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Azithromycin and Clarithromycin: Overview and Comparison with Erythromycin Marc S

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Azithromycin and Clarithromycin: Overview and Comparison with Erythromycin Marc S Clinical Pharmacology of Antibiotics EDITED BY W. MICHAEL SCHELD, MD Azithromycin and Clarithromycin: Overview and Comparison With Erythromycin Marc S. Whitman, MD; AIlan R. Tunkel, MD, PhD Macrolides currently account for 10% to 15% of (Figure). As erythromycin passes through the gastro- the worldwide oral antibiotic market.’ Erythromycin, intestinal tract, it rapidly undergoes acid-catalyzed the first macrolide antibiotic, was discovered in 1952 degradation. 5.6 The new macrolides are erythromycin from a strain of Streptomyces erythreus obtained analogues that resist acid-catalyzed cyclization by from soil samples in the Phillipines.2s3 Originally, modifying the erythromycin base at the functional erythromycin was marketed as an alternative to peni- groups that facilitate the degradation reaction; these cillin because of its activity against gram-positive include the ketone at C-9, the hydroxyl at C-6, the organisms such as staphylococci, pneumococci, and proton at C-8, and the diol moieties at C-11 and C-12.7 streptococci. Subsequently, its clinical use broadened Several 14-, 15-, and l&membered macrolides were to include species of n/lycoplasma, Legionella, Cmpy- developed using this approach. The l&membered lobacter, and Chlamydia. Although several other mac- macrolides, josamycin and spiramycin, are in use in rolides have been marketed in countries other than Europe.8 Roxithromycin, an oxime derivative, di- the United States, they have failed to achieve erythro- rithromycin, and flurithromycin are 1Cmembered mycin’s widespread use. Unfortunately, erythromycin macrolide antibiotics in various stages of develop- suffers from several drawbacks, including gastrointes- ment.4v911 In clarithromycin (6O-methylerythromy- tinal side effects, a short serum elimination half-life, tin), a methoxy group is substituted for the C-6 and only borderline in vitro activity against common hydroxyl group, yielding an acid-stable analogue (Fig- gram-negative respiratory pathogens such as Haemo- ure).12 Azithromycin (9-deoxo-9a-aza-9a-methyl-9a- philus inLkenzae.4 homoerythromycin) is produced via rearrangement of Several new macrolides, with improved the ketone at position C-9 (Figure). Azithromycin, pharmocodynamic and therapeutic profiles, now exist often termed an azalide, differs structurally from the in various developmental stages. The Food and Drug other macrolides by incorporating nitrogen into the Administration (FDA) recently approved two of these lactone ring structure, producing a 15-membered drugs, azithromycin and clarithromycin, for market- derivative containing a tertiary amino group.13 ing. This review focuses on these agents, comparing Erythromycin and the other macrolide antibiotics their pharmacokinetic properties and clinical indica- bind to the 50s ribosomal subunit of susceptible tions with those of erythromycin. organisms, inhibiting the translocation reaction dur- ing protein synthesis. 14,15 Erythromycin stimulates STRUCTURE AND MODE OF ACTION the dissociation of peptidyl-tRNA during transloca- Each member of the macrolide class of antibiot- tion.16 Azithromycin acts similarly to erythromycin, ics contains a macrocyclic lactone ring substituted by because both compete for the same binding site on one or more sugar moieties. The erythromycin base the 50s ribosome and inhibit mFWA-directed protein consists of a 14-membered ring attached to the amino synthesis.17 The primary mechanism of macrolide sugar, desosamine, and the neutral sugar, cladinose resistance is the synthesis of ribosomal RNA methy- From the Department of Internal Medicine (Infectious Diseases), The Medical College of Annsylvania, Philadelphia, Pennsylvania. Address reprint requests to Allan R. Tunkel, MD, PhD, Division of Infectious Diseases, Department of Medicine, The Medical College of Pennsylvania, 3300 Henry Avenue, Philadephia, PA 19129. Whitman MS, Tunkel AR. Azithromycin and cla&hromycin: overview and comparison with erythromycin. Infect Control Hosp Epidemiol. 1992;12:357-368. Downloaded from https://www.cambridge.org/core. University of Lausanne, on 03 Sep 2017 at 13:30:44, subject to the Cambridge Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.2307/30147135 358 INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY June 1992 TABLE 1 COMPARATIVESINGLEDOSEP HARMACOKINETICSOF MACROLIDEANTIBIOTICSIN HUMAN VOLUNTEERS AUC** %aa Lax 1.5 (hours x Drug-t Q&/ml) (hours) (hours) pg/ml) FIGURE. Structures of erythromycin, clarithromycin, and azithro- Clarithromycin 2.41 2 4.9 18.9 mycin (adapted from reference 7). 