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What antibiotics are macrolides?

Posed on  January 3, 2021, edited by Jason, category  

What are macrolides?

Macrolides are the general term for a class of antibacterial drugs with 12-16 carbon lactone ring in the molecular structure, which inhibits bacterial protein synthesis by blocking the activity of peptide acyltransferase in the ribosome for 50s.

It is a fast antibacterial agent, mainly used for the treatment of infections such as aerobic gram-positive and negative cocci, certain anaerobic bacteria, Legionella, Mycoplasma and Chlamydia. Studies have shown that in addition to antibacterial effects, macrolide antibiotics also have other extensive pharmacological effects.

If you drink milk at home, Ballya can also do a macrolides test to let you know if there are macrolides residues in the milk you drink in 10min.

Macrolides Classification

Macrolide antibiotics refer to 14 to 16-membered macrolide antibiotics (such as erythromycin derivatives, acetylspiramycin, etc.). In fact, generalized macrolide antibiotics include: 14 to 16-membered macrolide antibiotics, 24- or 31-membered macrolide antibiotics (such as tacorolimus and sirolimus) Sirolimus, immunosuppressant, polyene macrolide antibiotics (such as amphotericin B and pentamycin, antifungal antibiotics), and 18-membered new macrolide antibiotics (fidaxomycin, treatment drug for Clostridium difficile infection) etc.

Generally speaking, the macrolide antibiotics refer to the broad-spectrum antibiotics produced by Streptomyces. They have a basic lactone ring structure and are effective against both Gram-positive and Gram-negative bacteria, especially against Mycoplasma, Chlamydia, Legionella, Spirochetes and Rickettsia.

According to the number of carbon contained in the nucleus of the lactone structure, it can be divided into 14-membered, 15-membered and 16-membered ring macrolide antibiotics. The marketed macrolide antibiotics are mainly divided into three categories, namely, erythromycin, medicin and spiramycin. Erythromycin and its (ester) derivatives (such as erythromycin ethylsuccinate, roxithromycin, clarithromycin, dirithromycin and fluerythromycin) belong to the 14-membered macrolide Antibiotics. Azithromycin derived from erythromycin was the first 15-membered azamacrolide (azalide) antibiotic to be marketed, while midenomycin and its derivatives, and spiramycin and its derivatives belongs to the 16-membered macrolide. In addition, the newly marketed ketolides product telithromycin also belongs to the 14-membered macrolides.

The so-called first-generation macrolide antibiotics refer to erythromycin and its ester derivatives. The products include erythromycin, erythromycin ethylsuccinate, erythromycin stearate, erythromycin ethyl carbonate, Erythromycin acetate, erythromycin lactobionate, erythromycin et al. The second-generation macrolide antibiotics include azithromycin, roxithromycin, clarithromycin, dirithromycin and tylosin. The third-generation macrolide antibiotics marketed only telithromycin.

Erythromycin is a macrolide antibiotic produced by Streptomyceserythreus. It has broad-spectrum antibacterial activity against upper respiratory tract pathogens such as Mycoplasma, Chlamydia and Legionella pneumophila, and has been widely used to treat upper respiratory tract infections for more than forty years. The decreased activity of erythromycin is believed to be the result of the interaction of its 6-hydroxyl, 9-carbonyl, and 8-hydrogen, so it is unstable in gastric acid and quickly degrades into inactive by-products.

This acid instability makes erythromycin lose its antibacterial activity and its bioavailability is greatly reduced. Therefore, the structural modification of these sites and overcoming their acid instability became a research hotspot in the 1880s. Therefore, the second generation of macrolide antibiotics-clarithromycin, azithromycin, roxithromycin, Dirithromycin and fluoroerythromycin came into being, and they went on the market in the 1990s. Compared with erythromycin, the second-generation macrolide antibiotics have the following characteristics:

  • Stable to gastric acid, high oral bioavailability;
  • Plasma drug concentration, tissue fluid and intracellular drug concentration are high and durable;
  • The plasma half-life is prolonged, except that the half-lives of rotamycin and miokamycin are close to that of erythromycin, the others are longer than erythromycin. The plasma half-lives of roxithromycin and azithromycin are 8.4~15.5 h and 48~72 h respectively, which enhances patient compliance;
  • The adverse gastrointestinal reactions caused by it are also mild.
ClassificationRepresentative
Macrolides1. 14 ring: erythromycin, clarithromycin, roxithromycin, dierythromycin and so on.
2. 15-membered ring: Azithromycin.
3. 16 - ring: Medemycin, kitasamycin, spiramycin, etc.
Ketolactone antibioticsSimilar in structure to macrolide antibiotics, they are commonly used to treat respiratory infections caused by bacteria resistant to macrolide antibiotics, such as telomycin quinerythromycin.
Non-antimicrobial macrolidesSuch as tacrolimus, pimelimus, and sirolimus, used as a rabbit-plague inhibitor or as a rabbit-plague regulator.
Toxic macrolidesA toxic product produced by bacteria and used chiefly in the treatment of Mycobacterium.

