Protein Synthesis Inhibitors: Tetracyclines, Chloramphenicol, Aminoglycosides Flashcards
what is the shared mechanism for all protein synthesis inhibitors?
- bind to ribosomal subunits: usually 30s or 50s
- inhibit formation of polypeptide chains and block protein synthesis
discovery of tetracyclines
Compound isolated from an “ultra mold” that was dug from a dormant timothy hayfield on the University of Missouri campus in Columbia, MO by Dr. Benjamin Duggar who was mining actinomycetes soil bacteria as a consultant for American Cyanamid searching for new antibiotics.
what is great about tetracyclines?
first true “broad spectrum” antibiotics discovered as they act against:
- Gram + and Gram - bacteria
- Mycoplasma
- some mycobacteria
- most alpha-proteobacteria: anaplasma, rickettsia
- protozoan and filarial parasites
tetracyclines are active against
- Gram + and Gram - bacteria
- Mycoplasma
- some mycobacteria
- most alpha-proteobacteria: anaplasma, rickettsia
- protozoan and filarial parasites
tetracyclines are first-line drugs in what species?
food animals, aquaculture species, exotic animals, honeybees
less often utilized in small animals, horses, humans
tetracyclines
tetracycline, oxytetracycline, chlortetracycline, doxycycline and minocycline
MOA of tetracyclines
bind to the 16s rRNA and S7 protein of the 30s ribosomal subunit: inhibits tRNAs from binding to the docking site on the ribosome and mRNA codon to block peptide synthesis
what other unique effect do tetracyclines possess?
anti-inflammatory activity: can inhibit matrix metalloproteinase enzymes by binding to structural Zn2+ and Ca2+ ions, and can scavenge ROS
tetracycline chemistry
- complexes with Mg2+, Zn2+, Fe2+
- zwitterionic forms
- ROS
are tetracyclines bacteriostatic or bactericidal?
in general, they are bacteriostatic, but there is some evidence for time-dependent bactericidal activity for doxycycline
how are tetracyclines administered?
- not very soluble in water, thus formulated as salts that can be given orally or parenterally
- ionized at all pH values, however a null net charge of zwitterionic form favors passage across cell membranes
what is the representative drug for sensitivity testing?
tetracycline
why is tetracycline the representative drug for sensitivity testing?
media stability
potency of this group of drugs increases with increasing lipid solubility
resistance of tetracyclines
numerous mechanisms have been ID
- energy dependent efflux systems that exchange an extracellular H+ for a drug-Mg2+ complex
- ribosomal protection proteins that remove the tetracycline from the binding site near the tRNA docking site = protective proteins bind and yank it out
- 16s rRNA mutation
PK properties of tetracyclines
- oral bioavailabililty is poor and is worse in presence of cations: reduced when given with milk replacer or antacids
- wide tissue distribution and are one of only a few OSTEOTROPIC antimicrobial drugs!!!
what type of abx are osteotropic?
TETRACYCLINES
cation-chelating properties lead to deposition in teeth and sites of new bone formation
how are tetracyclines excreted
glomerular filtration, some biliary secretion depending on lipid solubility
enterohepatic circulation leads to longer half-lives than most drugs eliminated thru the kidneys
why do tetracyclines have a longer half life even thought they are excreted thru glomerular filtration?
enterohepatic circulation leads to longer half-lives than most drugs eliminated thru the kidneys
toxicities of tetracyclines
- generally safe, but are irritants and may cause vomiting after oral dosing and tissue damage at injection sites
- cause imbalance of intestinal flora = enterocolitis
what medication is associated with esophageal stricture in cats?
doxycycline
doxycycline is associated with what sequela in cats?
esophageal stricture
what are some toxicoses you might see with tetracycline administration?
- acute heart toxicity following high dose, rapid IV injection: associated w ability to bind calcium
- renal toxicosis is possible, high dose therapy in foals
- yellow discoloration of teeth in growing animals!
what is a side effect of giving tetracyclines to growing animals?
yellow discoloration of teeth
what drug might cause yellow discoloration of teeth in growing animals?
tetracyclines
what is the primary indication of tetracycline use?
treatment of bovine and porcine respiratory disease complexes: tetracycline and oxytetracycline and long-acting formulations
what is the drug of choice for treating plague, tularemia and listeriosis?
tetracyclines
what is the drug of choice for treating Rickettsial infections in small animals?
doxycycline
what is the drug of choice for Chlamidophila felis in cats?
doxycyline
why will treatments of tetracyclines often be longer?
because they are bacteriostatic, not bactericidal
chloramphenicol and derivatives
- derivatives of dichloroacetic acid and are potent inhibitors of microbial protein synthesis
- structural difference accounts for differences in toxicity profiles between chloramphenicol and others
- originally obtained from Streptomyces venezulelea
chloramphenicol MOA
binds irreversible to the 50s subunit of bacterial ribosome: inhibits peptidyl transferase which prevents amino acid transfer to the growing polypeptide chain
how does chloramphenicol lead to bone marrow suppression?
inhibits mitochondrial protein synthesis in mammalian bone marrow cells in a dose-dependent manner
are chloramphenicol and derivatives bacteriostatic or bactericidal?
generally bacteriostatic
chloramphenicol spectrum of activity
broad-spectrum effective against many G+ and G- aerobic and anaerobic bacteria
what does chloramphenicol have good activity against?
