Antibiotics- Inhibitors of Protein Synth Flashcards
Linezolid
Oxazolidinone
Mechanism: 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, Vancomycin Resistant Enterococci
Resistance: alterations or modifications in 23S ribosomal RNA
unique binding site does not result in cross-resistance with other drug classes.
Adverse Effects: Bone marrow suppression, binds to mt ribosome
Inhibits monoamine oxidase which can lead to Serotonin Syndrome (increased serotonin?) if taken with SSRI
hallucinations, increase heart beat, agitation, nausea
aminoglycosides
gentamicin, amikacin, tobramycin (neomycin, streptomycin)
Mechanism: Bactericidal- Prevents formation of initiation complex, causes misreading of mRNA, and induces early termination.
Spectrum: Extended spectrum needs active transport (ATP) to be transported into cell -anaerobes make less ATP
Resistance:
Intrinsic resistance- failure of antibiotic to enter bacterial cell (anaerobic and low pH environment)
Cotreat with cell wall inhibitor makes it easier for drug to get in
Acquired resistance-
Acquisition of enzymes which inactivate the drug through acetylation, phosphorylation, or adenylation
Amikacin- less susceptible to enzyme inactivation and broader spectrum
including Pseudomonas
concentration dependent killing
Adverse Effects: Tubular necrosis nephrotoxicity- drug retained in renal cortex (don’t coadmin loop diuretics, vancomycin- nephrotoxic) ototoxicity- vestibular and auditory dysfunction pregnancy class D- hearing loss in fetus
Important Facts:
Poor gut absorption usually administered by IV
Drugs are polar cations and excluded from CSF
Adverse Effects: Tubular necrosis nephrotoxicity- drug retained in renal cortex (don’t coadmin loop diuretics, vancomycin- nephrotoxic) ototoxicity- vestibular and auditory dysfunction pregnancy class D- hearing loss in fetus
Important Facts:
Poor gut absorption usually administered by IV
Drugs are polar cations and excluded from CSF
Concentration-dependent killing
Achieve more killing at a higher concentration
Peak concentration >10 times over MIC (minimum inhibitory concentration), 1 or 2 high daily doses
Aminoglycosides, fluoroquinolones
Time-dependent killing
t>MIC depending on the half life of the antibiotic may need to dose multiple times/day may not
Beta-lactams and vancomycin
tetracyclines
tetracycline, doxycycline, minocycline
Mechanism: Bacteriostatic-bind 30S preventing attachment of aminoacyl-tRNA
Spectrum: Broad
B. burgdorferi, H. pylori, Mycoplasma, Chlamydia
Resistance:
Increased efflux
Ribosomal protection proteins protect site so drug can’t bind
Adverse effects: form stable chelates with a number of metal ions such as calcium, magnesium, iron and aluminum decreasing gut absorption of the drug so take on empty stomach.
Gastrointestinal irritation and photosensitivity (abnormal sunburn reaction)
Discoloration of teeth and inhibits bone growth in children.
Pregnancy class D (should not be used)
drug resistance vs. drug persistence
Drug resistance- select for genetically resistant forms
Drug persistence- genetically homogenous forms shift between different phenotypes
Chloramphenicol
Mechanism: Bacteriostatic- binds 50S preventing peptide bond formation-
Peptidyltransferase can’t associate with amino acid substrate
Spectrum: Extended but use is limited due to severe side effects
Resistance: Reduced membrane permeability Acetyltransferase modifies drug preventing binding
Adverse effects: 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
Macrolides
erythromycin, azithromycin, clarithromycin
Mechanism: Bacteriostatic
Inhibits translocation by binding 23S rRNA of the 50S subunit
Spectrum: Broad coverage of respiratory pathogens- pharyngitis, pneumonia, otitis media
Chlamydia (single dose)
Use of Macrolides is limited by:
Resistance:
methylation of 23S rRNA binding site- also associated with clindamycin and quinupristin/dalfopristin resistance
increased efflux
hydrolysis of the the macrolide by esterases
Adverse effects:
GI discomfort- worse than others
All but azithromycin inhibitor of CYP3A4, Hepatic failure
Clarithromycin is not safe during pregnancy and Azithromycin can cause pyloric stenosis in infants
Drugs effective against Mycoplasma pneumonia
atypical pneumonia
Doxycycline, Azithromycin, Levofloxacin
Beta-lactams are not effective
Clindamycin
is a lincosamide
Mechanism: Bacteriostatic- blocks translocation at 50S ribosomal subunit
Spectrum: Gram positive including anaerobic- skin and soft tissue infections. Acne vulgaris
Resistance: mutation of ribosome, methylation of ribosomal RNA (D-test),
Cross resistance with macrolides and streptogramins
Inactivation of drug by adenylation
Adverse effects:
Diarrhea, abdominal pain, mucus and blood in stool
Superinfection with C. difficile
Hypersensitivity: rash
Streptogramins
Quinupristin/Dalfopristin
Mechanism:
Combined action is bactericidal for some organisms.
Binds 50S to inhibit translocation.
Spectrum: Quinupristin/dalfopristin should be reserved for
infections caused by multiple drug-resistant G+ bacteria.
Resistance:
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.
Adverse Effects:
High incidence of arthralgias.
Inhibits CYP3A4and is likely to have significant drug interactions.
Mechanisms of resistance: drug doesn’t reach its target
Primarily decreased uptake
Sulfonamides
Aminoglycosides
Chloramphenicol
Increased efflux Cephalosporins Aztreonam Tetracyclines Macrolides Quinupristin/dalfopristin Fluoroquinolones Sulfonamides
Mechanisms of resistance: target is altered
Altered Target
Beta-lactams – altered penicillin binding proteins (MRSA)
Vancomycin- altered alanine-alanyl of peptidoglycan subunit
Rifampin - DNA dependent RNA polymerase
Fluoroquinolones - DNA topoisomerase II or IV
Sulfonamides - Dihydropteroate synthetase
Trimethoprim - Dihydrofolate reductase
Linezolid – altered ribosome
Macrolides, clindamycin, quinupristin/dalfopristin – methyltransferase modified ribosome
Tetracyclines – production of proteins that interfere with ribosomal binding
Mechanisms of resistance: upregulation of substrate
Sulfonamides- Increased levels of para-amino benzoic acid synthesis
Mechanisms of resistance: drug isn’t active
Primarily by enzymatic alteration of antibiotic
Penicillins beta-lactamases
Cephalosporins beta-lactamases
Aminoglycosides Acetylation, Amikacin most resistant
Chloramphenicol Acetylation
Macrolides Esterases
Clindamycin Adenylation
Quinupristin/dalfopristin Acetylation
Metronidazole decreased drug activation
