MACROLIDE DERIVATIVES
Full Text

Members of the family -- structural / spectrum

·· ERYTHROMYCIN, CLARITHROMYCIN (new), TYLOSIN (vet med only), TILMICOSIN (new, vet med only). Relatively unimportant at present time: azithromycin (new), troleandomycin, josamycin

Source:

··· Erythromycin: Streptomyces erythreus, (Phillipines)

··· Tylosin: Streptomyces fradiae (Different strain from one that produces neoycin)

Structure/Chemistry: MACROLIDE -- large lactone ring, two deoxy sugars

WEAK BASE -- so at steady state conditions, intracellular concentration would exceed that of plasma (ion trapping). However, because the molecule is very large and does not diffuse through membranes easily, this condition is not always achieved.

POORLY WATER SOLUBLE -- so for iv use, have developed special water-soluble salts, e.g. erythromycin gluceptate or erythromycin lactobionate

ACID LABILE -- Erythromycin. Others sufficiently stable that can use orally without difficulty. For erythromycin, pharmaceutical chemists have developed special acid-resistant dose forms for oral administration. Examples are erythromycin ethylsuccinate in tablets,or suspension; erythromycin delayed-release capsules, erythromycin estolate.

ACID LABILITY -- a problem for erythromycin in stomach and in abscess pus.

Erythromycin

Action

Inhibits bacterial protein chain elongation by binding to the 50S ribosomal subunit. Appears to inhibit translocation step.

Resistant mutants -- subunits do NOT bind the drug

Gram (+) organisms accumulate 100-fold more erythromycin than gram (-) organisms.

Ribosomal binding site on S50 subunit overlaps sites for chloramphenicol and lincosamides. Binding of one may interfere with binding of the others.

Erythromycin is STATIC or CIDAL depending on

• drug concentration
• organism susceptibility, including growth rate
• size of inoculum

Pharmacokinetics

ABSORPTION

Route of admin. -- All (but topical is not favored)

Topical

• Ophthalmic preps exist.
• Preparations for "acne", apply directly to skin 2 to 4 times daily.
• ·Solutions 1.5 and 2% and e.g. A/T/S, EryDerm, Statcin
• ·Ointments, 1% Ilotycin

Oral

• Higher amounts of esters are absorbed than of the stearate, but only about 20% of esters are in blood as free base. Actual circulating eryth about same. The intact esters have little activity.

• Pharmacology / Pharmacokinetics of erythromycin preparations (See TYPICAL TABLE from USPDI below.)

Parenteral

• IV use: gluceptate and lactobionate
• IM use: ethylsuccinate injection (also PO)

DISTRIBUTION

• Vd = 0.72 L/kg in humans
• Broader than beta-lactams
• Despite large molecular size, lipid solubility is high enough to allow penetration of many membranes
• Concentration in most body tissues approach 50% of serum conc., including: aqueous humor, saliva, and prostate
• Concentrations in bile, urine and bronchial secretions exceed serum
• CSF only 2-13 % of serum. Insufficient for meningitis
• Protein binding 74% to alpha-globulin rather than albumin

BIOTRANSFORMATION

Not an important factor with this group of drugs

ELIMINATION

• Primarily bile and feces, less than 3-5% urine

             Pharmacology / Pharmacokinetics of Erythromycin              
                                                                          

    Base     Film-coated      Yes          Base          Yes       Decreased   
               tablets                                                         

    Base     Delayed-rele      No          Base          Yes       Unaffected  
                 ase                                                 (some     
               tablets*                                             brands)    

    Base     Delayed-rele      No          Base          Yes       Decreased   
                 ase                                                           
              capsules**                                                       

  Estolate    All dosage       No       Propanoate       Yes       Unaffected  
                forms                      ester                               

Ethylsuccina     Oral       Partial      Base and        Yes      Unaffected@  
     te       suspension               ethylsuccinat                           
               Tablets      Partial       e ester        Yes       Unaffected  

  Stearate   Film-coated      Yes          Base          Yes       Decreased   
               tablets                                                         

* Coating is acid resistant                                               
**Contains enteric-coated pellets                                         
@Some references indicate absorption may be increased with oral           
suspension                                                                
Table from USPDI94, p1297                                                 

• Nevertheless, no specific indications for biliary tract related diseases
• 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
• Impaired renal function INCREASES half-life to 4.8-6 h, BUT usually do not need to decrease dose
• Dialysis does not remove erythromycin

Toxicity

RELATIVELY SAFE antibiotic. Side effects are rare with all erythromycin dose forms, but the estolate derivative

