Pharmacology- Chen Macrolides Flashcards
Where do macrolides act?
They are protein synthesis inhibitors that block the 50S subunit
What was the first macrolide?
Erythromycin
What do macrolides end in?
-thromycin
What do aminoglycosides end in?
-mycin
What subunits are bacterial ribosomes made up of?
A 70S subunit, which made up of a 50S and 30S subunit
The 50S subunit is further divided into 5S and 23S (r RNA and proteins)
Where is the binding site for macrolides?
the 23S rRNA
What subunits make up human ribosome?
It is an 80S subunit that is composed of a 60S and a 40S subunit
What is the MOA for Macrolides (eryhtromycin, clarithromycin, azithromycin)?
- Binds the 50S ribosomal RNA polypeptide exit tunnel which is near the peptidyltransferase center
- It inhibits transpeptidation and translocation step of protein synthesis (blocks the movement of the peptides from P to A)
What domain do macrolides have a higher affinity for?
-Domain V of 23S rRNA
Are macrolides bacteriostatic or bactericidal?
- Bacteriostatic
- At higher drug concentrations it can become bactericidal for some organisms
What is the MOA of ketolides (telithromycin)?
-Binds to the 50S rRNA polypeptide and inhibits transpeptidation and translocation step of protein synthesis
What domains do ketolides have a higher affinity for?
Ketolides can bind domain V and also have a high affinity for domain II of 23S rRNA
If there is resistance that results in alteration of the structure of V, will macrolides work?, Ketolides?
- Macrolides will not work because this is the only place that they bind
- Ketolides will still work because they can also bind to the II domain as well
What are the 3 mechanisms of resistance to macrolides?
- Reduced permeability of the cell membrane or increased active efflux
- Modification of the ribosomal binding site
- Production of esterases that hydrolyze macrolides
Which mechanism of resistance is one of the most important for gram + organisms?
Reduced permability of the cell membrane or increased active efflux
What gene increases the activity of efflux pumps to get macrolides out of bacteria?
Macrolide efflux (mef) genes
Which types of antibiotics have no cross resistance with bugs that have macrolide efflux genes?
Ketolides (telithromycin), lincosamides (clindamycin), and streptogramins (quinupristin-dalfopristin)
Is cross resistance due to macrolide efflux genes complete between erythromycin and other macrolides?
Yes–> All macrolides are affected by this resistance
What is another important resistance mechanism for gram+ organisms?
Modification of the ribosomal binding site
What gene mediates modification of the ribosomal binding site?
Erythromycin ribosome methylase (erm) genes
How do the erm genes work?
They methylate an adenine residue in domain V of 23S rRNA and prevent binding of macrolides and ketolides here
How do ketolides overcome modification of the ribosomal binding site by erm genes?
They can bind domain II
Is modification of the ribosomal binding site a high level or low level resistance?
High level macrolide resistance
- This confers resistnace to mechanistically similar compounds such as clindamycin and streptogramins (these share the same ribosomal binding site)
- This methylates all of domain V
What gene mediates the production of esterases that hydrolyze macrolides?
Erythromycin esterase gene (ere)
How does the ere gene exert its affects?
Hydrolyzes the lactone ring of macrolides and inhibits macrolide activity
Why does erythromycin have to be administered with enteric coating?
Because erythromycin base is the only microbiologically active structure and the base is destroyed by stomach acid
What preparations is erythromycin given in?
Stearate and ester
Which macrolides are more acid stable and have greater oral bioavailability?
Clarithromycin, Azithromycin, and Telithromycin
Where are the levels of clarithromycin, azithromycin, and telithromycin greater than levels in the serum?
Lung tissue and alveolar macrophages
Do macrolides have good CSF penetration?
No
Which macrolide may require dose adjustments in patients with moderate to severe renal impairment?
Clarithromycin
Which macrolide is the choice for STD and why?
Asithromycin
-It has high tissue concentrations and a prolonged tissue halflife
Which macrolides are metabolized by CYP3A4?
Erythromycin, clarithromycin, telithromycin
Order the macrolides from most activity to least activity for gram + aerobes
Teli > Clari> Ery> Azi
Order the macrolides from most activity to least activity for gram - aerobes
Teli>Azi>Clari> Ery
What other pathogens are macrolides effective against?
Chlamydophilia pneumoniae
Mycoplasma pneumoniae
What community acquired respiratory tract infections are macrolides used for?
Pharyngitis, otitis media, sinusitis, acute infective exacerbation of chronic bronchitis, community acquired pneumonia, pertussis, legionnaires disease
Which conditions do you use Clari- and Azi- for?
Pharyngitis, otitis media, and sinusitis
What do you use for an acute infective exacerbation of chronic bronchitis?
Clari
What do you use for CAP?
Clari, Azi, Teli
What do you use for pertussis or legionnaires disease?
Ery
What non-respiratory conditions can macrolides be used for?
