True or false, a high concentrations inhibitors of protein synthesis are capable of inhibiting protein synthesis in mammalian cells
True
How do these antibiotics enter gram negative cells? (2 ways)
1- passive diffusion
2- energy-dependent active transport
Selectivity against bacterial cells at the clinical dose is attributed to what 2 things?
1- lack of 70s ribosomes in mammalian cells
2- lack of bacterial active transport systems in mammalian cells
Which 3 drugs have a site of action at the 30s ribosomal subunit?
1- aminoglycosides
2- tetracyclines
3- glycylcyclines (tigecycline)
Which 3 drugs are bactericidal?
1- aminoglycosides
2- streptogramins (quinupristin/dalfoprisitin)
3- ketolides (telithromycin)
Broad spectrum
Bactericidal
Not absorbed in the GI-tract
Cause nephrotoxicity, ototoxicity, and neuromuscular blockade
Serum concentrations are higher in the renal cortex than serum levels
Cross the placenta
Aminoglycosdies
Of all the aminoglycoside _______ is the least susceptible to enzymatic activation and is reserved for serious infections
Amikacin
What are the 3 mechanisms of microbial resistance to the aminoglycosides?
1- ribosomal alteration (target modification)
2- Production of inactivating enzymes
3- Inhbition of active trasport (downregulation)
The microbes resist aminoglycosides by inactivating enzymes by what 3 mechanisims?
1- acetylation
2- phosphorylation
3- adenylation
Broad-spectrim
Bacteriostatic
Distributed in the CSF
High concentrations will increase BUN levels
Phototoxic
Causes chelation when administered with Ca, Mg, Al, Fe
Contradicted in pregnancy and children <13
Tetracyclines
Tetracyclines have a _____ affinity for calcified tissues because they _______ calcium
high
chelate
The exent of teeth discoloration is directly proportional to......
.....the dose and duration of therapy
Which tetracycline is the MOST phototoxic (because of C-7 chlorine)?
Demeclocycline
What are the 5 mechanisms of resistance to tetracyclines?
1- ribsomal alteration
2- ribosomal protection
3- energy-dependent active efflux
4- decreased antibiotic influx
5- enzymatic activation
What is the MOA for tetracyline?
It binds to the 30s ribosome and blocks the binding of amino-acyl tRNA to the A-site
What is the MOA for Aminoglycosides (3 total)?
1- blocks the initiation of protein synthesis
2- blocks translation and elicits premature termination
3- incorporation of incorrect AA
What is the only glycylcycline on the market?
tigecycline
Broad-spectrum for IV infusion
Bacteriostatic
Structurally related to tetracyclines
Phototoxic
Contradicted in pregnancy and children <18
Glycylcyclines (Tigecycline)
True or false, Tigecycline has cross-resistance with other antibiotics.
False!
What is the glycylcycline MOA?
It binds to the 30s ribosome and blocks the binding of amino-acyl tRNA to the A-site
Tigecycline may be useful in treating bacterial infections caused by strains that are resistant to ________
tetracyclines
Tigecycline _______ warfarin clearance.
_________ time should be monitored with co-adminsitration.
decreases
prothrombin
What are the 5 macrolides?
1- erythromycin
2- azithromycin
3- clarithromycin
4- dirithromycin
5- troleandomycin
Intermediate spectrum
Bacteriostatic
Do NOT cross the BBB
Macrolides
Which 3 macrolides are inhibitors of cyt P450 enzymes in the liver?
1- erythromycin
2- clarithromycin
3- trolenadomycin
True or false, clarithromycin is not contraindicated in pregnancy.
False, it should NOT be used in pregnancy
What is the MOA for macrolides (2 total)?
1- Inhibit translocation from the A site to the P-site
True or false, streptogramins inhibit CYP3A4 isozyme which will decrease the effect and toxicity of other drugs
False, it will INCREASE the effect and toxicity of other drugs
What are the 2 resistance mechanisms to quinupristin?
