•       Derived in 1952 from Saccharopolyspora erythrea (Philippines)

•       Disadvantages

•       Poor bioavailability – Not very acid stable; gets degraded in the stomach

•       Drug interactions

•       Four times a day dosing – Problem with patient compliance

• Erythromycin
• Clarithromycin
• Azithromycin
• Telithromycin (historical interest only)

•       Pharmacokinetics – Better bioavailability; better dosing (twice or even once a day); more acid stable

•       Spectrum of activity (slightly) – more potent against some of the Gram +

•       Drug interactions (mainly azithromycin)

•       Inhibition of protein synthesis

•       Binds to Domain V of the 23s rRNA

•       Part of the 50S ribosomal subunit

Exit tunnel – for the growing AA chain. Macrolides block the exit tunnel, and the ribosome eventually dissociates and protein synthesis ceases. This prevents the growth of the bacteria.

Azithromycin can bind in two molecules at this site (versus one molecule for most macrolides)

• Reversible
• Stops growth
• Immune system does the killing

• Irreversible
• Damages cell leading to death
• Direct cell death
• Good for immunocompromised patients, whose immune systems may not be capable of doing the killing

• Both static and cidal
• Dose, site, organism dependent

Spectrum of activity - good

(HHMM...)

• atypicals
• H. influenzae
• M. catarrhalis
• H. pylori
• Mycobacterium avium

• S. pyogenes
• S. pneumoniae (telithromycin>macrolides)

• staphylocci
• enteric GNRs (azithromycin>clarithromycin)
• anaerobes
• enterococci

Gram positive spectrum of activity

(SSoP)

•       Staphylococcus aureus

•       Resistance has become common

•       MRSA are very likely to also be resistant to macrolides

•       Streptococcus pneumoniae

•       May be used for respiratory tract infections, CAP

•       Resistance has become common

•       Macrolides commonly used against S. pneumoniae

•       Other Streptococci

•       Variable activity against S. pyogenes

•       Modest activity against Viridans Streptococci

•       Macrolides not very good here

•       Poor Enterococcus activity

•       Helicobacter pylori

•       Moraxella catarrhalis

•       Haemophilus influenzae

•       Erythromycin is unreliable

•       Campylobacter jejuni – diarrhea-type symptoms; may lessen duration by a few days

•       Neisseria gonorrhoeae

•       Neisseria meningitides – possible prophylaxis

•       Bordetella pertussis

•       Poor coverage of Enterobacteriaceae

•       Respiratory disease, peptic ulcer disease, STDs

-          Poor anaerobic coverage

-          Macrolides excel in coverage of atypicals

–        Mycoplasma

–        Chlamydia

–        Legionella

–        Mycobacterium avium complex

-          Efflux

–        Mediated by mefA/E gene

–        Affects macrolides only

–        Can go from narrow spectrum to broader spectrum

-          Target site modification

–        Mediated by erm gene

–        Affects macrolides, clindamycin, and streptogramins

–        MLSB – Macrolide, Lucosamide (ex. Clindamycin), Streptogramins

Resistance in S. pneumoniae

-          About 15-30%

–        <5% in early 1990’s

-          Efflux > Methylation in US

-          Methylation conveys higher levels of resistance

-          Z-pak for respiratory infections; its overuse has driven up resistance

◦       Base (tabs) – has enteric coating to help it get through the stomach to the small intestine

◦       Stearate salt (tabs)

◦       Ethylsuccinate (tabs, chew-tabs, liquid)

◦       Estolate (tabs, capsules, liquid)

◦       Gluceptate (IV) – IVs can cause intense burning at the injection site

◦       Lactobionate (IV)

◦       Tabs, ER tabs, suspension

◦       No IV formation

—  least amount of drug interactions of the macrolides

◦       Tabs, suspension, IV

◦       Z-max – Sustained release for CAP and URIs. Good for TB patients, you watch them take their medication

•       Food decreases the absorption of erythromycin (except estolate and ethylsuccinate form)

•       Clarithromycin and azithromycin may be taken with or without food.

•       Decreases GI side effects

•       Azithromycin capsules should be no food 

•       Excellent tissue penetration

•       Produce high intracellular concentrations in several different cells (leukocytes, macrophages)

•       Poor CSF penetration – They are very hydrophilic, but can get into CSF tissue. Can be used for treatment failures with other drugs.

