Antibiotics II Flashcards
Bacterial ribosomes vs human ribosomes?
Bacteria have 70s ribosomes, people have 80s.
Very important for how we target bacteria without killing folks!
Describe the general mechanism of oxazoladinones
(linezolid) binds 50 S, prevents formation of initiation complex
Describe the general mechanism of tetracyclines
bind 30 S, Prevent binding of aminoacyl tRNA, preventing elongation of the peptide chain.
Describe the general mechanism of glycylcycline
(tigecycline) binds 30S. Prevents binding of aminoacyl tRNA.
Describe the general mechanism of Aminoglycosides
bind 30 S. Interfere with initiation complex and cause misreading of mRNA
Describe the general mechanism of chloramphenicol
binds 50 S and inhibits peptidyl transferase.
So when do we use oxazolidinones?
So these guys are bacteriostatic, and sometimes bactericidal, against gram positive strains. Prime use is against
- E.faecalis, even vancomycin resistant
- Methicillin resistant Staph aureus and epidermidis
- S haemolyticus
- S. pneumoniae (PCN resistant)
Review: Mechanism of oxazolidinones like linezolid
Prevents formation of the initiation complex and 70 S ribosomal complex
Binds the 50 S subunit and prevents protein synthesis.
Discuss the pharmocokinetics of oxazolidinones
- Penetrates the CNS
- Good oral or IV absorption
What causes bacterial resistance to oxazolidinones?
Mutations of the 23 S rRNA prevent binding of the drug
What kind of side effects will we see with oxazolidinones like linezolid?
Inhibits monamine oxidase (MAO) leading to nausea, vomiting, diarrhea
Bad side effects:
- Myelosuppression
- thrombOcytopenia
- Anemia
What bacteria can we cover with tetracyclines?
broad spectrum of bacteriostatic activity against Gram-positive and negative, aerobic and anaerobic bacteria; highly effective against all rickettsiae (e.g. Rocky Mountain spotted fever)
Tetra + cycline = Big four rings, so broad spectrum, positive and negative, aerobic and anaerobic, just about everything (but can’t kill them just stops them)
What is the mechanism of action of tetracyclines?
Binds the 30 S ribosomal subunit
- Prevents binding of the aminoacyl-tRNA during protein synthesis
- Cross the outer membrane of Gram-negative bacteria by passive diffusion through the porin channel. An energy-dependent active transport is required for transport through the plasma membrane; mammalian cells lack this active-transport system.
Discuss the pharmacokinetics of tetracyclines
With tetracyclines, we have adequate but incomplete oral absorption, which is further impaired by food (except doxy and minoclycline), dairy products, antacids and cation supplements (think of it as it’s so big that it gets confused for food and doesn’t absorb like it should)
These guys also penetrate the CNS
Discuss resistance mechanisms to tetracyclines
Resistance to one tetracycline frequently confers resistance to the others
Decreased intracellular accumulation due to decreased influx or acquisition of an energy-dependent efflux mechanism
Decreased access to the ribosome because of ribosome protecting proteins (TetO genes)
Enzymatic inactivation of the drug (including TetX modification with tet(X) genes)
What can tetracyclines do to your gut, teeth, and bones?
GI: nausea, vomiting, diarrhea, Pseudomembranous enterocolitis
- Teeth and bones: Stains teeth
Again, stick with big-bulky-food idea, you get stains on your teeth and if you eat too much you get N/V/D leading to enterocolitis
When do we use glycylcyclines?
Bacteriostatic against gram-positive and gram-negative organisms, especially drug-resistant strains (including tetracycline-resistant)
For skin infections including MRSA, E. faecalis, E. coli, S. pyogenes and B. fragilis, and for intra-abdominal infections with E. coli, S. anginosus, B. fragilis and K. pneumoniae
Discuss how Glycylcyclines work
Binds to the 30S subunit on the ribosome and inhibits binding of the aminoacyl-t-RNA molecules into the A site of the ribosome
Prevents incorporation of the amino acid residues into the elongating peptide chain.
Discuss mechanisms of resistance against glycylcyclines
So ribosomal protection proteins and efflux pumps, like in tetracycline, DO NOT WORK on this guy. It doesn’t react with other antibiotics, and other mechanisms that work against b lactamases, target site modifications, macrolie efflux pumps, and enzyme changes ALSO DO NOT WORK
TetX gene is the only thing that allows a bacteria to fight back. Other than that, the only thing connected with resistance is AcrAB transport system, which reduces susceptibility to Tigecycline, a glycylcycline.
Names you should associate with Aminoglycosides (just recognize these)
streptomycin, neomycin, gentamicin, kanamycin, tobramycin, sisomicin, amikacin, netilmicin
Aminoglycosides Got STANKS (smells bad) G - Gentamicin S - Streptomycin T - Tobramycin A - Amikacin N - Neomycin K - Kanamycin S - Sisomycin
Where do aminoglycosides get their name?