1- ribosomal alteration (target modification)
2- Production of lactonases (inactivate quinupristin)
What are the 2 resistance mechanisms to dalfopristin?
1- production of acetyltransferases (inactivate dalfopristin)
2-production of ATP binding efflux proteins
Is there cross-resistance with strepogramins--more specifically quinupristin, with macrolides, lincosamides?
Yes, they all share the same binding site
What happens if dalfopristin binds and quinupristin doesn't?
The effect will be static instead of cidal
What is the MOA for dalfopristin (2)?
It binds to a site nearby resulting in a conformational change in the 50s ribosome enhancing the binding of quinupristin
It interferes with polypeptide chain formation
What is the only Ketolide on the market?
Telithromycin
Intermediate spectrum (treats mild/moderate community aquired pnemonia)
Bacteriocidal
Structurally related to macrolides but more specifically to erythromycin
Ketolides (Telithromycin)
_______ are semi-synthetic 14 membered ring lactones
Ketolides (telithromycin)
Ketolides have a _______ affinty for binding than macrolides
higher
What is the MOA for ketolides (1)?
2 binding sites on the 50s!
One is shared with the macrolides (erythromycin), licosamdides, and streptogramins
True or false, efflux pumps that work for macrolides do not work for ketolides
True, ketolides are poor substrates for the active efflux pump
True or false, methylases alter both binding sites for telithromycin
False, it only alters the shared binding site
Telithromycin will _______ the effect or anticoagulants, digoxin, any other drug metabolized by ______ isozyme.
increase
CYP3A4 (statin, benzos)
Telithromycin is a(n) ________ of CYP3A4 isozyme
inhibitor
True or false, you can use of CYP3A4 inducers and inhibitors with telithromycin.
False, plasma levels will be altered
Hepatoxicity leading to hepatitis and jaundice
Prolonged QT leading to fainting and increased risk for ventricular arrhythmias
Visual disturbances including blurred vision
Transient loss of conciousness
Ketolides (telithromycin)
Broad spectrum
Bacteriostatic
Allosteric inhibitors are macrolides and lincosamides
Contraindicated in infants and newborns because of gray baby syndrome
Chloramphenicol
What is the MOA for Chloramphenicol?
It binds on the 50s ribsosome near the site of action of macrolides and lincosamides--which will interfere with the binding of chloramphenicol
Inhibits the trans-peptidation step
What toxicities are caused by Chloramphenicol?
-Dose-related bone marrow depression
-immunosuppresion
-aplastic anemia
-inhibition of Vitamin K
-alcohol intolerance
Bacteriostatic
Poor activity against Gram negative aerobic or anaerobic bacteria
Contradicted in patients taking MAOIs
Treats VREF, MRSA, Step, nosocomial pneumonia, and bacteremia
Oxazolidinones (Linezolid)
What are the toxicities associated with Oxazolidinones (Linezolid)? (2)
-PMC (pseudomembraneous colitis)
- thrombocytopenia (myelosuppresion)
What is the MOA for Oxzaolidinones (Linezolid)?
Binds to the P-site of the 50s inhibiting the initiation step in protein synthesis by inhibiting the ribosome assembly step and the formation of the fMet-tRNA complex
How can bacteria resist Linezolid?
Via target modification due to a mutation of the ribosomal binding site
Bacteriostatic (will be cidal at high concentrations)
Topical
Treats MRSA and impetigo
Pleuromutilins (Retapamilin)
What are the resistance mechanisms to Pleuromutilins (Retapamilin)? (2)
1- Ribosomal alteration (target modification)
2- active efflux
What is the MOA for Pleuromutilins (Retapamilin)?
Binds to the 50s subunit inhibiting peptidyl transfer, blocking the P-site interactions, preventing normal formation of active 50s ribosomal subunits
Which 2 subclasses are the inhibitors of bacterial nucleic acid synthesis?