•       Azithromycin has longest WBC half-life and highest concentration

•       Allows concentration of drug at site of infection 

•       Average tissue half-life is 2-4 days

•       Therapeutic concentrations in tissue 5 days or more after completion of therapy

•       Serum concentrations suffer as a result

•       Use in primary bacteremia is questionable

•       CYP450 system substrates

•       Erythromycin and clarithromycin are inhibitors of CYP enzymes

HEPATIC METABOLISM

•       Theophylline

•       Erythromycin or clarithromycin may be associated with increased levels of theophylline

•       Theophylline used to be used for asthma (not so much anymore)

•       Type I antiarrhythmic drugs:

•       Disopyramide, quinidine, procainamide

•       Erythromycin enhances the effects of these agents and should be used with extreme caution.

•       At high concentrations, antiarrhythmics can actually become proarrhythmics

•       Antacids:  decrease absorption of azithromycin

•       Warfarin

•       Increase in anticoagulant effect

•       Carbamazepine

•       Inhibition of carbamazepine’s metabolism

•       May lead to toxic levels

•       50% reduction in dose may be necessary

•       Monitor carbamazepine serum concentrations

•       Digoxin

•       May increase digoxin levels leading to toxicity

•       Cyclosporine

•       May increase cyclosporine levels leading to toxicity

•       Respiratory tract infections

•       CAP

•       Potential empiric use

•       Excellent agents when atypicals are suspected

•       Streptococcal pharyngitis

•       Erythromycin is an alternative to PCN/Cephs

•       Acute exacerbations of chronic bronchitis (AECB)

•       Clarithromycin and azithromycin may be better due to likelihood of H. influenzae

•       Sexually Transmitted Diseases

•       Azithromycin as 2g single dose will cover N. gonorrhoeae and C. trachomatis

•       Peptic Ulcer Disease

•       Clarithromycin in combo with other antibiotics and acid suppressants

•       Cat scratch fever (Bartonella henselae)

•       Whooping cough (Bordetella pertussis)

•       Lyme Diseases (Borrelia burgdorferi)

•       Mycobacterium avium complex (MAC) – Protozoal infection, but macrolides will cover it

•       Treatment

•       Prophylaxis (CD4<50 in HIV patients)

•       Gastrointestinal

•       Abdominal pain (1-12%)

•       diarrhea (1-10%)

•       nausea (2-8%)

•       Erythromycin stimulates GI motilin

•       Mild elevation of liver enzymes 

•       Central Nervous System

•       Mild headache or dizziness

•       Dose-related hearing loss or tinnitus with high doses (reversible)

•       Hypersensitivity Reactions

•       Anaphylactic reactions (rare)

•       Cardiovascular

•       QTc prolongation and torsades de pointes

•       Pregnancy:

•       Azithromycin and erythromycin: Category B

•       Animal studies show no risk, but human studies not adequate or animal toxicity but human studies show no risk

•       Clarithromycin: Category C

•       Animal studies have shown an adverse effect on the fetus/ no adequate studies in humans

-          Activity in addition to antimicrobial effect

–        First seen in type of bronchiolitis

-          Limit production of pro-inflammatory cytokines

-          Reduce neutrophil chemotaxis

-          Decrease sputum and mucus production

-          Reduced exacerbations

-          Increased time to exacerbation

-          Decreased toxins

-          Inhibition of biofilms and quorum sensing

-          Daily or MWF

-          Reservoir for resistance? Especially H. influenza

Diabetic Gastroparesis

-          Azithromycin’s side-effect can actually help here, to decrease gastroparesis. It increases gastric emptying by about 50%

-          Delayed gastric emptying

–        Fullness

–        N/V

–        Bloating

-          Motilin-receptor agonist

–        Second line

–        Erythromycin

                           -   Before meals

methylation

(Efflux>Methylation in the US)

No, they exhibit poor CSF penetration (they are very hydrophilic drugs)

They pass the CNS "somewhat" - not very well.

Erythromycin:

Bioavailability?

Elimination?

Half - life?

• Bioavailability = 18 - 45%
• Elimination = Partially unchanged in bile
• Half-life = 1 - 2 hours

You don't have to adjust doing for impaired renal funcion (CrCl <30)

Clarithromycin:

Bioavailability?

Elimination?

Half-life?

• Bioavailability = 50 - 55%
• Elimination = Primarily renal
• Half-life = 4 - 7 hours

Azithromycin:

Bioavailability?

Elimination?

Half-life?

• Bioavailability = 35 - 40%
• Elimination = Unchanged in bile, 20% unchanged in urine
• Half-life = 29 - 96 hours

You don't have to adjust dosing for impaired renal function (CrCl <30)