MACROLIDES: MECHANISM OF ACTION, CLASSIFICATION AND EFFECTS - MEDICINE - 2025

The macrolides are a group of antimicrobial drugs that act by preventing the formation of bacterial proteins. In most organisms this action inhibits bacterial growth; however, in high concentrations it can cause cell death.

First described in 1952, when McGuire and his team discovered erythromycin, they have become one of the most widely used groups of antibiotics in the world. Since the 1970s, the first synthetic macrolides - such as azithromycin and clarithromycin - were developed, mainly to be administered orally.

Erythromycin, like many other antibiotics, was isolated from a bacterium, Saccharopolyspora erythraea. Formerly known as Streptomyces erythraeus, it is a bacterium present in the soil whose cytochore P450 is responsible for synthesizing the antibiotic through a partial hydroxylation process.

Mechanism of action

Macrolides act at the ribosomal level, specifically on the 50S subunit, blocking its action. By doing this, they inhibit the protein synthesis of sensitive microorganisms without affecting the ribosomes of mammals. This effect manages to prevent the growth of bacteria.

Due to their mechanism of action, macrolides are considered bacteriostatic antibiotics. However, depending on the dose and the sensitivity of the bacteria, they can become bactericidal. It is important to note that macrolides only have an effect on cells that are replicating or in the growth phase.

An important characteristic of macrolides is their ability to concentrate within macrophages and polymorphonuclear cells. It is for this reason that they are the antibiotics of choice for intracellular bacteria or atypical germs. In addition, they have a prolonged postantibiotic effect, and can be used with comfortable doses.

Immunomodulatory effect

Many biological activities have been described for macrolides, including the ability to modulate inflammatory processes.

This fact has led them to also be indicated to treat neutrophil-mediated inflammations in many diseases of the respiratory sphere with diffuse bronchiolitis or cystic fibrosis.

These immunomodulatory actions appear to work in different ways. One of these is related to the inhibition of extracellular phosphorylation and the activation of the nuclear factor Kapa-B, both actions with anti-inflammatory results.

Furthermore, its intracellular presence has been linked to the regulation of the immune activity of the cell itself.

The main concern generated by the use of macrolides as immunomodulators is bacterial resistance. Researchers are currently working on creating a non-antibiotic macrolide to be used only as an immune modulator without the risk of antimicrobial resistance.

Classification

According to its chemical structure

Due to its chemical structure, in which there is a common macrocyclic lactonic ring for all macrolides, there is a classification that considers the number of carbon atoms present in said ring.

14 carbon atoms

- Erythromycin.

- Clarithromycin.

- Telithromycin.

- Dirithromycin.

15 carbon atoms

- Azithromycin.

16 carbon atoms

- Spiramycin.

- Midecamycin.

According to its origin

Certain publications offer another classification of macrolides based on their origin. While not universally accepted, the information provided below is valuable:

Natural origin

- Erythromycin.

- Myocamycin.

- Spiramycin.

- Midecamycin.

Synthetic origin

- Clarithromycin.

- Azithromycin.

- Roxithromycin.

According to generations

A third classification organizes the macrolides according to generations. It is based on the chemical structure and the pharmacodynamic and pharmacokinetic characteristics.

First generation

- Erythromycin.

Second generation

- Josamycin.

- Spiramycin.

- Myocamycin.

Third generation

- Azithromycin.

- Roxithromycin.

- Clarithromycin.

Fourth generation (ketolides)

- Telithromycin.

- Cethromycin.

Some authors consider ketolides as a group apart from antibiotics, although the strictest ones claim that it is an important modification of macrolides, since it preserves the same original ring and mechanism of action.

The most important difference between the parent macrolides and ketolides is the spectrum of action. Macrolides up to the third generation have greater activity against Gram-positive; instead, ketolides are effective against Gram-negative, especially Haemophilus influenzae and Moraxella catarrhalis.

Adverse effects

Most macrolides have the same side reactions, which, although rare, can be uncomfortable. The most important ones are described below:

Gastrointestinal disorders

They can present as nausea, vomiting, or abdominal pain. It is more frequent with the administration of erythromycin and is attributed to its prokinetic effects.

Some cases of pancreatitis have been described after the administration of erythromycin and roxithromycin, related to spastic effects on the sphincter of Oddi.

A rare but severe complication is hepatotoxicity, especially when ketolides are involved. The mechanism of liver damage is not well understood, but it subsides when the drug is withdrawn.

It has been described in pregnant women or young people and is accompanied by abdominal pain, nausea, vomiting, fever and jaundice tint of the skin and mucous membranes.

Hypersensitivity

It can manifest in different systems, such as the skin and blood, in the form of a rash or fever and eosinophilia. These effects subside when treatment is stopped.

It is not known exactly why they occur, but the immunological effects of macrolides may be involved.

Cardiovascular effects

QT prolongation is the most reported cardiac complication after macrolide administration. Cases of polymorphic ventricular tachycardia have also been described, but they are very rare.

In 2017, the FDA (drug regulatory body in the United States) reserved ketolides only for cases of community-acquired pneumonia due to cardiac complications and other adverse effects that it caused, ceasing to be indicated in cases of sinusopathy, pharyngotonsillitis or complicated bronchitis.

Although most macrolides are prescribed orally, existing intravenous forms can cause phlebitis. Slow administration is recommended through a large peripheral line or a central line, and highly diluted in saline solution.

Ototoxicity

Although it does not occur routinely, cases of ototoxicity with tinnitus and even deafness have been described in patients who consume high doses of erythromycin, clarithromycin, or azithromycin. This adverse effect is more frequent in the elderly and patients with chronic liver or kidney failure.

Other undesirable effects

The administration of these medications by any route, especially oral, can cause a bad taste in the mouth.

Ketolides have been associated with transient visual disturbances. Its use should be avoided in pregnant women - since its action on the fetus is not known with certainty - and in patients with myasthenia gravis.

Caution is necessary when administered in conjunction with any other drug that is metabolized through the cytochrome P450, isoenzyme 3A4 system.

It can raise serum levels of digoxin and have an antagonistic effect when administered with chloramphenicol or lincosamines.

References

1. Encyclopaedia Britannica (2017). Macrolide. Recovered from: britannica.com
2. Kanoh, Soichiro and Rubin, Bruce (2010). Mechanisms of Action and Clinical Application of Macrolides as Immunomodulatory Medications. Clinical Microbiology Reviews, 23 (3), 590-615.
3. Mazzei, T; Mini, E; Novelli, A and Periti, P (1993). Chemistry and mode of action of macrolides. Journal of Antimicrobial Chemotherapy, Volume 31, 1-9.
4. Zhanel, GG et al. (2002). The ketolides: a critical review. Drugs, 62 (12), 1771-1804.
5. Wikipedia (last edition 2018). Macrolides. Recovered from: es.wikipedia.org
6. Cosme, Veronica (nd). Macrolides. Recovered from: infecto.edu.uy
7. Cobos-Trigueros, Nazaret; Ateka, Oier; Pitart, Cristina and Vila, Jordi (2009). Macrolides and ketolides. Infectious Diseases and Clinical Microbiology, 27, 412-418.