MACROLIDES Chemische Eigenschaften,Einsatz,Produktion Methoden
Indications
The macrolide antibiotics clarithromycin
and azithromycin have demonstrated in
vitro activity against mycobacteria, although they have
limited activity against M. tuberculosis. Clarithromycin
is four times as active as azithromycin against M. aviumintracellulare
in vitro. Azithromycin’s lower potency
may be compensated for by its greater intracellular penetration
and its two-fold higher tissue levels than
plasma levels. Clarithromycin with azithromycin, in
combination with other drugs, has gained an important
role in the prevention and treatment of MAC in HIVinfected
patients.
Antimicrobial activity
The 14-, 15- and 16-membered-ring macrolides share the same antibacterial spectrum, including most Gram-positive organisms, Neisseria spp., Haemophilus spp., Bordetella pertussis, Moraxella catarrhalis and both Gram-positive and Gramnegative anaerobes. They are inactive or poorly active against Enterobacteriaceae and non-fermentative Gramnegative bacteria such as Pseudomonas aeruginosa.
Pharmakokinetik
Erythromycin is characterized by poor water solubility and rapid inactivation by stomach acidity, resulting in widely varying bioavailability after oral administration. Derivatives of erythromycin A have improved pharmacological properties, including bioavailability, gastrointestinal tolerance, higher peak plasma levels, longer apparent elimination plasma halflives and improved tissue concentrations.
Oral absorption is rapid, with plasma peaks varying between 0.4 mg/L (azithromycin) and 11 mg/L (roxithromycin). Maximum concentrations are reached between 0.5 h (rokitamycin) and 3 h (clarithromycin) and are dose dependent.
The apparent elimination half-life varies from 1 h (miokamycin) to 44 h (dirithromycin)： the absolute bioavailability varies between 10% (dirithromycin) and 55–60% (roxithromycin, clarithromycin). The main elimination route is via the bile and feces： a proportion of clarithromycin is excreted via the intestinal mucosa. A substantial part of the administered dose of clarithromycin is eliminated in urine. The long apparent elimination half-lives of roxithromycin, azithromycin and dirithromycin allow them to be administered as single daily oral doses.
Clinical Use
The macrolides retain the classic clinical applications of erythromycin, including activity against Gram-positive cocci and intracellular pathogens such as Legionella, Chlamydia and Rickettsia spp. The improved pharmacokinetic properties and tissue distribution of some semisynthetic compounds may prove useful in more unusual settings such as infections due to mycobacteria (M. avium complex) and protozoa (e.g.Toxoplasma gondii, Entamoeba histolytica, Plasmodium falciparum). Other target infections are chronic gastritis (H. pylori) and borreliosis.
Nebenwirkungen
Macrolides are generally safe and serious adverse events are rare. A notable exception is erythromycin estolate, which is hepatotoxic and may cause severe hepatitis, probably as a result of the mixture of lauryl sulfate and the 2′-propionyl ester. Gastrointestinal complaints (nausea, vomiting, abdominal pain or, less frequently, diarrhea) are most common; they present a problem mainly with erythromycin doses higher than those recommended and are partly due to a hemiketal degradation product that acts on motilin, an intestinal endopeptide.
The semisynthetic 14- and 15-membered-ring macrolides are more acid stable than erythromycin A and are better tolerated.
MACROLIDES Upstream-Materialien And Downstream Produkte
Upstream-Materialien
Downstream Produkte