G+ aerobes including Actinomyces spp, Bacillus anthracis, some strains of MRSP, Gm - aerobes, anaerobes including Bacteroides and Clostridium
what does chloramphenicol have intermediate activity against?
Rhodococcus equi
what does chloramphenicol have poor activity against?
mycobacterium, nocardia, resistance often develops in Gm- enterics like E coli
what is the most frequent mechanism of resistance against chloramphenicol
- enzymatic inactivation by acetylation of the drug by bacterial chloramphenicol acetyltransferases (CATs)
- efflux of drug from bacterial cells by transporters
what are CAT genes and what role to they play?
chloramphenicol acetyltransferases: CAT genes are found on plasmids in enterobacteriacea and pasteurellacea. they acetylate the drug chloramphenicol and make it inactive
PK properties of chloramphenicol
- absorbed from oral and parenteral administration
- wide distribution, including CNS and eye
- hepatic metabolism with glucoronidation = prolonged in cats with limited glucuronidation capacity
chloramphenicol toxicity/adverse effects
- inhibitor of cytochrome P450 enzymes = drug interaction potential
- main toxicity is bone marrow suppression bc of inhibition of mitochondrial protein synthesis
- idiosyncratic, aplastic anemia occurs in people: PROBLEM
- dose-dependent bone marrow suppression observed in animals
- thiamphenicol and florfenicol don’t cause aplastic anemia in people but do cause dose-dependent bone marrow suppression
- BANNED FROM USE IN FOOD ANIMALS
what is the main toxicity of chloramphenicol
bone marrow suppression bc of inhibition of mitochondrial protein synthesis
- idiosyncratic, aplastic anemia in people (NOT dose dependent)
- dose-dependent bone marrow suppression in people
what chloramphenicol derivative drugs don’t cause aplastic anemia in people but do cause dose-dependent bone marrow suppression?
thiamphenicol and florfenicol
what drug is banned from use in food animals?
chloramphenicol: if there would be any residues that end up in food = BAD
clinical applications of chloramphenicol
- food animal applications use florfenicol
- can be used in small animals for anaerobic infections and use has increased lately with increase in MRSP infections
- BUT has more adverse side effects than doxy, clindamycin, amikacin
what is chloramphenicol used for?
serious ocular infections, prostatitis, otitis media/interna and salmonellosis in horses, dogs, cats
- use has increased lately with MRSP infections
how long should the treatment of chloramphenicol be?
should not exceed 10 days, esp in cats
what is one of the few abx drugs that can be safely administered to horses by mouth
chloramphenicol
you see a horse who has salmonellosis. what is a potential drug treatment option?
chloramphenicol- and can be given by mouth!!
first treatment for tuberculosis
aminoglycosides
structure of aminoglycosides
very water soluble and thus don’t penetrate cells well. glycoside = carb/sugar
are aminoglycosides bactericidal or bacteriostatic?
bactericidal
MOA of aminoglycosides
- inhibit protein synthesis by binding to the 30s ribosomal subunit (same as tetracyclines) and cause misreading of the genetic code
- must penetrate bacterial cell wall first, so combo with cell-wall inhibitors can be synergistic
how do aminoglycosides get into bacteria?
bacteria pump aminoglycosides into the cell via an oxygen-dependent mechanism?
why are aminoglycosides not effective against anaerobic infections?
because bacteria actively pump aminoglycosides into the cell wall via an oxygen-dependent mechanism
T/F: aminglycosides only work in anaerobic infections
FALSE it’s the opposite bc they need O2 for bacteria to pump them in
are aminoglycosides time or concentration dependent?
concentration dependent: target concentration at site of infection is at least 10x the MIC of infecting organism
will you give aminoglycosides more or less frequently?
high doses less frequently; are concentration dependent
target concentration at site of infection is at least 10x the MIC
what drugs have a significant post-antibiotic effect?
aminoglycosides
aminoglycoside activity is markedly influenced by what?
pH: has most activity in alkaline environments
what is the post-antibiotic effect? what drugs have it?
