Protein Synthesis Inhibitors (Fitz) Flashcards
List aminoglycoside abx:
Amikacin GENTAMICIN Kanamycin NEOMYCIN Streptomycin TOBRAMYCIN
Brucellosis can be treated with this combo including an amino glycoside:
Gentamicin + doxycycline
Tularemia can be treated with this aminoglycoside
gentamicin
Yersinia pestis can be treated with this combo including an aminoglycoside
streptomycin + doxycycline
Pseudomonas aeruginosa can be treated with this combo including an amino glycoside:
Tobramycin + Pipericillin or ticarcillin
klebsiella can be treated with this combo including an aminoglycoside
Gentamicin + pipericillin or ticarcillin
What is the spectrum of activity of amino glycosides?
Pathogenic gram - rods:
- Escherischia, Enterobacter, Serratia
- Pseudomonas, Acinetobacter
- Klebsiella spp., Yersinia pestis, Brucella spp., F tularensis
What are some indications for Aminoglycosides?
- Gram - infx resistant to other safer antimicrobials (as 2nd line therapy)
- Combo therapy for serious pseudomonas aeruginosa infx and brucellosis, tularemia, plague..
- Synergistic tx with B lactam for streptococcal and enterococcal endocarditis
This oral amino glycoside can be used for sterilizing the bowel prior to colonoscopy or bowel surgery
Oral neomycin –> acts as topical abx in the gut where it eradicates flora
what is the MOA of amino glycosides?
Diffuse into gram - via porins (outer membrane) –> enter cytosol via O2-dependent active transporter –> bind 30s ribosome sub-unit and disrupt protein synthesis (alters AA sequence and eventually protein becomes defective and bacteria dies)
what are some mechanisms of resistance to amino glycosides?
- depletion/deficit of porins (MDR)
- O2 deficit/ anaerobic orgs
- Enzymatic alteration of amino glycoside structure (acetylation, phosphorylation, adenylation)
- mutation of 30s ribosome
___ are intrinsically resistant to aminoglycosides
anaerobes
Gram + rods: Clostridia
Gram - rods: bacteroides, fusobacteria
List adverse effects of amino glycosides:
- Nephrotoxicity (accumulate in renal cortex)
- Ototoxicity/vestibular toxicity (CN VIII defects) (accumulate in ear perilymph)
- neuromuscular blockade
the risk of neuromuscular blockade by amino glycosides is greatest with:
intra-peritoneal administration or large doses, or rapid IV infusion. Can produce apnea or resp arrest
this tetracycline has a high potency, complete intestinal absorption, highly photo toxic, and is the preferred agent parenterally; preferred with renal impairment
Doxycycline
what is the spectrum of activity for tetracyclines?
- broad spectrum
- atypical orgs
- intracellular orgs
What atypical orgs can be treated with Doxycycline?
- Rickettsial (IC) –> tick-born RMSF, Q fever, typhus
- Chlamydia trachomatis –> Major STD, urethritis, PID, lymphogranuloma venerum
- Chlamydia psittaci –> psittacosis pneumonia
- Mycoplasma pneumonia –> young adults, close quarters (alternate - erythromycin)
List the amino glycoside + tetracycline combo for the following:
- Brucellosis
- Tularemia
- Plague
Brucellosis –> Gentamicin + doxycycline
Tularemia –> Gentamicin + a tetracyclne
Plague –> Streptomycin + doxycycline
What is the MOA of tetracyclines?
passive diffusion into bacterial cytosol –> bind to 30s ribosomal unit –> BLOCK BINDING OF AMINOACYL-tRNA –> inhibit protein synthesis –> exert bacteriostatic effects
what are mechanisms of resistance to tetracyclines?
