Flashcards in Mechanisms of Antimicrobial Action and Resistance 2 Deck (76):
What does vancomycin do? Is it a different mechanism than penicillin?
Inhibits peptidoglycan synthesis
What does vancomycin bind to?
D Ala - D Ala substrate
Is vancomycin resistant to beta-lactamases?
Vancomycin: depsipentapeptide vs pentapeptide
Pentapeptide is vancomycin sensitive (binds to D alanyl - D alanine)
Depsipentapeptide is vancomycin resistant (can't bind to D alanyl - D lactate)
What did vancomycin used to be considered as?
Vancomycin resistant bacteria do what?
Synthesize D-Ala - Lactate substrate and the depsipentapeptide
Destroy the D-Ala - D-Ala substrate and pentapeptide
What is single-gene resistance used for?
The bla gene encodes what?
mecA gene encodes what?
PBP 2A - methicillin resistance
How many separate van genes are there?
5 - multiple gene resistance
Drugs that act on ribosomes do what?
Act on subunits of bacterial ribosome to disrupt translation
What do aminoglycosides do?
Affect the 30S subunit of ribosomes and are bactericidal (gram positives and negatives)
What does tetracycline do?
Affects 30S subunit and is bacteriostatic
Which drugs affect the 50S subunit?
Chloramphenicol, macrolides, clindamycin
Gentamicin (aminoglycoside) inhibits what?
30S ribosomal subunit and mitochondrial ribosomes
What acts as a barrier to gentamicin?
Mammalian cells and mitochondrial membranes
Mechanism of resistance to gentamicin?
Proteins modify and inactivates gentamicin and other aminoglycosides
Resistance is additive
Proteins encoded on plasmids
Can there be resistant ribosomal proteins?
Its very rare but when it happens it is highly resistant
Types of kanamycin inactivation?
Chloramphenicol binds to what, inhibits and does not inhibit what?
Binds to 50S
Inhibits mitochondrial 70S
Does not inhibit mammalian 80S
Chloramphenicol can cause what, in what percent of cases?
Aplastic anemia in 1/25k-40k administrations
Erythromycin is what type of antibiotic?
Erythromycin inhibits, doesn't inhibit, doesn't cross?
Does not inhibit mammalian 80S
Inhibits mitochondrial 70S
Doesn't cross mitochondrial membrane
Mechanism of resistance to erythromycin?
Resistance by rRNA methylation
Erythromycin is often used as an alternative to what?
Penicillin because of allergies
Clindamycin has a similar spectrum as what? Binds to what?
Binds to 50S
similar spectrum as erythromycin
Clindamycin is frequently associated with what?
Bowel superinfection with clostridium difficile colitis
AKA pseudomembranous colitis
What is clindamycin used for?
Used to treat anaerobic infections
What are tetracyclines?
Bacteriostatic inhibitors with broad spectrum
What are tetracycline mechanism of action?
Block binding of aminoacyl-tRNAs to A site of 30S
Resistance to tetracyclines due to what?
Efflux and insensitive ribosomes
Quinupristin/Dalfopristin do what?
Act synergistically on the ribosome to prevent protein synthesis
Quinupristin/Dalfopristin are active against what?
VRSA and VRE (E. faecium not E. faecalis)
Quinupristin/Dalfopristin used often? Why?
No, lots of side effects and must be given IV
Linezolid (zyvox) mechanism of action? What bacteria does it work against?
Inhibits protein synthesis at the ribosome
Bacteriostatic against staphylococci and enterococci, VRSA and VRE (E. faecium not E. faecalis)
Linezolid (zyvox) is administered how? How is it tolerated?
Orally or IV
Telithromycin (ketek) is structurally related to what?
Macrolides, which include erythromycin
How does telithromycin work? Treats what?
Blocks protein synthesis
Treats gram positive staph aureus (not VRSA) and s. pneumoniae
Telithromycin (ketek) problem?
Reports of serious hepatotoxicity
Tigecycline (Tygacil) is active against what?
MRSA and probably VRE in vitro
Is tigecycline (tygacil) broad spectrum?