CHOLESTATIC HEPATITIS

• Intrahepatic cholestatic jaundice caused by "estolate" derivative and only rarely with other derivatives such as the ethyl succinate or stearate
• May represent a hypersensitivity reaction to the estolate ester
• Signs start after 10-20 days of treatment
• Characterized by nausea, vomiting, and abdominal cramps, signs which mimic acute cholecystitis. Unneeded surgeries have been performed!
• Jaundice and other signs follow
• Syndrome is COMPLETELY REVERSIBLE after cessation of therapy with all signs disappearing after 3 days or so

Allergic reactions

Fever, eosinophilia, and skin eruptions singly or in combination. All disappear shortly after cessation of therapy

Interference with LABORATORY Results

• Elevation of glutamic oxalacetic transaminase. Estolate may cause artifactual elevation of glutamic oxalacetic transaminase if assay is colorimetric. Enzymatic assay is not affected.
• Small number of patients (e.g. 16/161 pregnant women, ~10%) may have mild elevations of SGOT with estolate. Only 3/97 in those receiving the sterate, ~3%.

THROMBOPHLEBITIS is common with too rapid iv administration of large doses.(1 g)

Severe PAIN -- with PO (epigastric pain) or IM (at site) administration of large doses.

Drug Interaction

May POTENTIATE effects of other drugs, possibly by interferring with their metabolism. Examples

• carbamazepine, corticosteroids, digoxin, and theophylline (may be serious)
• terfenadine (Antihistamine - H1) -- may increase risk of cardiotoxicity (e.g., torsades de pointes -- recurrent fainting and death!)

Example of signs listed in USPDI

• Signs indicating need for medical attention
• Dark or amber urine
• Pale stools
• Stomach pain
• Unusual tiredness or weakness
• Yellowing of eyes or skin (Cholestatic jaundice) estolate -- Intrahepatic cholestatic jaundice. Syndrome includes severe abdominal pain. Follows previous adm. or by 3rd week of therapy. Reversible after ca. 1 week. Mainly adults, children apparently low risk.
• Less severe signs
  • ·Diarrhea
  • Nausea
  • Sore mouth or tongue
  • Stomach cramping and discomfort
  • Vomiting

Clinical use

• ·· Typically used for pneumonias, upper respiratory tract, genitourinary tract, and soft-tissue infections caused by susceptible organisms
• ·· Antibacterial spetrum: at attainable serum levels of <= 1.5 ug/ml.
• ·· Penicillin substitute --
• ··· for many gram positives, esp. beta-lactamase producers.
• "especially also, for soft tissue staphylococcal infections, pharyngitis caused by group A streptococci and diphtheria." Year Book of Drug Therapy, eds, Hollister and Lasagna, 1983, p226.
• ··· Mycoplasmas and chlamydiae
• ··· Drug of choice for Legionella pneumophilia -- Legionnaires' disease.
• ··· Actinomyces. Not usually for Nocardia. A. viscosus in dogs.
• ··· Many atypical Mycobacteriae, e.g. M. kansasii.
• 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 -- Is synergistic with cefamandole vs Bacteroides fragilis and with ampicillin vs Nocardia asteroides

Azithromycin [ZITHROMAX]

First representative of a new class of antibacterials -- Azalides Related to erythromycin

Structure / Chemistry

• Azalide, MW 785

Mechanism of Action

• Inhibits RNA-dependent protein synthesis by binding to the 50S ribosomal subunit of susceptible organisms
• Cidal for S. pyogenes, S. pneumoniae, and H. influenzaeI
• Static for staphylococci and most aerobic gram-negative species

Pharmacokinetics

Absorption

• Rapidly absorbed
• Food decreases absorption (decreases peak and AUC by approximately half)
• Oral F = 37%

Distribution

• Rapidly and widely distributed
• Intracellular concentration 10 to 100 times plasma concentration
• Highly concentrated in phagocytes and fibroblasts. Phagocytes carry drug to site of infection where, in contact with bacteria, they release the drug more rapidly than otherwise.
• CSF concentrations very low
• Vd = 31 [!!] l/kg (steady state)

Biotransformation

• Hepatic -- 35% by demethylation. As many as 10 metabolites

Half-life

• Serum -- 11 to 14 h (after one dose); after multiple doses, approaches the tissue half-life
• Tissues -- 2 to 4 days

Elimination

• Over 50% eliminated in bile unchanged
• 4.5% in urine unchanged w/in 72 hr

Adverse Effects

Precautions

• Hypersensitivity -- may be cross-reaction in patients allergic to erythromycin
• Antacids, aluminum- and magnesium-containing -- decrease peak by 24%, but no change in AUC
• Administer 1 hr before or 2 hr after meals

