MACROLIDE DERIVATIVES
Outline

Members

• Used heavily human / vet
• Erythromycin
• Used only vet
• Tylosin [Tylan^R]
• Tilmicosin [Micotil^R]
• Pirlamycin [Pirsue^R]
• Approved only human and relatively new(1966)
• Clarithromycin.
• Azithromycin
• Relatively unimportant in US
• Troleandomycin
• Josamycin

Erythromycin

Source:

• Streptomyces erythreus
  (From Phillipines)

Structure/Chemistry

• Macrolide
  large lactone ring, two deoxy sugars
• Weak base -- traps on more acid side of membrane
• Large molecule -- diffuses through membranes slowly
• Poorly water soluble
  special salts for IV use
• erythromycin gluceptate
• erythromycin lactobionate
• Erythromycin -- acid labile; others stable
• special dose forms

Action

• Inhibits translocation step of protein synthesis
• Accumulation in G(+) is 100-fold that of G(-)
• Resistant mutants NOT bind drug
• Static at usual concentrations

Pharmacokinetics

Absorption

• Topical
• Ophthalmic
• Oral
• Parenteral
• IV use: gluceptate and lactobionate
• IM use: ethylsuccinate injection (also PO)

Distribution

• Vd = 0.72 L/kg in humans
• Broader than beta-lactams
• Can penetrate cells, but slowly
• Effective concentrations in tissues
• Greater than serum -- bile, urine, bronchial secretions
• 50% of serum in most tissues -- including aqueous humor, saliva, and prostate
• Insufficient
• 2-13% CSF

Elimination

• Elimination half-life
• human adults -- normal --1.4-2.0 h
• human infants
  estolate -- 3.5 to 4.2 h
  ethylsuccinate -- 1.4 to 1.7 h
• Biotransformation -- not important
• Excretion
• Primarily bile and feces
• Less than 3-5% urine

Adverse Effects

• Relatively safe antibiotic
• Biological
• Allergic
• Not major problem
• Toxic
• Irritant
• Thrombophlebitis
• Epigastric pain with PO administration
• IM site pain
• Drug Interaction -- Potentiates other drugs
• corticosteroids
• digoxin
• terfenadine (H1-antihistamine)
  increase risk of cardiac toxicity -- fainting and death
• Cholestatic hepatitis -- jaundice with estolate
• May be hypersensitivity to estolate
• 10-20 days into treatment
• nausea, vomiting, abdominal cramps
• jaundice
• Reversible within 3 days or so
• Interfere with Laboratory tests
• Estolate: False elevation of SGOT if colorimetric assay

Clinical use

• Typically used for pneumonias, upper respiratory tract, genitourinary tract, and soft-tissue infections caused by susceptible organisms
• Antibacterial spetrum
• Penicillin substitute for many gram positive organisms
• Mycoplasmas and chlamydiae
• Drug of choice for Legionella pneumophilia -- Legionnaires' disease.
• Actinomyces (Not usually for Nocardia)
  A. viscosus in dogs.
• with Rifampin for Rhodococcus pneumoniae infections in horses
• Gram negatives
• Highly susceptible - Neisseria meningitidis,
  Neisseria gonorrhoeae
• Moderately sensitive - Bacteroides fragilis and Haemophilus influenzae.
• Most of rest INSENSITIVE
• Positive Drug Interaction -- Synergistic with --
• cefamandole vs Bacteroides fragilis
• ampicillin vs Nocardia asteroides

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Tylosin -- veterinary medicine only

• Source: Streptomyces fradiae (not strain that produces neomycin)
• Structure, pharmacology, etc. very similar to erythromycin
• Should not be mixed with other drugs given parenterally
• Available in many preparations as feed/water additive
• stable
• Absorption from gut
• Tylosin tartrate --Well
• Tylosin phosphate -- Limited
• IM adminstration -- rapid absorption

Distribution

• Similar to erythromycin

Elimination

• PO -- 8 h duration approx
• IM -- 12-24 h duration approx.
• goat -- IM inj
• serum t1/2 4-5 hr
• Peak -- 1.5 ug/ml at 2 h
• Excreted unchanged(?) via liver and kidney.