- tetracycline efflux pump (Tet A efflux pump)
- ribosome protection (methylation of ribosome)
___ is the only tetracycline safe to use in renal impairment because it is cleared almost entirely by biliary excretion
doxycycline
List some adverse effects of tetracyclines:
- GI disturbance –> superinfx; can disrupt commensal flora of gut and allow pathogenic orgs to thrive; C diff thrives; Pseudomembranous colitis occurs-can be life-threatening
- Accumulation in teeth and bone –> chelate Ca and Mg in calcified tissues; contraindicated < 8 yrs old
- Fatal hepatotoxicity –> fatty liver, esp during pregnancy; Contraindicated in pregnancy and breast feeding and children < 8 yrs of age
- Phototoxicity
- Vestibular problems–> minocycline
- Diabetes insipidus –> demeclocycline
this improved relative of tetracyclines has no drug interactions, is excreted biliary, and safe in pts with renal impairment. It has decreased susceptibility to resistance by yet A efflux pumps and ribosomal protection. Its has a broad spectrum of activity including Gram + aerobes including MRSA, VRE, Gram -, Anaerobes such as C perfringens, bactericides spp
Tigecycline
List some macrocodes and ketolides:
Erythromycin
Clarithromycin
Azithromycin
Telithromycin (ketolide)
a major indication for macrolide/ ketolides is ___
URT-CAP
Covers atypicals such as Legionella pneumophila, Chlamydiphila pneumonia, Mycoplasma
__, a once-daily, 5 day regimen is as effective as 10 day courses of other macrolides
azithromycin
What is the MOA of macrolides?
bind to 50s subunit –> inhibit translocation step of protein synthesis –> ribosome cannot ratchet forward to the next codon –> inhibit bacterial protein synthesis
what are mechanisms of resistance to macrolides?
- methylation of ribosome –> erm genes confer high level macrolide resistance
- macrolide efflux pumps –> mef E pump macrolides out of cytosol
___ are intrinsically resistant to macrolides due to decreased permeability to the outer cell envelope
Enterobacteriaceae
Pseudomonas spp
Acinetobacter spp
What are some adverse effects and clinical complications of macrolides and ketolides?
- GI–> nausea, vomiting, diarrhea
- Hepatotoxicity (rare, serious) –> cholestatic jaundice- erythromycin estolate (hypersensitivity), fatal hepatotoxicity (telithromycin)
- Cardiac–> QTc interval prolongation, blockade of Ikr channel (inward rectifying K channel), increases risk for Torsades; QT prolongation Erythromycin > clarithro/azithromycin
- Drug-drug interactions –> CYP3A interaction
- Reversible hearing loss
This macrolide is associated with ~2fold increase in risk of sudden cardiac death overall and 5fold increase in pts taking drugs that are CYP3A4 inhibitors-which causes elevations in this drugs circulating levles
Erythromycin
These macrolides are the safest in pregnancy:
Erythromycin and Azithromycin
Name a Lincosamide:
Clindamycin
What are some Clindamycin distinctions from erythromycin?
-Anaerobes-Primary clinical use (e.g., abdominal anaerobic infx with bactericides fragilis associated with trauma such as gunshot or stabbing)
what is the main adverse event associated with Clindamycin?
Pseudomembranous colitis caused by overgrowth of C diff (manage with metronidazole, vancomycin PO)
The antimicrobial spectrum of this Abx is wide but clinical use is rare. Its clinical use is restricted to life-threatening infx for which there is no alternative (some meningitis infx)
Chloramphenicol
Name some lethal toxicities of Chloramphenicol
- Aplastic anemia –> idiosyncratic
- Gray baby syndrome –> can penetrate human cells and disrupt their mt protein synthesis; drug concentration dependent caused by impaired glucuronidation in neonates and impaired renal clearance
List ontogenic and pediatric catastrophes associated with:
- Sulfonamides: __
- Chloramphenicol: __
Sulfonamides –> kernicterus
Chloramphenicol –> gray baby syndrome
What does the OTC diarrhea drug Intestinomicine contain that should be a concern for people with anemia and other low blood cell counts?
Chloramphenicol
What is the MOA of Chloramphenicol?
Bind 50s ribosomal subunit –> inhibits peptidyl transferase step of protein synthesis
Can enter host cells and impair host mt protein synthesis –> produces toxicity
chloramphenicol resistance involves its enzymatic modification by ___
Acetyltransferase (CAT)
Name an oxazolidinone
Linezolid
This oxazolidinone is used when orgs are vancomycin resistant:
Linezolid
Describe Linezolid clearance and toxicity
- Non enzymatic oxidation
- Not a CYP450 substrate, inhibitor, or inducer
- Renal clearance
- Long term use: Increase ALT
- decreases platelets, MAO interaction
- Peripheral neuropathy
