How are macrolides classified? Understanding the Categories

October 6, 2025 •

4 min read

The macrolide class of antibiotics, first pioneered with the discovery of erythromycin in the 1950s, comprises a diverse range of drugs used to treat various bacterial infections. Understanding how are macrolides classified is key to appreciating the differences in their spectrum of activity, pharmacological properties, and clinical applications.

Quick Summary

Macrolides are categorized primarily by the size of their macrocyclic lactone ring into 14-, 15-, and 16-membered types. They are also classified by generation, from early natural products to later semi-synthetic derivatives and ketolides designed to combat resistance.

Key Points

Ring Size Classification: Macrolides are most commonly classified by the size of their central macrocyclic lactone ring into 14-membered, 15-membered (azalides), and 16-membered varieties.
Generational Classification: An alternative classification sorts macrolides into generations (First, Second, Third), which reflects their development history and improvements in properties over time.
Impact of Structural Modifications: Key chemical modifications, such as adding a nitrogen atom to create azalides like azithromycin, or replacing a sugar with a keto group to create ketolides, alter a drug's pharmacokinetic profile and antibacterial efficacy.
Overcoming Resistance: Third-generation macrolides (ketolides) were specifically developed to counter increasing bacterial resistance to older macrolide drugs.
Non-Antibiotic Macrolides: The broader macrolide family includes compounds with non-antibacterial functions, such as the immunosuppressants tacrolimus and sirolimus.
Clinical Implications: The specific classification of a macrolide dictates its stability, half-life, spectrum of activity, and potential for drug interactions, all of which are crucial for safe and effective clinical use.

Macrolides are a class of antibacterial agents defined by a macrocyclic lactone ring attached to sugar moieties. This unique chemical structure is the most fundamental way how are macrolides classified. However, they are also categorized by their generation, reflecting the timeline of their development and modification to improve effectiveness and overcome resistance. This article details these classification systems and explains the key differences between the major types of macrolides.

Classification by Macrocyclic Ring Size

The most common method for classifying macrolides is by the number of atoms forming their central lactone ring. This structural feature significantly influences a drug's pharmacological profile, including its acid stability, tissue penetration, and spectrum of activity.

14-Membered Macrolides

This group represents the first generation of macrolides and their early semi-synthetic modifications. They contain a 14-atom lactone ring.

Natural Origin: Erythromycin was the first macrolide discovered and is the prototypical example. Oleandomycin is another natural member.
Semi-synthetic Derivatives: Modifications of erythromycin led to second-generation drugs with improved characteristics. Examples include clarithromycin, roxithromycin, and dirithromycin. Clarithromycin, for instance, has a methoxy group addition that improves its acid stability compared to erythromycin.

15-Membered Macrolides (Azalides)

This is a distinct subclass of macrolides, where a nitrogen atom is incorporated into the lactone ring, expanding it to 15 members. This modification, compared to the 14-membered rings, offers several advantages.

Key Example: Azithromycin is the most well-known azalide. It exhibits improved tissue penetration, a longer half-life, and less interaction with drug-metabolizing enzymes compared to erythromycin and clarithromycin. Its longer duration of action allows for less frequent dosing.

16-Membered Macrolides

This group contains a larger, 16-atom lactone ring. These macrolides are generally less common in human medicine than the 14- and 15-membered varieties but are important nonetheless.

Key Examples: Josamycin and spiramycin are examples of 16-membered macrolides. Spiramycin is used extensively in some parts of the world, though its use is less common in the United States.

Classification by Generation

Another way to categorize macrolides is by their generation, which reflects the sequence of their discovery and refinement. This system highlights the development of drugs with enhanced properties to overcome the limitations of earlier compounds.

First-Generation Macrolides

These are the original macrolides isolated from natural sources, primarily from Streptomyces species. Erythromycin is the classic example. While effective, it suffers from poor acid stability, leading to significant gastrointestinal side effects.

Second-Generation Macrolides

These are semi-synthetic derivatives developed to overcome the shortcomings of first-generation agents. They boast improved acid stability, better oral absorption, enhanced tissue penetration, and a wider spectrum of antibacterial activity. Clarithromycin and azithromycin are prime examples of this generation.