Adverse Effects

• Wide margin of safety
• Reactions noted in swine (in which it is most heavily used)
• Edema and erythema of rectal mucosa.
• Anal protrusion/pruritis
• Diarrhea
• Dogs
• Tendency toward ventricular tachycardia & fibrillation
  during acute myocardial ischemia if greater than 5 mg/kg/day

---

Tilmicosin [MICOTIL^R]
veterinary medicine only

• Shipping fever pneumonia in cattle -- Pasteurella spp., H. somnus.
• Similar activity to "long-acting" oxytetracycline in calves (See article JAVMA Jan1, '96, p102)
• Cardiac toxicity in --
• dogs
• swine
• Contraindicated!

Pirlamycin [Pirsue^R]
veterinary medicine only

• Staphylococcal mastitis in cows via intramammary infusion

Azithromycin [Zithromax^R]

Structure / Chemistry

• First of new class related to erythromycin -- Azalides

Clinical Applications

• Many gram - positive and gram - negative aerobic and anerobic bacteria
• Cidal for S. pyogenes, S. pneumoniae, and H. influenzaeI
• Static for staphylococci and most aerobic gram-negative species
• Bronchitis
• Cervicitis (chlamydial)
• Pharyngitis (streptococcal)
• Pneumonia (H. influenzae and Streptococcus pneumoniae)
• Skin and soft tissue infections (staphylococcal and streptococcal)
• Urethritis (chlamydial)
• Pneumonia (mycoplasmal)

Clarithromycin [Biaxin^R]

Distribution

• Widely distributed into tissues and fluids
• High concentration in respiratory tract, including nasal mucosa, tonsils, and lungs
• Readily enters leukocytes and macrophages
• Tissue concentrations higher than serum as expect of macrolide

Adverse effects

• Relatively minor

References

• GG7th -- pp 1184-1188. Erythromycin
• JBM5th -- Erythromycin -- 756-757; Tylosin -- 764
• KAGAN -- Chapter 7
• [AMADExx--ss:pp] AMA Drug Evaluations Subscription Series. xx = year of monograph, ss = section, pp = page.
• Year Book of Drug Therapy, eds, Hollister and Lasagna, citation of article by Turck on "Alternative Antibiotics for the Penicillin-Sensitive Patient", page 226, 1983 edition.
• [USPDI94] United States Pharmacopeia Drug Information. Volume I. Drug Information for The Health Care Professional. 14th ed. 1994.
• [USPDI95] United States Pharmacopeia Drug Information, Drug Volume I. Information for the Health Care Professional. USP, 1995.
• Munson95: Principles of Pharmacology: Basic Concepts and Clinical Applications, Paul L. Munson, Robert A. Mueller, and George R. Breese, eds. Chapman & Hall, New York, 1995
• Egle, John L., Jr. Chapter 93, Aminoglycosides, Tetracyclines, Chloramphenicol, Erythromycin and Related Macrolides, and Other Protein Synthesis Inhibitors in Principles of Pharmacology: Basic Concepts and Clinical Applications, Paul L. Munson, Robert A. Mueller, and George R. Breese, eds. Chapman & Hall, New York, 1995
• GG8th: Goodman and Gilman's The Pharmacological Basis of Terapeutics, Gilman, A.G., T.W. Rall., A.S. Nies, P. Taylor, eds, Pergamon Press, New York, 1990.
• Sande, M.A. and G.L. Mandell, Chapter 48, Tetracyclines, Chloramphenicol, Erythromycin, and Miscellaneous Antibacterial Agents in Goodman and Gilman's The Pharmacological Basis of Terapeutics, Gilman, A.G., T.W. Rall., A.S. Nies, P. Taylor, eds, Pergamon Press, New York, 1990.
• JAVMA Jan 1, 1996, p. 102: Comparison of Tilmicosin and long-acting oxytetracycline in calves [Need full reference]