Inhibitors of Protein Synthesis Lecture Sep 16 Flashcards
What allows protein synthesis inhibitors to display selective toxicity against bacteria?
They bind and inhibit prokaryotic ribosomes without blocking the eukaryote ribosome
What are the 2 30S inhibitors?
aminoglycosides and tetracycline
What are the 5 50S inhibitors?
linezolid
macrolides
chloramphenicol
clindamycin
quinupristin/dalfrpristin
What ABx block the initiation step of protein synthesis?
elongation?
termination?
- Initiation- linezolid, aminoglycosides
- Elongation- aminoglycoside, tetracycline, macrolide,
chloramphenicol, clindamycin,
quinupristin/dalfoprisitin - Termination- aminoglycoside
Are most ribosome inhibitors bacteriostatic or bacteriocidal? what’s one exception?
Most are bacteriostatic except for aminoglycosides
What are 3 abx that interfere with mitochondrial ribosomes as well? What does this lead to?
Linezolid
Tetracycline
chloramphenicol
This causes bone marrow suppression
What are the 3 steps of initiaion in prokaryotes?
- Initiation factors associate with the 30S ribosomal subunit.
- Formylmethionine initiator tRNA and mRNA bind to 30S subunit.
- 50S ribosome then binds and you have the complete initiation complex.
How does linezolid block initiation?
How do aminoglycosides block initiation?
Linezolid binds to the P-site on the 50S so that the formylmethionin tRNA can’t bind
Aminoglycosides bind to the 30S ribosome and freeze the initiation complex. (you get the development of monosomes)
What is the mechanism and spectrum of linezolid?
Bacteriostatic-inhibits protein synthesis by binding to the 23S ribosomal RNA on the 50S subunit and preventing formation of the initiation complex.
Spectrum: gram +, including MRSA and VRE
How does resistance to linezolid develop?
alterations or modifications in 23S ribosomal RNA
this is unique binding site, so it does not result in cross-resistance with other drug classes.
What are the adverse effects of linezolid?
Bone marrow suppression
Inhibits monoamine oxidase which can lead to Serotonin Syndrome
What are the 5 aminoglycosides we need to remember?
gentamicin
amikacin
tobramycin
neomycin
streptomycin
What is the mecanism and spectrum of the aminoglycosides?
Mechanism: Bactericidal- Prevents formation of initiation complex, causes misreading of mRNA, and induces early termination.
Spectrum: Gram negative aerobic
Why do anaerobic bacteria have intrinsic resistance to the aminoglycosides?
How can acquired resistance develop?
Intrinsic resistance- the drug is polar, so it has to be transported into the cell, which requires energy. Because anaerobic bacteria don’t produce as much energy as aerobic bacteria, the drug doesn’t reach high enough concentrations in anaerobic bacteria to be effective.
Acquired resistance-Acquisition of enzymes which inactivate the drug through acetylation, phosphorylation, or adenylation
Which aminoglycosides is less susceptible to enzyme inactivation?
It also has a broader spectrum which includes pseudomonas
amikacin
How are aminoglycosides administered?
One single large dose via IV (poor gut absoprtion from oral)
in a concentration that is over 10 times the MIC most effective at killing the organism
What does cumulative dose mean?
the area under the curve of a concentration by time plot.
What are the adverse effects of aminoglycosides?
THe use is limited due to side effects.
Tubular necrosis: nephrotoxicity- drug retained in renal cortex (reversible)
ototoxicity- vestibular and auditory dysfunction (irreversible)
pregnancy class D- hearing loss in fetusCan aminoglycosides be used for CNS infections?
No–they are polar and thus excluded from the CSF
Which aminoglycoside is synergetic with penicillin and used to treat some gram positive organisms?
gentamycin
What are the three tetracyclines we need to remember?
tetracycline
doxycycline
minocycline
What is the mechanism of tetracyclines?
Spectrum?
Bacteriostatic–bind to 30S preventing attachment of aminoacyl-tRNA
Spectrum was broad initially, but not anymore due to resistance. Still used for B burgdorferi, H pylori, and Mycoplasma pneumonia
What are the intrinsic and acquired resistance mechanisms for tetracycline?
Intrinsic: decreased uptake
Acquired: Increased efflux*
Alteration of ribosomal target
Rarely enzymatic inactivation of drug (acetyl)
What are the adverse effects of tetracyclines?
form stable chelates with a number of metal ions such as calcium, magnesium, iron and aluminum decreasing gut absorption of the drug.
Gastrointestinal irritation and photosensitivity (abnormal sunburn reaction)
Discoloration of teeth and inhibits bone growth in children.
Pregnancy class D (should not be used)
What is the mechanism and spectrum for chloramphenicol?