PAE: drug concentrations have dropped but damaged bacteria are more susceptible to host defenses
aminoglycosides!
aminoglycosides have the most activity at what pH?
alkaline environments: alkalinizing urine will increase efficacy for urinary tract infections
is the activity of aminoglycosides increased or reduced in presence of purulent debris?
reduced: abscesses or purulent infections must be debrided prior to using an aminoglycoside. it “sticks” to pus/grossness
what is first exposure adaptive resistance? what drugs does it relate occur with?
after the initial binding and uptake of an aminoglycoside, bacteria that survive develop an adaptive resistance via reduced uptake
- can last 16 hours with partial susceptibility returning by 24 hours
- clinical implications: frequent dosing or CRI is less effective than high-dose, once-daily dosing
aminoglycosides
gentamycin, tobramycin, amikacin, arbekacin
you see a 5 year old lab for an abscess and plan to administer an aminoglycoside like gentamycin. you remember hearing something in vet school about these drugs and their effectiveness with abscesses. what do you need to do?
debride the wound/clean the abscess; otherwise the aminoglycoside won’t be as effective
spectrum of activity of aminoglycosides
aerobic, Gm - bacteria
- some Gm + susceptible: staph, often effective against MRSP
- efficacy against strep can be improved by combining with a beta lactam
NOT EFFECTIVE AGAINST ANAEROBIC BACTERIA OR EVEN AEROBIC BACTERIA IN AN ANAEROBIC ENVIRONMENT
- often active against enterococci
rank aminoglycosides in potency, spectrum of activity, and stability against enzyme-mediated inactivation
Amikacin>tobramycin≥gentamycin>neomycin=kanamycin>streptomycin
resistance to aminoglycosides usually comes from
plasmid-mediated enzymes that acetylate the aminoglycoside which prevents it from binding to the 30s ribosomal subunit - at least 11 enzymes have been discovered that can inactivate these drugs
with aminoglycosides, why is high-dose, once-daily dosing better for aminoglycosides than frequent dosing or CRI?
because of aminoglycoside first exposure adaptive resistance: after initial binding and uptake, bacteria that survive develop an adaptive resistance via reduced uptake
what aminoglycosides might still be active if resistance is due to the first exposure adaptive resistance acetylation? why?
Gentamycin and Kanamycin B: bacteria use an inactivating reaction that resembles an N-acetylation reaction. theses are the 2 aminoglycosides that don’t have NH2 and thus aren’t susceptible
PK properties of aminoglycosides
- poorly absorbed orally, thus parenterally given
- can get effective concentrations in fluids
- relatively small volume of distribution with distribution to total body water
- excreted entirely thru renal elimination with short half-lives
how are aminoglycosides eliminated?
renally
how can you avoid adverse effects of systemic aminoglycoside therapy?
Regional perfusion techniques and impregnated polymethyl methacrylate beads allow local delivery without adverse effects
what is the most common adverse effect of aminoglycoside therapy?
acute tubular necrosis: associated w accumulation in PT cells and thus is NOT associated with peak concentrations, but with duration of therapy and amount, age, acidosis, and elevated trough concentrations
toxicity of aminoglycosides
- all aminoglycosides cause varying degrees of ototoxicity and nephrotoxicity
- acute tubular necrosis is the most common adverse effect of therapy
what aminoglycoside is most likely to cause renal toxicity?
Relative risk of renal toxicity: Neomycin > kanamycin ≥ gentamicin > amikacin = streptomycin
how do aminoglycosides cause acute tubular necrosis?
Due to binding of cationic aminoglycoside with anionic phospholipids of cells, internalization and accumulation in lysosomes, resulting in interference with normal lysosomal processes leading to cell swelling and rupture.
how often should you administer aminoglycosides?
once daily in higher doses to allow trough concentrations to drop below critical level before next dose
what are some ways you can reduce risk of nephrotoxicity with aminoglycosides?
- calcium supplementation: reduces risk: cationic calcium displaces/prevents cationic drug from binding anionic phospholipid
- feeding a high protein diet/high calcium diet like alfalfa to large animals and >25% protein diet to small animals. high protein also increases GFR and renal blood flow, which reduces the drug accumulation
- administer once-daily in higher doses, allow trough concentrations to drop below critical level before next dose
how can you monitor renal toxicity with aminoglycosides?
- therapeutic drug monitoring (TMD) to evaluate plasma concentrations
- sample approx 1 hour and 8 hours after dosing to estimate elimination half-life = increased elimination half-life is a very sensitive indicator of early tubular insult!
if TDM (therapeutic drug monitoring is not available, what can you do to monitor renal function while administering aminoglycosides?
– Increase in urine gamma glutamyl transferase (GGT)
– Increase in urine GGT:creatinine ratio
– Development of proteinuria is next best indicator
– Elevations in BUN and Creat are not seen until at least 7 days after significant damage has occurred.
clinical applications of aminoglycosides
- Toxicity has largely restricted the use of aminoglycosides.
- More toxic drugs (neomycin) mostly restricted to topical or oral use for treatment of Enterobacteriacea.
- Less toxic drugs reserved for parenteral treatment of severe sepsis caused by Gm(-) aerobes and the treatment of MRSP infections.
- Residues can persist in renal tissues for up to 18 months and thus extra-label use should be avoided.
non-renal toxicities of aminoglycosides
- Mechanism of ototoxicity is the same as for renal toxicity
– Tendency to produce vestibular (streptomycin, gentamicin) or cochlear toxicity (amikacin, kanamycin, neomycin) varies with drug. - Rapid IV administration of all causes bradycardia and reduced blood pressure.
- Neuromuscular blockade is rare, but if given post-sx can potentiate the effects of other non-depolarizing neuromuscular blocking agents.
– Treat with Ca-chloride or Ca-gluconate.