Is tigecycline a substrate for tetracycline antiporters?
What is tigecycline approved to treat? Administration?
Complicated intra-abdominal and skin suture infections.
Nystatin binds to what?
Binds to ergosterol (found in fungi membranes)
Nystatin mechanism of action?
Forms pores, leading to potassium efflux, depolarization, and cell death
Nystatin used to treat what?
Mold and yeast infections
Polymyxins effective against what gram?
Gram negative but not gram positive
Bactericidal, affecting outer membrane
Polymyxins are used as what?
Topical creams because they are too toxic for systemic use
Daptomycin (cubicin) is what?
Daptomycin: how does it work, what is it effective against?
Binds to membrane of gram positives and depolarizes it
Effective against VRSA and VRE
How is daptomycin administered and what is it approved for?
Treatment of complicated skin and skin suture infections
What is sulfanilamide?
First sulfonamide discovered 4 years after penicillin (1932)
Red dye that cured strep/staph in mice
Sulfonamide antagonizes what?
para-aminobenzoic acid (PABA)
Sulfonamides vs PABA (compete for uptake by bacteria)
PABA is 1000 times more effective
Small amounts PABA negate sulfonamides
Not a problem because we don't get a lot of PABA in our diets and it is rapidly excreted
We lack dihydropteroic acid synthase, so we require what in our diet?
How are bacteria different from humans when it comes to folic acid?
Bacteria must synthesize it with dihydropteroic acid synthase
They can't use an external source
Are sulfonamides effective in the presence of folic acid?
What happens when sulfonamides are used?
There is a deficit in tetrahydrofolic acid
Sulfonamides bacteriostatic or bactericidal?
They are bacteriostatic if they block RNA/protein synthesis
They are bactericidal if RNA/protein synthesis continues (if there are methionine and purines in the environment such as in blood or urine)
Why are sulfonamides ineffective in purulent lesions?
Rich in methionine, purines, and thymidine from lysed cells so RNA/DNA/protein synthesis can continue
Sulfonamides introduced the problem of what?
Bacterial resistance to drugs
Sulfonamides were introduced to treat what?
Bacterial dysentery in WWII
How many years did it take for bacteria to become resistant to sulfonamides?
And about 10% of cases were resistant to other drugs
True/False: resistance to multiple drugs is more common than resistance to a single drug. Why?
R factors (transposons) carry multiple resistance genes
What are three mechanisms of resistance to sulfonamides?
Reduced uptake (antiporter)
Altered dihydropteroic acid synthase
Increased synthesis of PABA (rare)
Trimethoprim: what does it do?
Trimethoprim blocks a step in biosynthesis of tetrahydrofolic acid
It is a competitive inhibitor of dihydrofolic acid reductase
Trimethoprim is a competitive inhibitor of dihydrofolate reducate: do humans or bacteria have this?
Both humans and bacteria have dihydrofolate reductase
If humans have dihydrofolate reductase, which trimethoprim is a competitive inhibitor for, how is it ok for us to use it?
The human dihydrofolate reductase is 60k fold less sensitive to trimethoprim than the bacterial dihydrofolate reductase
Resistance to trimethoprim?
Dihydrofolate reductases with reduced sensitivity to trimethoprim
It is not a mutant form of the bacterial enzyme, but a new gene
How do sulfonamides and trimethoprim work together?
They are synergistic, meaning you can use smaller doses.
Use of the drugs together (5 parts sulfamethoxazole: 1 part trimethoprim) reduces the frequency of resistance
What is bactrim?
5 parts sulfamethoxazole: 1 part trimethoprim
Which drug was the first quinolone?
Naldixic was used for what?
Treatment of UTIs
Rapidly excreted in urine but too toxic for systemic use
How does naldixic work?
Inhibits A subunit of DNA gyrase - rapidly inhibits DNA synthesis
The human analog (topoisomerase II) is several hundred fold less sensitive
Bactericidal unless growth is prevented
What are three mechanisms of resistance to quinolones?
Missense mutations in DNA gyrase subunit A
Plasmid-encoded resistance genes that reverses the inhibition of DNA gyrase subunit A