Toxicity

• Rarely, has caused serious allergic reactions
  Anaphylaxis and angioedema
  In some patients, signs of allergic reactions have recurred despite cessation of azithromycin therapy and successful treatment of the original bout of allergic reaction. Requires continued observation and therapy
• "less frequent" -- gastrointestinal disturbances (abdominal pain, diarrhea, nausea, vomiting)

Clinical Applications

• Many gram - positive and gram - negative aerobic and anerobic bacteria
• Bronchitis
• Cervicitis (chlamydial)
• Pharyngitis (streptococcal)
• Pneumonia (H. influenzae and Streptococcus pneumoniae)
• Skin and soft tissue infections (staphylococcal and streptococcal)
• Urethritis (chlamydial)
• Pneumonia (mycoplasmal)

References

• USPDI94
• 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.

Clarithromycin [BIAXIN]

Source

Structure

• Macrolide derivative with MW of 747.96

Pharmacokinetics

Absorption

• "Well absorbed" [USPDI94] from gastrointestinal tract, but F is only 55%!
• Food delays rate, but not extent of absorption
• Time to peak conc PO = 2 h.
• Peak conc at 250 mg q12h --> 1 mcg/mL; 500 mg q12h --> 2-3 mcg/mL

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

Biotransformation

• Hepatically metabolized by 3 major paths, one of which leads to a 14-hydroxy derivative that is as active as erythromycin. This derivative, 14-hydroxyclarithromycin, may act synergistically with clarithromycin vs H. influenzae\
• Metabolic paths (demethylation and hydroxylation) are saturable, so kinetics are not linear with dose. Half-life increases with dose.
• Nonlinear kinetics in presence of normal renal function.
  • Dose: 250 mg q12h --> 3-4 h half-life
  • 500 mg q12h --> 5-7 h half-life
• Half-life of the 14-hydroxyderivative is 5-6 h at dose of 250 mg q12h clarithromycin and increases to 7 at dose of 500 mg.

Elimination

• in urine unchanged
• in urine as 14-hydroxy derivative
• in feces unchanged
• Renal Impairment (Clcreatinine < 30 ml/min human) --
• clarithromycin half-life increases toward 22 h.
• 14-hydroxy metabolite increases to 47h (from 5-6h)

Toxicity -- relatively minor

• Abnormal taste - 3%
• Gastrointestinal disturbances -- 2-3% (abdominal discomfort or pain, diarrhea, nausea)
• Headache ·· - 2%

References

[USPDI95] United States Pharmacopeia Drug Information, Drug Volume I. Information for the Health Care Professional. USP, 1995.

Tylosin -- veterinary medicine only

Source and structure

Streptomyces fradiae strain diff from the one that produces neomycin.

Structure, pharmacology, etc. very similar to erythromycin

• Slightly soluble in water
• Unstable in acid media (< pH 4).
• Should not be mixed with other drugs given parenterally.
• Available in many preparations as feed/water additive.

Action

Bacterial Cross resistance with erythromycin has been shown.

Pharmacokinetics

Administration / absorption

Tylosin tartrate --> Well absorbed from intestine with PO adm.

Tylosin phosphate has limited absorption.

Can be administered im. -- rapid absorption.

Distribution -- similar to erythromycin

Elimination

Excreted unchanged(?) via liver and kidney.

Peak serum concentration / Duration / half-life

goat -- IM inj: serum t1/2 4-5 hr. Peak of 1.5 ug/ml at 2 h

PO -- 8 h duration approx

IM -- 12-24 h duration approx.

Typical dose in range of 1-2 mg/lb, IM

Toxicity

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

After 5 mg/kg/day, greater tendency to have ventricular tachycardia and fibrillation during acute myocardial ischemia.

Tilmicosin [MICOTILR]-- veterinary medicine only

• Shipping fever pneumonia in cattle -- Pasteurella spp., H. somnus.
• Contraindicated for use in dogs or swine because of cardiac toxicity

Pirlamycin [PirsueR] Veterinary medicine only

• Staphylococcal mastitis in cows via intramammary infusion

References

• GG7th -- pp 1184-1188. Erythromycin
• JBM5th -- Erythromycin -- 756-757; Tylosin -- 764
• [USPDI94] United States Pharmacopeia Drug Information. Volume I. Drug Information for The Health Care Professional. 14th ed. 1994.
• 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.

Muller, Roger D.; Tylan Injection Veterinarian's Hand book, published by Elanco Products Company 1982.