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Natural and Semisynthetic Macrolides

Macrolides

For medical students2 min readUpdated 2026-10-10

Macrolides are a class of antibacterial drugs divided into natural and semisynthetic agents based on their origin and chemical structure. They are considered among the safest antibiotics, characterized by high activity against intracellular pathogens and the ability to accumulate extensively in body tissues.

Half-lifeUp to 35–55 hours for azithromycin, allowing once-daily administration.

Safety profileRegarded as one of the safest classes of antibiotics, despite the risk of dyspepsia.

Drug of choiceSpiramycin is the first-line treatment for toxoplasmosis in pregnant women.

Producer organismThe natural antibiotic oleandomycin is synthesized by the bacterium *Streptomyces antibioticus*.

Natural Macrolides

Historically, natural agents were the first to appear in clinical practice. A prominent representative is oleandomycin, produced by Streptomyces antibioticus. Its antimicrobial spectrum is similar to that of erythromycin, but it is less potent. Consequently, the drug requires frequent administration (4–6 times daily). To slow down the development of bacterial resistance, oleandomycin is often combined with tetracycline—a combination known as oleandomycin-tetracycline.

Natural 16-membered macrolides (spiramycin, josamycin, midecamycin) deserve special attention. Their primary clinical advantages include:

Retaining activity against staphylococcal and streptococcal strains that have already developed resistance to erythromycin.
Better tolerability (significantly lower incidence of dyspeptic disorders).
Stable bioavailability, as food intake has virtually no effect on their absorption.

Spiramycin (administered 2–3 times daily) is widely used in dentistry for treating gingivitis and periodontal infections. It is also the drug of choice for toxoplasmosis. Josamycin and midecamycin are administered every 8 hours. Notably, midecamycin acetate is a semisynthetic prodrug: it is absorbed and penetrates tissues much more efficiently than its native form.

Semisynthetic 14-Membered Macrolides

This group includes roxithromycin and clarithromycin. Their molecules were modified to solve the primary drawback of early macrolides—unstable pharmacokinetics.

These newer agents are readily absorbed from the gastrointestinal tract regardless of food intake, achieve high tissue concentrations, and possess a prolonged duration of action. This makes dosing regimens much more convenient for patients: roxithromycin is taken 1–2 times daily, while clarithromycin is taken every 12 hours (available for both oral and intravenous administration).

Clarithromycin has several specific indications:

Eradication of Helicobacter pylori in peptic ulcer disease.
Treatment and prophylaxis of opportunistic infections in HIV-positive patients (specifically those caused by Mycobacterium avium complex).
Treatment of infections caused by intracellular pathogens (mycoplasma, chlamydia, legionella).

Azalides (Azithromycin)

Azithromycin is a 15-membered semisynthetic macrolide. Because a nitrogen atom is incorporated into its lactone ring, the drug is classified into a separate structural subclass known as azalides.

Compared to erythromycin, azithromycin's spectrum of activity is shifted: it is less active against staphylococci, but exhibits greater efficacy against gram-negative flora (enterobacteria, Haemophilus influenzae) and intracellular agents (toxoplasma, legionella).

The pharmacokinetics of azithromycin are unique. It achieves record-breaking tissue concentrations among all class representatives, and its elimination half-life ranges from 35 to 55 hours. The primary clinical advantage of this kinetic profile is the ability to administer the antibiotic just once daily.

Adverse Effects

Although macrolides are considered among the safest antibacterial agents, their administration can be accompanied by characteristic adverse reactions. Typical side effects include:

Allergic reactions of varying severity.
Dyspeptic disorders: patients frequently complain of nausea and epigastric discomfort, which occurs because these drugs can stimulate gastrointestinal motility.
Hepatotoxicity: potential development of cholestatic hepatitis and elevated plasma transaminases.
Ototoxicity: rare cases of hearing impairment.

Mnemonic

To remember the typical side effects of macrolides, use the mnemonic «A-D-H-O»: Allergy, Dyspepsia (motility stimulation), Hepatotoxicity (cholestatic hepatitis), Ototoxicity (hearing impairment).

Frequently asked questions

What is the mechanism of antibacterial action of macrolides?

The mechanism of action of macrolides involves the inhibition of intracellular protein synthesis at the ribosomal level, producing a bacteriostatic effect.

Molecular target — 50S subunit of the bacterial ribosome.
Site of action — translocation step (the ribosome is blocked from moving along the mRNA by one codon).
Pathogenesis — the drug binds to a ligand inside the ribosomal tunnel, blocking the transfer of the peptide from the A-site to the P-site and the exit of synthesized peptides.

Additionally, peptidyl transferase enzyme activity is blocked, leading to premature termination of the elongating peptide chain.

Which macrolides are approved for use during pregnancy?

Medical references explicitly identify spiramycin as the primary drug for treating acute toxoplasmosis in pregnant women. For chlamydial infections, systemic antimicrobial therapy may be used at any stage of pregnancy while considering fetal safety. For certain macrolides, particularly erythromycin, associations with adverse neonatal outcomes have been reported.

Which antibiotics belong to natural 14-membered macrolides?

Natural 14-membered macrolides include erythromycin and oleandomycin.

Erythromycin — the baseline drug of the group, used as a comparator for other macrolides.
Oleandomycin — an antibiotic produced by Streptomyces antibioticus. It is similar to erythromycin in its antimicrobial spectrum, but less potent. It is administered 4–6 times daily, including in combination with tetracycline to delay resistance development.

Which macrolides are cytochrome P450 enzyme inhibitors?

Macrolides that inhibit cytochrome P450 enzymes include erythromycin and clarithromycin. They suppress the activity of the following isoenzymes:

CYP3A4/3A5 — slow down the metabolism of warfarin (bleeding risk) and other drugs.
CYP1A2 — reduce enzyme activity, potentially increasing substrate concentrations in the blood.

Inhibition of microsomal enzymes slows the metabolism of co-administered drugs utilizing these pathways, increasing their blood concentrations and the risk of toxicity.

What is the main difference between semisynthetic macrolides and erythromycin?

They feature improved pharmacokinetics: excellent GI absorption independent of food intake, high tissue concentrations, and a longer duration of action, allowing for less frequent dosing.

Why is azithromycin classified into a separate subgroup?

Azithromycin belongs to azalides. Its chemical structure features a nitrogen atom inserted into the 15-membered lactone ring, which ensures record-breaking tissue accumulation and a very long half-life.

Why is oleandomycin combined with tetracycline?

This combination is used to slow down the development of microbial resistance, which occurs much faster with monotherapy using either of these antibiotics alone.

Which macrolide is safe for treating toxoplasmosis in pregnant women?

The drug of choice in this case is the natural 16-membered macrolide spiramycin.

Go deeper

Mechanism of Helicobacter pylori eradication by clarithromycin
Prodrug pharmacokinetics using midecamycin acetate as an example
Management of opportunistic infections in HIV
Mechanisms of cholestatic hepatitis induced by macrolides
Comparative activity of macrolides against gram-negative flora