Clinical Pharmacokinetic Properties of the Macrolide Antibiotics

Abstract

The pharmacokinetic aspects in humans of macrolide antibiotics that are currently or soon to be on the market (i.e. erythromycin, oleandomycin, spiramycin, josamycin, midecamycin, miocamycin, rosaramycin, roxithromycin and azithromycin) are reviewed. Macrolide antibiotics are basic compounds, poorly soluble in water, which are mostly absorbed in the alkaline intestinal environment. They are acid unstable, but the newer semisynthetic derivatives (i.e. roxithromycin and azithromycin) are characterised by increased stability under acidic conditions. Macrolides are highly liposoluble and consequently penetrate well into tissue, especially bronchial secretions, prostatic tissue, middle ear exudates and bone tissues, as evidenced by tissue/serum concentration ratios greater than 1. They do not penetrate well into the CSF. Macrolides undergo extensive biotransformation in the liver. With a few exceptions (e.g. miocamycin), the metabolites of these drugs are characterised by little or no antimicrobial activity. Plasma protein binding is variable from one compound to another. At therapeutic concentrations, protein-bound erythromycin accounts for 80 to 90% of the total drug present in the blood, and the fraction is 95% for roxithromycin. The lowest values of protein-bound fraction are observed for midecamycin and josamycin (about 15%), and intermediate values are reported for spiramycin and miocamycin. However, the clinical relevance of this parameter is not clearly established. Plasma half-life (t1/2) values vary for the macrolides described: erythromycin, oleandomycin, josamycin and miocamycin have a t1/2 ranging from 1 to 2 hours; spiramycin, erythromycin stearate, the mercaptosuccinate salt of propionyl erythromycin and rosaramicin have an intermediate t1/2 (about 7, 6.5, 5 and 4.5 hours, respectively); the newer semisynthetic compounds roxithromycin and azithromycin are characterised by high t1/2 values (i.e. 11 and 41 hours, respectively). Under normal conditions, the major route of elimination is the liver. Renal elimination also takes place but it contributes to total clearance only to a small degree, as evidenced by low renal clearance values. The degree of modification of macrolide pharmacokinetics by renal insufficiency or hepatic disease is usually not considered clinically relevant, and no recommendation for dose modification is necessary in these patients. The pharmacokinetics of macrolides are modified in elderly patients. Accordingly, their use must be accompanied by a closer than usual clinical monitoring of the older patient.(ABSTRACT TRUNCATED AT 400 WORDS)

Update on the use of the macrolides for community-acquired respiratory tract infections

“…This modification is thought to enhance the Gram-negative activity when compared with erythromycin [8][9][10]. Azithromycin is protected against acid degradation, has higher tissue penetration (compared with erythromycin) and a longer elimination half-life as a result of its structural modifications [10][11][12]. Clarithromycin has a methylated hydroxyl group at position 6, resulting in protection from acid degradation and improved bioavailability, as well as reduced GI side effects [1,13].…”

“…The following characteristics are associated with azithromycin and its 15-member macrolide ring structure (Table 2): increased acid stability, a longer elimination half-life and an increased tissue penetration compared with erythromycin [10][11][12]. Azithromycin is also well absorbed and has a low serum concentration in the presence of protracted serum and tissue half-lives [68,73,74], and food decreases the bioavailability of azithromycin by up to 50%.…”

PharmGKB summary

“…The class includes erythromycin, clarithromycin, and azithromycin, among others [1]. Macrolides are used to treat both local and systemic infections, including infections of the skin, respiratory tract, gastrointestinal tract, and genital tract [2].…”

“…Zuckerman, et al 2011 and Periti, et al 1989 provide an overview of the pharmacokinetics and pharmacodynamics of other macrolides, such as telithromycin, tigecycline, and roxithromycin [1, 2]. …”

Enhanced Production of Nargenicin A1 and Generation of Novel Glycosylated Derivatives

“…Most of the macrolide antibiotics have poor water solubility [9]; thus, in such cases, it accounts for limitation in therapeutic uses [10]. Glycosylation has been an effective tool for diversification of natural products [11] by enhancing the solubility and stability, broadening the biological potency and applications [12], and sometimes even alteration of biological properties of the compounds [13].…”