Aminoglycosides contain amino sugars linked to an aminocyclitol ring by glycosidic bonds
What pathogens are covered by aminoglycosides and how do they work before hitting the ribosomes?
Broad spectrum bactericidal activity, but primarily effective against gram-negative bacteria (gram negatives have a thin cell wall = more prone to drugs that stank)
In Gram-negative bacteria, these drugs cross the outer membrane by passive diffusion through the porin channel and cross the inner membrane by energy-dependent active transport (need energy to get stanky drugs into the bacteria, mammalian cells are smart enough to not have pumps that do this)
What restricts the transport of aminoglycosides?
Transport is inhibited by divalent cations, hyperosmolarity, lowered pH, and anaerobic conditions
(Transport is also oxygen-dependent—inactive against anaerobes!)
(You gotta breathe in the stank for it to work)
Discuss the ribosomal mechanism of action of aminoglycosides
Bind the 30 S subunit (to a site within the 16 S rRNA) irreversibly inhibiting protein synthesis
Mechanisms of action include:
1) interference with formation of the initiation complex
2) misreading of the mRNA code resulting in incorporation of incorrect amino acids. In contrast with other protein synthesis inhibitors which are bacteriostatic, aminoglycosides are bactericidal because they can cause the build-up of abnormal proteins that can ultimately damage the bacterial membrane.
3) premature termination by dissociation of the polysomes
Discuss important pharmacokinetics stuff for aminoglycosides
- Polycationic charges = no good for gut absorption unless you have ulcers (which is cheating, really)
- Low accumulation in CSF
- Excreted by the kidney rapidly
- Enhanced activity with B lactam antibiotics (synergistic) (lots of A’s in BetA lActAms)
Discuss resistance to aminoglycosides
Primary:acquisition of inactivating enzymes – acetylases, adenylases, phosphorylases (plasmid encoded)
Secondary resistance may occur if the drug fails to permeate the inner bacterial membrane
3 big categories of bad stuff with aminoglycosides (one of the reasons we tend to avoid these guys)
3 A’s
Auditory - Ototoxicity—vestibular and auditory dysfunction, may be irreversible
Accumulation - Nephrotoxicity, may be reversible (proximal tubular damage; drug accumulates in perilymph and endolymph—avoid prescribing loop diuretics at the same time!)
Arrest - Curare-like NM blockade (with high doses), can result in respiratory paralysis, treat with Calcium and neostigmine and support ventilation if necessary
What does chloramphenicol cover?
Broad spectrum; bacteriostatic for most microorganisms but is bactericidal for H. influenzae, Strep. pneumoniae, and N. meningitidis
Limited use of chloramphenicol: only for infections where the benefits outweigh the risks of potential toxicities
Note: not used in US but you will see it in foreign countries because of very low cost.
Discuss the mechanism of action of chloramphenicol
Enters the bacterium by facilitated diffusion
Binds reversibly to the 50 S ribosomal subunit to prevent binding of the aminoacyl tRNA in the A site, thus inhibiting the peptidyl transferase step of protein synthesis
Discuss the pharmacokinetics of chloramphenicol
Rapidly absorbed in the GI, given orally or IV
Well distributed in body fluids and therapeutic concentrations occur in CNS and cross the placenta
Half-life has been correlated with plasma bilirubin concentrations (requires hepatic function for later secretion in urine—this is why infants cannot process it)
How do bacteria become resistant to this nasty chloramphenicol?
Decreased membrane permeability (influx)
Chloramphenicol acetyl transferase (plasmid encoded)
Chloramphenicol has a shit ton of toxic side effects, which is why it is cheap and why the U.S. says no.
What does it do in the bone marrow?
Two effects on the bone marrow:
a) Direct toxicity due to dose-related normocytic anemia, due to erythroid suppression of the bone marrow; reversible
b) Allergic reaction resulting in idiosyncratic blood dyscrasias which can cause aplastic anemia, usually reversible but sometimes fatal; can also have allergic reactions resulting in macular or vesicular skin rash
Chloramphenicol has a shit ton of toxic side effects, which is why it is cheap and why the U.S. says no.
What does it do to our cells?
Inhibits protein synthesis in mammalian mitochondria (70 S ribosomes)
What is gray baby syndrome?
“Gray baby syndrome”- Toxicity in infants from chloramphenicol is manifested as vomiting, flaccidity, hypothermia, respiratory distress, gray pallor and shock, 40% fatality rate. Mechanisms include inadequate glucuronic acid conjugation (due to inadequate enzyme activity of the liver in the first 3-4 weeks after birth) and inadequate renal excretion of unconjugated drug.
What drug interactions are associated with chloramphenicol?
Chloramphenicol inhibits CYP3A4 and other CYPs.
May prolong the half-lives of drugs normally metabolized by these enzymes
Antagonizes the effects of macrolides and clindamycin (binds to similar position in the ribosome, thus competing for the same binding site)
Examples of macrolides!
MACE - Macrolides: ACE - erythromycin, clarithromycin, azithromycin
What do macrolides cover?
