Aminoglycoside Antibiotics Flashcards
Core structure of aminoglycoside antibiotics
1,3-diaminocyclitol
sually linked to one or more aminoglycoside rings
Three core structures of…
Streptidine
2-Doxystreptamine
Spectinamine
Seven clinically important aminoglycosides…
Tobramycin Kanamycin A Amikacin A Gentamycin C2 Neomycin B Streptomycin Spectinomycin
How do aminoglycosides work?
Inhibit protein biosynthesis by binding the 30S ribo. subunit
Where on the ribosome to aminoglycosides bind?
16S rRNA forming the A site.
Specifically, what cellular activities go awry with Aminoglycoside binding
Formation of initiation complex
Blockes further translation
Elicits premature termination
Impaired proofreading fxn – nonsense protein formation
Effect of Aminoglycoside caused nonsence proteins
Impaired bacterial cell wall function
Damaged membranes let in more aminoglycosides until a full stop is reached
Ultimate long term kill move of aminoglycosides
Leakage of ions and disruption of the cytoplasmic membrane
Cell death
Initial entry of positively charged aminoglycosides through the outer membrane
Displacement of Mg, Ca ions that form salt bridges with phosphates of the phospholipids in the membrane
This increases permeability
Type of process passage of aminoglycosides through the cytoplasmic membrane is…
Active Transport
Three bacterial resistance mechanisms to aminoglycosides
- Metabolism by acetylation, adenylation, and p-ation
- Altered Ribosomes
- Altered Aminoglycoside uptake
When bacterial resistance is altered by changes in ribosomes, what happens? Example?
16s rRNA binding site altered through point mutations
TB
Main form of reversible and irreversible toxicity associated with aminoglycosides?
Irrev – Ototoxicity
Rev – Nephrotoxicity
Consequences of Ototoxicity from aminoglycosides
Tinnitus, High Freq hearing loss
Vertigo, Balance Loss, Ataxia
Risk factors for ototoxicity with aminoglycosides?
Concurrent use with other ototoxics
Compromised renal fxn
Compromised renal fxn
Genetic vulnerability
Nephrotoxicity with aminoglycosides is precipitated by
Use of loop diuretics Nephrotoxic antimicrobials (vancomycin, amhotericin)
What to do with appearance of nephrotoxicity or ototoxicity?
Stop the drug/Adjust the dose
Very large doses of aminoglycosides can cause what less common side effect?
Curare-like effects Respiratoy Paralysis (reversed by neostigmine, calcium gluconate)
Why are aminoglycosides often spared as a treatment option?
More effective and less toxic alternatives are usually available.
How are aminoglycosides typically provided therapeutically?
G-
Given w/ penicillin
Special rules for aminoglycoside penicillin administration
Chemical reaction between the two classes of drugs prevent mixture into one solution
Put them in their respective arms
Aminoglycosides/Penicillins combinations treat…
Bacterial Endocarditis
Streptomycin is most often used to treat…
TB
The most important of the aminoglycosides?
Gentamicin
Gentamicin is used to treat…
UTI
Burns
Pneumonias
Joint and Bone Infections caused by G-
Aminoglycoside-resistant strains are a big deal.
Who is nobody resistant to…
Amikacin
yay Amikacin…
What is Streptogramins?
Semisynthetic derivatives of Pristinamycin I and pristinamycin II isotlated from Strep. pristinaspiralis
What is Synercid?
30% quinupristin
70% dalfopristin
Why make the synthetic forms of pristinamycins?
Pristinamycins lack suitable solubility for reliably dosages The derivatives (quinu and dalfo) have amino side chains that allow salt formation and enhance water solubility.
Quinupristin and Dalfopristin. Isolated Effect? Synnergistic effects?
Bacteriostatic Together
Bactericidal as a mixture
How are streptogramins administered?
Parenterally
How does Dalfopristin work?
Blocks Peptidyl transferase (which would normally catalyze formation of a peptide bond between the two AAs present)
How does Quinupristin work?
Binds in the ribosomal tunnel and causes blockage of the tunnel
“Ribosomal Constipation”
Therapeutic use of Synercid
VR-Enterococcus faecium bacteremia or UTI (70% success)
Skin infections from MRSA
Types of Resistance to Synercid (2)
- Quin resistance from methylation of A2058 in 23SRNA
2. Efflux and Enzymatic Activation by resistant bacteria
What does the prof say has to stop to deal with all the resistance
Use of streptogrammins (Virginiamycin) in animal feeeds
Side effects of Synercid?
No known toxicity
Some SEs –> inflamm/pain at injection site, nausea, diarrhea, muscle weakness, rash
Average half life of Synercid/streptogramins?
1.5 hours in serum
Linear relationship between the dose and AUC
Effects of Synercid/streptogramins on BBB, placental barrier?
None
These barriers aren’t penetrated
Clearance of Synercid/streptogramins is __% biliary excretion. The remainder leaves through _____
75%
Urine
Drug interactions of Synercid/streptogramins?
They inhibit Cytochrome CYP3A4
Less metab. of warfarin, diazepam, astemizole, terfenadine, cisapride, non-nucleosie RTIs, cyclosporine
What do Oxazolidinones do?
Inhibit bacterial protein synthesis
COmmon Oxazolidinone?
Linezolid (Zyvox)
Oxazolidinone Mechanism of Action
Potent interaction with the 50S ribosomal subunit
Normally, 50S would assocaited with fMet-tRNA to form the 70S. Can’t form 70S with Linezolid.
Linezolid interacts specific with…
23S rRNA
Linezolid is used to treat
VR enterococcus faecium
Nosocomial pneumonia caused by MRSA
Skin Infections from MRSA
How’s the bioavailabiltiy for Linezolid
Excellent oral bioavailability
IV administration
Why don’t we treat everything with Linezolid
Save the magic bullet
Linezolid resistance occurs where/how?
Enterococcus
Target site modification
G to U substitution in the peptidyl transferase center of 23S rRNA at position 2576
Less serious Side effects of Linezolid?
NBD
GI Upset, Vomiting, Diarrhea
Headache, Tongue Discoloration, Candida
More serious side effects of linezolid
Thrombocytopenia
Gi Bleeding
Anemia
Neuropathy (treatment over 6months)
Bioavailability of Linezolid?
100% after oral administration
Half life of Linezolid?
Half-life of 4-6 hours
Drug interactions of Linezolid
Reversible, nonselective inhibitor of monamine oxidase
Interaction with adrenergic and serotonergic agents
Linezolid taking patinets should avoid eating lots of food or beverages that are rich in _______. It will…..
Tyramine
cause a significant pressor response
