2: Aminoglycosides, Streptogramins, and Oxazolidinones Flashcards
core structure of aminoglycosides
1,3-diaminocyclitol linked to one or more aminoglycoside rings
name 7 clinically important aminoglycosides
- tobramycin
- kanamycin A
- amikacin A
- gentamicin C2
- neomycin B
- streptomycin
- spectinomycin
aminoglycoside MOA
bind 16S rRNA of 30S:
- interferes with formation of initiation complex
- blocks further translation
- elicits premature termination
- impairment of proofreading
- formation of nonsense proteins that impair bacterial cell wall function
- damage membranes, allowing increased transport of drug into cell -> stops protein synthesis completely
what do aminoglycosides ultimately lead to?
leakage of ions and disruption of the cytoplasmic membrane, resulting in cell death
describe bacterial aminoglycoside uptake
drugs displace Mg2+ and Ca2+ ions that form salt bridges with phosphates of the phospholipids of the membrane
-makes the membrane more permeable
passage of aminoglycosides through membrane: active or passive
active transport process
three mechanisms of resistance to aminoglycosides
- metabolism via acetylation, adenylation, phosphorylation
- 16S rRNA binding site altered via point mutations
- reduced uptake of drug
metabolic resistance to aminoglycosides: describe where each of the processes occurs (on what functional groups)
adenylation and phosphorylation on -OH groups
acetylation on amino groups
what are the toxicities of aminoglycosides
irreversible ototoxicity
reversible nephrotoxicity
in large doses- curare-like effects
describe aminoglycoside ototoxicity
- tinnitus, high-frequency hearing loss
- vertigo, loss of balance, ataxia
how can you monitor ototoxicity during aminoglycoside use
serial audiograms
risk factors for ototoxicity with aminoglycosides
- concurrent use of other ototoxic compounds (loop diuretics, vancomycin)
- compromised renal function
- genetic vulnerability
name two loop diuretics that can potentiate nephrotoxicity in aminoglycosides
- ethacrynic acid
- furosamide
name two nephrotoxic antimicrobial drugs that can potentiate nephrotoxicity in aminoglycosides
- vancomycin
- amphotericin
how can you monitor nephrotoxicity during aminoglycoside use
creatinine clearance and dosage decrease
what are the curare-like effects you can get with aminoglycosides and how do you reverse them?
respiratory paralysis - can usually be reversed by neostigmine or calcium gluconate (AChEi)
what increases likelihood of aminoglycoside toxicity
length of treatment period
use of aminoglycosides
both G(+) and G(-) but almost always reserved for G(-)
what are aminoglycosides often paired with
penicillins due to synergism, but they are administered in different compartments to avoid a chemical rxn between the two drugs
what are penicillin/aminoglycoside combos used to treat
bacterial endocarditis
what is streptomycin most often used to treat
TB
what is gentamicin usually used for
UTIs
burns
some pneumonias
joint and bone infections caused by susceptible G(-)’s
which aminoglycoside has retained antibacterial activity against resistant strains
amikacin
what are the streptogramins
semisynthetic derivatives of a natural mixture of pristinamycin I and pristinamycin II
what is synercid a combination of
30% quinupristin
70% dalfopristin
why do we not use the parent combination of streptogramins
less suitable solubility for reliable solubility
-the amino side chains of quinupristin and dalfopristin allow salt formation and enhance water solubility
synercid: bacteriostatic or bacteriocidal
each component is bacteriostatic on its own, but combination is bacteriocidal
how is streptogramin administered
parenterally
dalfopristin MOA
directly interferes with peptidyl transferase-catalyzed step of peptide bond formation
quinupristin MOA
binds in the ribosomal tunnel and causes blockage of the tunnel
“constipation of the ribosome”
what is another way you can get resistance to streptograim that involves gating the exit tunnel
mutation of A2062
IV synercid used to treat what
- VRE bacteremia
- MRSA skin infections
- VRE UTIs
resistance mechanisms for synercid
- adenine methylation of A2058 = blocks quinupristin, but no effect on dalfopristin (makes it bacteriostatic)
- efflux and enzymatic inactivation (metabolism)
what is streptogramin often reserved for
serious life-threatening G(+) infections
what will continue to result in more resistant bacterial strains to streptogramins
continued use of virginiamycin in animal feeds
in some patients, what has a 14d course of synercid selected for?
resistant forms of E. faecialis, E. faecium, and S. aureus
streptogramin side effects
no known significant toxicity several mild side effects: -inflammation/pain at injection site -nausea -diarrhea -muscle weakness -rash
why are the PK of streptogramins complicated?
different elimination rates for each component and their metabolites
half life of streptogramins
1.5h - linear relationship b/w dose and AUC
does synercid cross any barriers?
nope - not BBB or placental barriers
what do macrophages do to synercid?
concentrate it up to 50x the extracellular fluid concentrations
describe elimination of synercid
75% via biliary excretion (fecal matter)
25% via urine
DDI with streptogramins
inhibit CYP3A4
-potential DDI w/ warfarin, diazepam, astemizole, terfenadine, cisapride, non-nucleoside reverse transcriptase inhibitors, and cyclosporine
what are two oxazolidinones
linezolid and eperezolid
linezolid MOA
interacts with 23S rRNA of 50S with uM affinity - prevents the formation of the 70S initiation complex
what is linezolid used to treat
- VRE
- nosocomial pneumonia (MRSA)
- MRSA skin infections
why is linezolid a magic bullet
- excellent oral bioavailability
- can be given oral or IV
- half life 4-6h
linezolid resistance in what species
initially Enterococcus
now resistant strains of MRSA, E. coli, and others
linezolid mechanism of resistance
target site modification
- G2576U in peptidyl transferase center of 23S rRNA: reduced affinity of linezolid to 50S
- other sites of mutation (T2500A) in S. aureus are close to P site
linezolid side effects: mild, more severe, and long term
- GI: nausea/vomit/diarrhea
- headache
- tongue discoloration
- oral Candida infection (thrush)
more severe:
- thrombocytopenia
- GI bleeding
- anemia
long-term:
- fully reversible myelosuppression
- neuropathy
what should be monitored in linezolid therapy and how often
CBC weekly
DDI with linezolid
neither inhibits nor induces cyt p450
reversible, nonselective MAOi -potential to interact w/ adrenergic/serotonergic agents (should not consume large amounts of food/drinks rich in tyramine to avoid significant pressor response)