Broad spectrum, and modifications of clarithromycin and azithromycin broaden the spectrum of activity
Fidaxomicin –FDA approved May 2011 for treatment of Clostridium difficile infections
Where do macrolides hit?
Usually bacteriostatic, but can be bactericidal in high concentrations against susceptible bacteria
Bind 50 S ribosomal subunit and inhibit the translocation step of protein synthesis
Discuss the pharmacokinetics of macrolides
Erythromycin is inactivated by gastric acid, but is absorbed in upper small intestine.
Clarithromycin and azithromycin modifications improve acid stability and tissue penetration.
Insertion of the azo-group into the lactone ring increases bioavailability and stability; azithromycin requires only once a day dose instead of 3 times a day dosing.
Where do macrolides go and how do we get rid of them?
Generally, wide distribution throughout the body EXCEPT cerebrospinal fluid
Elimination: erythromycin and azithromycin primarily liver; clarithromycin renal and non-renal (yea…thanks note set)
Everything kills macrolides. Discuss the 4 resistance methods
Efflux via an ATP-dependent pump
Production of a methylase that modifies the ribosomal target, leading to decreased drug binding
Hydrolysis by esterases
Mutation of the ribosome—specifically the 23 S rRNA to which the macrolides bind
Basically if you can imagine it, it works.
Discuss the adverse effects of macrolides
Some hypersensitivity reactions
GI (nausea, vomiting, diarrhea, stimulates GI motility)
Hepatic (chloestatec hepatitis)
Cardiac (arrhythmia—QT prolongation with VT)
Discuss drug interactions we see with macrolides
Erythromycin and clarithromycin (but not azithromycin) inhibit hepatic enzymes (e.g., CYP3A4), resulting in multiple drug interactions.
Erythromycin interactions with liver p450s inhibit the metabolism of a variety of other drugs.
What type of drug is clindamycin?
Lincosamide
Clindamycin is a congener of lincomycin that has improved pharmacokinetics and less toxicity
Clindamycin hits what?
Bacteriostatic primarily against susceptible strains of Gram-positive cocci (Clindamycin - c - cocci)
Can be active against some strains that are macrolide-resistant
Effective against anaerobes
Site/mechanism of action of clindamycin
Binds the P and A sites in the 50 S ribosomal subunit and suppresses protein synthesis
PA-Ce your protein synthesis
Discuss the distribution of clindamycin and where it gets wasted
Goes everywhere, even the bone and placental barrier, BUT NO CNS
Lost in urine and bile
How do we get rid of clindamycin
Resistance can occur due to ribosomal methylation which can be plasmid encoded
Efflux pump DOES NOT WORK (can work in species that pump out macrolides, which is why we use it when macrolides fail)
Adverse effects of clindamycin
GI effects: diarrhea; modification of GI flora can lead to life threatening Pseudomembranous enterocolitis associated with overgrowth of C. difficile
Can inhibit neuromuscular transmission
Skin rashes, more common in HIV patients
What are Type B streptogramins?
Semisynthetic derivatives of the naturally occurring pristinamycins
What do Type B Streptogramins cover?
Bactericidal against Gram-positive cocci; synergy between the two compounds
Largely inactive against Gram-negative strains
Use is often reserved for vancomycin-resistant strains of E. faecium or multiple-drug-resistant Gram-positive organisms.
Site of action for streptogramins
Streptogramin B binds 50 S ribosomal subunit and inhibits translocation step; occupies the same site as the macrolides
Streptogramin A binds nearby and induces a conformational change in the 50 S ribosomal subunit, enhancing binding of quinupristin.
Discuss the pharmacokinetics of streptogramin
IV only with a short half life.
Excreted in the bile, and we use this with other stuff for additive effects
Resistance mechanisms for streptogramin
Methylase modification of ribosomal binding site (MLS-B) and lactonases
Streptogramin A: active transport efflux and acetyltransferases
Adverse effects of streptogramins
Infusion-related pain and phlebitis at site of infusion; arthalgias, myalgias
What do we use Nitrofurantoin on?
E. coli, S. aureus, E. faecalis
Not effective against acinetobactor, pseudomonas or proteus species
Mechanism of action for nitrofurantoin
Bactericidal at high concentrations
Multiple mechanisms of action: DNA damage, binding and inhibition of ribosomal proteins, inhibition of other bacterial enzymes; it is not known which activity is critical
We only really use nitrofurantoin for:
UTIs - bactericidal at concentrations reached in the urine
Important pharmacokinetics for this weird UTI drug, Nitrofurantoin
Metabolized by the liver, and 25% secreted by the kidney unchanged
Distribution only to the bladder where the drug is concentrated in the urine
Not for use in patients with decreased kidney function!!!
Pregnancy safe for first 2 trimesters
Adverse effects of nitrofurantoin?
Mostly anorexia, nausea vomiting; some neuropathies and hemolytic anemia with G6P deficiency