Bacteriostatic–binds 50S preventing peptide bond formation
peptidyltransferase can’t associate with the amino acid susbstrate
Spectrum: extended, but use is limited due to severe side effects
HOw does resistance develop to chloramphenicol?
acetyltransferase
modifies drug to prevent binding to
the ribosome
What are the adverse effects of chloramphenicol?
TOXIC: bone marrow depression and aplastic anemia
Gray baby syndrome- premature infants
lack the enzyme UDP-glucuronyl transferase and have decreased renal function so high levels of the drug accumulate, which can lead to cardiovascular and respiratory collapse
What are the 3 macrolides we need to remember?
erythromycin
azithromycin
clarithromycin
What is the mechanism and spectrum for the macrolides?
bacteriostatic–inhibit translocation by binding the 23S rRNA of the 50S subunit
Spectrum is broad coverage of respiratory pathogens and chlamydia (in a single dose)
What are the three ABx that can be used against mycoplasma pneumonia?
doxycycline
azithromycin
levofloxacin
(beta lactams not effective)
What are the mechanisms of resistance for the macrolides?
methylation of 23S rRNA binding site- also associated with clindamycin and quinupristin/dalfopristin resistance
increased efflux
hydrolysis of the the macrolide by esterases
What are the adverse effects of the macrolides?
Which one can’t you use during pregnancy?
GI discomfort, Hepatic failure, and Prolonged QT interval
Inhibitors of cytochrome P450 enzymes (check with other medications)
Clarithromycin is not safe during pregnancy
What is the mechanism and spectrum of clindamycin?
It’s a bacteriostatic abx that blocks translocation at the 50S ribosomal subunit.
Spectrum gram positive including anarobes.
Treats acne
How does resistance develop for clindamycin?
mutation of ribosome, methylation of ribosomal RNA (D-test),
Cross resistance with macrolides and streptogramins
inactivation of drug by adenylation
What are the adverse effects of clindamycin?
Hypersensitivity: rash and fever
Diarrhea, abdominal pain, mucus and blood in stool
Superinfection with C. difficile
What is the streptogramin combo we need to remember?
quinupristin/dalfopristin
What is the mechanism and spectrum of quinupristin/dalfopristin?
combined action is bactericidal for some organisms
they bind the 50S to inhibit translocation
They should be reserved for infections caused by multiple drug-resistant G+ bacteria
How does resistance develop to streptogramins?
Ribosomal methylase prevents binding of drug to its target.
Enzymes inactivate the drugs.
Efflux proteins that pump them out of the cell.
Cross resistance with macrolides and clindamycin.
What are the adverse effects of streptpgramins?
High incidence including arthralgias and myalgias are common.
Inhibits a cytochrome P450 enzyme and is likely to have significant drug interactions.
What are the two ABx you shouldn’t use with newborns? why?
chloramphenicol
sulfonamides
they can’t glucoronidate
What 2 ABx should you not use in children?
tetracyclines
fluoroquinolones
Which ABx shouldn’t you use in pregnancy?
tetracycline
aminoglycosides
clarithromycin
fluoroquinolones
chloramphenicol
sulfonamides
What three classes of drugs need to be adjusted in the elderly with reduced renal function?
beta-lactams
aminoglycosides
fluoroquinolones
What are the 5 instances when combination drug therapy is appropriate?
- Enhancement of antibacterial activity in the treatment of specific infections (synergism)
Trimethoprim – Sulfamethoxazole
Inhibits multiple steps in folate synthesis
Aminoglycoside + Penicillin Penicillin increases permeability of cell membranes increasing the ability of aminoglycosides to enter the cell
- Treatment of mixed bacterial infections caused by two or more microbes.
Therapy of severe infections in which a specific etiology is unknown.
Not to be used as a shortcut but used until clinical and lab data allow the selection of a specific antimicrobial
- Prevention of the emergence of resistant organisms.
Treatment of Tuberculosis - Addition of inhibitors to prevent degradation or excretion of the enzyme
Ampicillin-sulbactam, Amoxicillin-clavulanate, Piperacillin-tazobactam, Ticarcillin-clavulanate
Imipenem-cilastatin (blocks renal dehydropeptidase) Penicillin- probenecid (decrease renal excretion
What are the 5 drawbacks of combination drug therapy?
- Risk of toxicity from two agents
Vancomycin or Aminoglycosides each alone have some nephrotoxicity. If given together you get marked renal impairment.
- Antagonism
Pneumococcal meningitis
Penicillin - 21% mortality
Penicillin + Tetracycline - 79% mortality - Selection of microorganisms resistant to antibiotics
- Superinfection
- Extra cost
Are aminoglycosides concentration or time dependent for dosing?
How about beta lactams?
How about linezolid?
Aminoglycosides are CONCENTRATION dependent, so you administer 1 huge IV dose
Beta lactams are TIME dependent, so you have to dose them multiple times–their effectiveness depends on the amount of time being over the MIC in the body
Most drugs, including linezolid are more dependent on a comination of the two - the cumulative dose (AUC)