Macrolides Mechanism of action

Macrolides-Mechanism-of-action
Macrolides-Mechanism-of-action

What everyone is familiar with is the antibacterial effect of macrolides. In addition, macrolides have other effects.

1. Antibacterial effect

It acts by inhibiting the synthesis of protein. It is usually a fast bacteriostatic agent and a fungicide at high concentrations.

It is effective against most G+ bacteria, some G- bacteria, anaerobic bacteria and some atypical pathogenic bacteria (have strong antibacterial activity against Staphylococcus, various groups of streptococci, pneumococcus, tetanus, anthracis, diphtheria, gonococcus Serratia, Neisseria meningitidis, Bacillus pertussis, Legionella, etc.; it also has a good antibacterial effect against atypical pathogens such as Treponema pneumoniae, Leptospira, Mycoplasma pneumonia, Chlamydia, Toxoplasma gondii, and atypical mycobacterium.)

Macrolides have a strong post-antibiotic effect (PAE) against aerobic G+ cocci.

2. Non-antibacterial effect

In addition to the antibacterial effects of macrolides, they also play a certain role in anti-inflammatory and regulating airway secretion, immune regulation, and hormone saving effects.

Anti-inflammatory and regulating airway secretionIt is related to inhibiting the release of inflammatory mediators, reducing mucus secretion, reducing neutrophil chemotaxis and adhesion, and promoting inflammatory cell apoptosis.
ImmunomodulationMacrolides can still interfere with bacterial protein synthesis even below the MIC, indicating that the antimicrobial effect of these drugs is not dependent on their direct antibacterial activity, but their immunomodulatory effect, which is an indirect effect.
Hormone saving effectReduce the dosage of hormone-dependent or resistant asthmatic hormones and reduce the adverse effects of hormones.
Antiviral effectIntercellular adhesion molecule-1 is the rhinovirus receptor of airway epithelial cells. Macrolides exert antiviral effects by inhibiting its upregulation, and can also inhibit the production of pro-inflammatory cytokines triggered by viral infection.
Promote gastrointestinal motilityErythromycin has a motilin-like effect and can promote gastric emptying.

Clinical application

As we mentioned above, macrolide drugs have antibacterial and non-antibacterial effects. Therefore, when we talk about clinical application, we also talk about it from these two aspects.

1. Clinical application of antibacterial

Macrolides can act on most bacteria

A. Streptococcal infection

It can be used to treat acute tonsillitis, acute pharyngitis, sinusitis, scarlet fever, cellulitis, etc. caused by streptococcus.

B. Legionnaires' disease

It can treat pneumonia and community-acquired pneumonia caused by Legionella pneumophila, Legionella mykdad and other Legionella bacteria.

C. Mycoplasma and Chlamydia infection

It can treat eye infections such as conjunctivitis caused by Chlamydia trachomatis; respiratory infections such as pneumonia and bronchitis caused by bronchial pneumonia/chlamydia; and urogenital infections such as urethritis, cervicitis and pelvic inflammatory disease caused by bronchial/chlamydia.

D. Corynebacterium infection

It can treat diphtheria, coryneform bacteria, sepsis, etc. Erythromycin can eradicate diphtheria bacillus and effectively improve the condition of acute and chronic diphtheria carriers. The effective rate can reach 90% in adults, but it cannot change the course of acute infection.

E. Helicobacter pylori infection

Clarithromycin can be combined with other drugs to eradicate Helicobacter pylori infection.

F. Mycobacterium avium infection

Clarithromycin and azithromycin can be used for the treatment of nontuberculous mycobacteria such as Mycobacterium avium in immunodeficiency patients.

