-14
Antibiotic resistance can be accomplished by what four general mechanisms?
(i) reduced permeability (i.e., exclusion),
(ii) active export of the antibiotic by multidrug-resistance (MDR) pumps so that an efficacious concentration cannot be reached within the bacterium,
(iii) target alteration by mutation or creation of new analogous activity, or
(iv) drug inactivation, by modification or destruction.
How can innate resistance through exclusion occur?
by the absence of an appropriate porin or transport system in Gram negative outer membranes or by the peptidoglycan cell wall, both of which can exclude antibiotics on the basis of size. This explains the resistance to beta-lactams exhibited by some Gram negative bacteria.
Mechanisms of exclusion can also be acquired. How?
compliant porin and transport systems can be deleted or altered so that they no longer allow an antibiotic to cross into the cell, and membrane lipids can be altered to reduce drug binding or diffusion.
An example is the increased thickening of the Gram positive cell wall in vancomycin- intermediate Staphylococcus aureus strains (VISA) that traps the antibiotic before it can reach it’s D-Ala D-Ala target in peptidoglycan
Multidrug-resistance efflux pumps are often induced in the presence of drug, and frequently belong to the class of _____.
ATP-binding cassette (ABC) transporters
While these transporters can typically export multiple drugs, this is a particularly important mechanism for resistance to ____ antibiotics.
tetracycline
Altered targets are key mechanisms of resistance for antibiotics that inhibit what kinds of cellular components?
ribosome, topoisomerase, and RNA polymerase activity.
Some of the more significant examples of altered targets are the penicillin-binding proteins (transpeptidases) where mutations reduce the affinity of beta-lactams and allow cell wall synthesis to continue in the presence of drug. Because such alterations must still allow the transpeptidases to function to some degree, the resistance conferred by such changes is sometimes incomplete and limited in terms of the classes of antibiotics affected.
What is unique about methicillin-resistant Staphylococcus aureus (MRSA)?
the microbe is resistant to all beta-lactams.
How is MRSA resistant to all beta-lactams?
The difference is that MRSA strains have acquired a transposon containing the mecA gene, which encodes an altered minor transpeptidase that functions when the principal transpeptidases are inactivated by beta- lactams. Because the principal transpeptidases remain unaltered, they are fully functional in the absence of methicillin, and consequently, MRSA strains are not compromised in the absence of drugs.
T or F. Target-site mutations most rapidly arise if the antibiotic binds a single site
T. Therefore, newer drugs are designed to bind multiple sites, reducing the likelihood of a single “knockout” alteration that results in antibiotic resistance. Still, as evidence by MRSA, bacteria can acquire new, analogous activities that produce an altered target.
As additional examples, vancomycin-resistant strains of Enterococci (VRE) and Staphylococcus aureus (VRSA) harbor a plasmid containing the vanA gene, which encodes an enzyme that synthesizes D-Ala D-Lactate instead of D-Ala D-Ala at the end of the peptidoglycan pentapeptide
Principal transpeptidases can recognize the D-Ala D-Lac structure, but vancomycin cannot, and therefore resistance occurs. This is particularly distressing when MRSA strains acquire the vanA gene because vancomycin is the drug of choice in treating MRSA infections