Third-Generation Macrolides (Ketolides)

Ketolides represent the newest generation of macrolide antibiotics. They were specifically developed to combat the increasing prevalence of macrolide-resistant strains of bacteria.

Key Modification: Ketolides feature a keto group in place of the cladinose sugar found in erythromycin and related macrolides. This modification allows them to bind more tightly to the bacterial ribosome, making them more effective against macrolide-resistant pathogens.
Key Example: Telithromycin was one of the first ketolides but has been associated with a number of adverse effects, including liver toxicity and visual disturbances.

Comparison of Major Macrolide Antibiotics


Feature	Erythromycin (First Gen)	Clarithromycin (Second Gen)	Azithromycin (Second Gen)	Telithromycin (Third Gen)
Ring Size	14-membered	14-membered	15-membered	14-membered
Acid Stability	Poor	Improved	High	High
Gastrointestinal Side Effects	Common	Less common	Less common	Notable
Half-Life	Short	Moderate	Long	Long
Spectrum of Activity	Narrower	Wider (including H. influenzae)	Wider (including H. influenzae)	Enhanced against resistant strains
CYP3A4 Interaction	Strong inhibitor	Strong inhibitor	None/Minimal	Strong inhibitor

The Broader Macrolide Family

It is worth noting that the term macrolide technically refers to a broader class of natural products, not all of which are antibiotics. Some macrolides exhibit other pharmacological properties, including immunosuppression, antifungal activity, and antiparasitic effects. Examples include:

Immunosuppressants: Tacrolimus and sirolimus (rapamycin), which are used to prevent organ rejection.
Antiparasitic: Ivermectin, used to treat parasites in humans and animals.
Antifungal: Polyene antimycotics like amphotericin B.

Conclusion

Macrolides are a vital class of antibiotics with classifications based primarily on their core chemical structure—the size of the macrocyclic lactone ring—and their evolutionary generation. This systematic categorization helps clinicians select the most appropriate agent for a specific infection, considering the drug's stability, half-life, and potential for drug-drug interactions. For example, the development of semi-synthetic derivatives like clarithromycin and azithromycin addressed the limitations of the first-generation erythromycin, while third-generation ketolides were created to combat resistance. This continuous evolution underscores the dynamic nature of pharmacology and the ongoing effort to combat bacterial resistance.

For more detailed information on specific macrolide drugs, consult reputable pharmacology resources like the National Center for Biotechnology Information (NCBI) Bookshelf.

List of Common Macrolides:

14-Membered: Erythromycin, Clarithromycin, Roxithromycin
15-Membered: Azithromycin
16-Membered: Josamycin, Spiramycin
Ketolides: Telithromycin

Frequently Asked Questions

Macrolides are primarily classified based on the number of atoms in their macrocyclic lactone ring, with the main categories being 14-membered, 15-membered (azalides), and 16-membered.

An azalide is a subclass of macrolide where a nitrogen atom is incorporated into the macrocyclic lactone ring, expanding it to 15 members. Azithromycin is the most common example of an azalide.

The third generation of macrolides, known as ketolides, was developed to combat the rise of bacterial resistance to first- and second-generation macrolides. They achieve this with a modified structure that binds more effectively to bacterial ribosomes.

The structural classification impacts a drug's properties and side effect profile. For example, first-generation erythromycin is less acid-stable and causes more gastrointestinal side effects than newer, more stable semi-synthetic generations like clarithromycin and azithromycin.

Common examples of 16-membered macrolides include josamycin and spiramycin. These are used less frequently in human medicine compared to the 14- and 15-membered rings.

A ketolide is a third-generation macrolide, such as telithromycin, which features a keto group substitution. This modification increases its binding affinity for the bacterial ribosome, making it effective against macrolide-resistant pathogens.

Azithromycin's classification as an azalide is significant because its 15-membered ring structure gives it a longer half-life, excellent tissue penetration, and minimal interaction with drug-metabolizing enzymes (CYP3A4), resulting in a more convenient dosing regimen and fewer drug interactions.

No, not all macrolides are antibiotics. While many are, the broader class of macrolides also includes compounds with other properties, such as the immunosuppressants tacrolimus and sirolimus.