STDs, skin and soft tissue infections, H. Pylori infections, MAC in AIDS patients
What STDs can only Azi be used for?
Uncomplicated urethritis or cervicitis and chancroid
What do you use for chlamydial infections?
Ery, Azi
What do you use for syphillis?
Ery
Which drugs are used for skin and soft tissue infections?
Ery, clari, azi
What drug is used for H. Pylori infections?
Clari
Which drugs are used for MAC in aids patients?
Clari, azi
What CV AE do macrolides cause?
QT interval prolongation
What GI AE do macrolides cause?
N/V/D
Which macrolide most commonly causes GI issues and why?
Ery because it is a direct agonist of motilin receptor
What MSK AE do macrolides cause?
Myasthenia Gravis
What ophthalmic AE do macrolides cause?
Abnormal vision and blurred vision
What otic AE do macrolides cause and which one specifically does this?
Reversible ototoxicity- Ery
What hepatic AE do macrolides cause?
Cholestatic hepatitis, hepatitis and liver toxicity, life-threatening liver failure (teli)
Other indications for teli were removed when it was realized that this drug can cause hepatitis and liver failure
What drugs are contraindicated with ery, clari, teli?
Theophylline, warfarin, CCBs, cyclosporine
Why does this contradiction exist?
Ery, clari and teli are oxidized by CYP3A4 to a metabolite which forms an inactive metabolite-enzyme complex by binding to the heme of the CYP3A4 enzyme–> This results in reduced clarance of other agents that are metabolized by CYP3A4
How does ery, clari, and teli increase digoxin levels in the blood?
- Macrolides destroy the gut flora that normally metabolizes digoxin to inactive products
- Macrolides inhibit P-glycoprotein mediated renal secretion and excretion of digoxin (reduces elimination of digozin)
What is the MOA for oxazolidinones (linezolid)
Binds to the 50S ribosomal RNA (rRNA) and interferes with the formation of the complex that associates mRNA, fmet-tRNA, and 50S ribosome which blocks protein synthesis
Is there any cross resistance with other drug classes for linezolid?
No, it has a unique binding site
Is linezolid bacteriostatic or bactericidal?
It is bacteriostatic, but at higher concentrations may become bactericidal
What is the mechanism of resistance for linezolid?
Mutation of the linezolid binding site on 23S rRNA
Is linezolid have good oral bioavailability?
Yes, it’s 100%
Does linezolid affect CYP3A4?
No
What hematologic AE are associated with linezolid?
Thrombocytopenia**
Also anemia and neutropenia in patients with underlying BM suppression
What GI AE are associated with linezolid?
N/V/D
What neurological AE are associated with linezolid?
Peripheral neuropathy
What endocrine/metabolic AE are assocaited with linezolid?
Lactic acidosis
What is the most common AE with linezolid?
Thrombocytopenia
What are the respiratory uses for linezolid?
CAP and nosocomial pneumonia (this drug is very good for these)
What are the non-respiratory uses for linezolid?
Skin and soft-tissue infections
Vancomycin-resistant enterococcus faecium infection
When do we want to use linezolid?
As a last resort for multi-drug resistant infections
(We want to prevent bacteria from developing resistance to this
What is warfarin predominantly metabolized by?
CYP3A4
Why does warfarin dose need to be adjusted carefully when used with a macrolide?
Because it has a narrow therapeutic window and macrolides inhibit CYP3A4 thus messing with the normal metabolism of warfarin
What % of digoxin is converted to inactive metabolites in 10% of the population by normal gut flora?
40%
What do macrolides do to gut flora?
They reduce the number of normal gut flora
What effect does macrolides reducing gut flora have on the metabolism of digoxin?
It reduces the conversion of digoxin to inactive metabolites and can increase digoxin toxicity
What is one mechanism for digozin excretion?
Through secretion mediated by P-glycoprotein in the kidney
What do macrolides do to P-glycoprotein and what is the implication of this for digoxin?
Macrolides inhibit P-glyoprotein mediated transport and increase serum levels of digoxin
What are the 2 common presentations of myasthenia gravis?
Muscle weakness and ocular symptoms (diplopia and ptosis)
What effect do macrolides have on myasthenia gravis?
They can unmask it
Which macrolide was originally used for legionnaire’s disease?
Eryhtromycin
Which macrolide is indicated for H. Pylori infections, upper and lower respiratory tract infections and MAC?
Clarithromycin
Which macrolide is indicated for STDs and MAC and why?
Azithromycin
-Due to high tissue concentration and long tissue half life
What domain is the ketolide telithromycin more selective for?
Domain II of 23S rRNA
Why were other respiratory indications removed for telithromycin?
RIsk of hepatitis and high-mortality liver failure
Why does linezolid have no cross resistance with other agents
It has a unique binding site on the 50S rRNA
When should linezolid be used?
As a reserve antibiotic… used sparingly and as a last resort against multidrug-resistant infections
