Harrold Macrolides

The macrolide class of antibiotics consists of:

Erythromycin

Clarithromycin

Azithromycin

Telithromycin

Fidaxomycin (unique)

Two chemical characteristics common to all macrolides

A large lactone ring containing 12-16 atoms

Glycosidically linked sugars

All macrolides except for fidaxomycin contain the amino sugar _____

Desosamine

Erythromycin, clarithromycin, and azithromycin contain the neutral sugar _____

Cladinose

_____ is the only naturally occurring macrolide used therapeutically

Erythromycin

The desosamine sugar makes macrolides _____

Basic

Optimal pH for erythromycin solution

7.4

• Both acid and base unstable

_____ occurs when erythromycin is in a basic environment

Hydrolysis of the lactone ring

When erythromycin is in an acidic environment, it undergoes _____

A two step rearrangement reaction that renders the drug inactive:

• C₆-OH attacks the C₉ ketone to form a hemiketal

• C₁₂-OH attacks the hemiketal

Erythromycin can be used in its free base form for oral delivery, but it suffers from two problems:

Bitter taste

Irregular absorption

• Due to acid lability and poor solubility

Positives and negatives of enteric coating or delayed release erythromycin

Positive → successfully overcomes the bitter taste

Negative → only marginally improved absorption problems

• Oral absorption requires BOTH acid stability and a balance between water and lipid solubility

Two types of chemical modifications made to erythromycin

Salts of the dimethylaminogroup of desosamine

Esters of the 2’-OH group of desosamine

Advantages of erythromycin stearate

Lipid soluble organic salt

• Increases acid stability

• Does not dissolve in saliva → patient can’t taste it

Unique characteristics of erythromycin ethylsuccinate

Lipid soluble ester that inhances acid stability

Prodrug that requires in vivo hydrolysis

Can be used PO or IM, but not IV due to poor water solubility

Therapeutic advantage of erythromycin lactobionate

Greatly increases water solubility → allows the drug to be concentrated in a small volume for IV use

Erythromycin is primarily excreted unchanged via _____

Bile and feces

Mechanism of macrolides

Bind to the 23S subunit of the 50S ribosome and inhibit translocation

The binding site for macrolides overlaps with the binding sites for _____, so these drugs should not be used in combination

Chloramphenicol and clindamycin

Mechanisms of bacterial resistance to macrolides

Drug efflux by an active pump mechanism

Ribosomal protection by inducible or constitutive production of methylase enzymes

• Methylates an adenine residue on the 50S subunit to prevent macrolides from binding → ribosome can still synthesize proteins

Macrolide hydrolysis by esterases produced by enterobacteriaceae

Ribosomal protection (via methylation) against macrolides can lead to cross resistance with _____

Clindamycin and other lincomycins

• NOT chloramphenicol

The structural differences between clarithromycin/azithromycin and erythromycin provide _____

Superior acid stability

Although it is active, clarithromycin is converted in vivo to _____

An active C₁₄-OH metabolite

Why can the acid-catalyzed cyclization reaction not occur in clarithromycin?

The C₆-OH required for the initial attack on the C₉ ketone is not present

• Instead, it is a C₆-OCH₃, which is not nucleophilic and cannot attack the ketone

Why can the acid-catalyzed cyclization reaction not occur in azithromycin?

The ring has been expanded by one extra atom and the C₉ ketone has been removed

Erythromycin can cause _____, primarily in patients with underlying cardiac disease

Cardiac arrhythmias, including QT prolongation with ventricular tachycardia

Both erythromycin and clarithromycin are associated with significant drug interactions because they are _____

Strong/moderate inhibitors of CYP3A4

Unlike erythromycin and clarithromycin, _____ does NOT inhibit CYP3A4

Azithromycin

How does telithromycin compare to the macrolides?

Same mechanism, classified as a ketolide

Proposed to have a higher affinity to the bacterial 23S portion of the 50S subunit

A ketone replaces the neutral sugar, still contains desosamine

Acid stability provided by C₆-OH

Inhibitor of CYP3A4

Telithromycin is contraindicated in patients with _____

Myasthenia gravis

What makes fidaxomicin unique from the other macrolides?

Slightly larger ring

Much more lipid character

Unique sugars → none are basic

Mechanism of fidaxomicin

Appears to be different from other macrolides

Inhibits RNA synthesis by inhibiting sigma-dependent (promoter region) transcription of bacterial RNA polymerases and may act at the early stages of transcription

Bacteriocidal effect on C. diff

Pharmacokinetic properties of fidaxomicin

Minimal systemic absorption → actions essentially confined to the GI tract

Hydrolyzed to an active metabolite