14OH clarithromycin 0.66 - 7.2 6.0 Azithromycin 0.40 2 411 3.4 lases that methylate an adenine residue in the 23s Erythromycin 0.3-2.0 4 1.4 - ribosomal RNA of the 50s subunit, leading to macrolide ’ Adapted from references 22,23,26,27. t Unless indicated, drug was administered orally at a dose of 500 mg. lincosamide-streptogamin B (ML&J co-resistance.ls $ T., after a 500 mg IV dose. MIS, resistance can be plasmid-based or chromo- l * Area under the concentration curve. somally located.lg Plasmids encode for methylases in Staphylococcus aureus, Streptococcus species, and Bacteroides species; resistance determinants occur rarely on chromosomes in Streptococcus pneumo- The single-dose pharmacokinetics of erythromy- niae. Although methylase genes have been character- tin, clarithromycin, and azithromycin in human volun- ized in gram-negative organisms, many gram-negative teers are shown in Table 1.22~23~26,27 Clarithromycin, bacteria are inherently resistant to the macrolides on unlike the other macrolides, is metabolized to a the basis of an impermeable outer membrane alone.lg microbiologically active form, 14-hydroxyclarithromy- In addition, ML.?& resistance may be inducible or tin. Azithromycin remains largely unchanged within expressed constitutively. Both the 14-membered mac- the body, with minor metabolism into several inactive rolides, including erythromycin and clarithromycin, forms occurring via demethylation. Clarithromycin and the 15membered azithromycin induce expres- displays a nonlinear increase in peak serum concen- sion of RNA methylases in susceptible bacteria.17J0 trations as the dose increases; a decrease in meta- Other mechanisms of macrolide resistance occur bolite formation with an increase in urinary excretion infrequently. Erythromycin esterases found in isolates of the parent compound suggests that the metabolism of Escherichia coli hydrolyze the lactone ring.21 of clarithromycin to the 14hydroxy derivative is Another novel mechanism, described in S aureus and saturable, accounting for these disproportionate phar- Staphylococcus epidermidis, confers resistance by macokinetic properties.28 altering antibiotic efflux.18 Following administration, the macrolide antibiot- ics accumulate within the extravascular compartment. PHARMACOKINETICS The volume of distribution of azithromycin is 23 l/kg A major advantage offered by the new mac- compared with 1.5 l/kg for erythromycin; no pub- rolides, compared with erythromycin, is their mark- lished value for the volume of distribution of clarithro- edly improved pharmacokinetic properties. Longer mycin is available.29 Both erythromycin and half-lives and unique tissue penetration allow once- or azithromycin concentrate readily within polymorphonu- twice-daily dosing of these compounds. Oral absorp clear leukocytes (PMNs) and macrophages. After two tion is adequate for all of the macrolides. Erythromy- hours of incubation, azithromycin achieved an intra- tin’s oral bioavailability is variable, depending on the cellular to extracellular (I/E) ratio (i.e., intracellular preparation studied. The oral bioavailabilities of clar- concentration of drug/extracellular concentration of ithromycin and azithromycin are 55% and 37%, respec- drug) of 79 in human PMNs versus 16 for erythromy- tively.22,23 If clarithromycin is administered tin; azithromycin continues to accumulate withii immediately after a meal, however, its bioavailability human PMNs for up to 24 hours, reaching an I/E ratio increases by 25%. Absorption of azithromycin is of 226, whereas erythromycin uptake was complete at reduced up to 50% in the presence of food, and peak 30 minutes.30 Human fibroblasts also concentrate serum concentrations, but not total absorption, are azithromycin, accumulating 21-fold more azithromy- reduced by concomitant administration of aluminum- tin at 72 hours of incubation than erythromycin.31 In and magnesium-containing antacids.24 Both erythro- another study that examined the in vitro uptake of mycin and clarithromycin inhibit theophylline and radiolabelled antibiotic within human PMNs, erythro- carbamazepine metabolism; carbamazepine and theo- mycin and clarithromycin demonstrated similar intra- phylline concentrations were not altered by a five-day cellular concentrations, with I/E ratios of 7.3 and 9.2, course of azithromycin.a4Js respectively.32 Downloaded from https://www.cambridge.org/core__---- ..---__. University of Lausanne, on 03 Sep 2017 at 13:30:44____, subject to the Cambridge ---Core terms of use, available at https://www.cambridge.org/core/terms. https://doi.org/10.2307/30147135 -. Vol. 13 No. 6 CLINICAL PHARMKOLOGY OF ANTIBIOTICS 359 TABLE 2 ANTIBIOTIC CONCENTWIONS OF MACROLIDE ANTIBIOTICS IN SERUM AND TISSUES Serum Tonsil Nasal mucosa Lung mug (mg) (pg/mU (mW/kg) (mWh9 (mWW Azithromycin 500x 1 dose 0.4 1.0 - 9.03 1.0 - 9.oi: 1.0 - 9.og Clarithromycin 250 bid x 3 days 1.8k2.2 6.7 + 2.8 8.3 k 2.6 - Clarithromycin 500 bid x 3 days 2.8 2 0.5 - - 17.5k3.3
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