G. Other

It can replace penicillin for patients with staphylococcal, streptococcal or pneumococcal infection allergic to penicillin. It can also be used to treat skin and soft tissue infections caused by sensitive bacteria. It can be used as an alternative medicine for the treatment of cryptosporidiosis and toxoplasmosis.

2. Clinical applications other than antibacterial effects

Secondly, the non-antibacterial effects of macrolides are also widely used clinically.

A. Respiratory diseases

Anti-inflammatory, regulating airway secretion and immunomodulatory effects of macrolides that do not rely on antibacterial effects are important reasons for their widespread application in the respiratory system.

a. Diffuse panbronchiolitis (DPB)

The most effective drug for the treatment of DPB (16-membered ring has been proven ineffective), and its mechanism of action is related to its anti-inflammatory effect and potential immune regulation mechanism, and has little to do with anti-bacterial infection.

b. Chronic sinusitis (CRS)

At present, more than 30% of patients with CRS still have symptoms that are difficult to control after comprehensive treatment. Biofilm may be an important factor in the occurrence and persistence of recurrent and refractory CRS inflammation. Therefore, drugs that can decompose or prevent the formation of biofilms have become a new choice for the treatment of refractory CRS.

Macrolides have the functions of anti-infection, anti-inflammatory, immune regulation, inhibition of mucus secretion, and inhibition of bacterial biofilm formation. They have been clinically applied to the treatment of CRS.

The European Society of Allergy and Clinical Immunology CRS and Nasal Polyp Diagnosis and Treatment Guidelines (EPOS 2012 Edition) pointed out that long-term use of macrolide drugs such as clarithromycin in the treatment of chronic sinusitis can achieve the same effect as surgery or hormone application.

The Chinese CRS Diagnosis and Treatment Guidelines (2012 edition) point out: 14-membered ring macrolide drugs can be used for CRS without nasal polyps, poor conventional drug treatment, no eosinophilia, normal IgE, allergens Non-allergic CRS patients tested negative. It is recommended that small doses of macrolides (1/2 the conventional dose) be taken orally for a long time, and the course of treatment should not be shorter than 12 weeks.

c. Chronic obstructive pulmonary disease (COPD)

The 2007 Guidelines for the Diagnosis and Treatment of Chronic Obstructive Pulmonary Disease in China pointed out that for acute exacerbations of grade I and II COPD, the pathogenic microorganisms are usually Haemophilus influenzae, Streptococcus pneumoniae, Moraxella catarrhalis, etc. Macrolides can be used for treatment.

In 2014, the Lancet Journal of Respiratory Medicine suggested that azithromycin should be considered as maintenance treatment for COPD patients with frequent attacks and resistance to standard therapies.

In 2015, the American Thoracic Society/European Society of Respiratory Diseases "Consensus on Chronic Obstructive Pulmonary Disease" pointed out that long-term use of macrolides can prevent repeated exacerbations of COPD.

In addition, macrolides can also treat bronchiectasis, pulmonary cystic fibrosis, severe asthma, cryptogenic organizing pneumonia, and respiratory virus infections. However, some of the current evidence is insufficient or controversial, and more researches are needed to verify them.

B. Digestive system diseases

As a motilin receptor agonist, it can stimulate intestinal peristalsis. At present, erythromycin and azithromycin are commonly used.

It can be used for the treatment of gastrointestinal motility disorders such as gastrointestinal neurogenic motion sickness, postoperative gastrointestinal emptying disorder, gastroparesis; because of its anti-HP effect, it can be used to treat peptic ulcers.

C. Malignant tumors

Because of its unique immunomodulatory effect, it can be used in the treatment of tumors, such as erythromycin and roxithromycin. In addition, we need to be wary of the 2018 US FDA warning that long-term use of azithromycin after hematopoietic stem cell transplantation can increase the risk of tumor recurrence.

D. Immune diseases

It is mainly used in cases related to HP infection, such as rheumatoid arthritis. It can also effectively treat common clinical autoimmune diseases such as alopecia areata, autoimmune thrombocytopenic purpura and Sjogren's syndrome.

E. Skin diseases

It is used to treat chronic and refractory skin diseases such as psoriasis, vitiligo, allergic purpura, and rosacea through multiple mechanisms such as anti-HP, anti-inflammatory, anti-allergic and immune regulation.

Macrolides Side effects

Macrolides-Side-effects
Macrolides-Side-effects

1. Gastrointestinal dysfunction

The most common, it may be related to pro-gastrointestinal motility. The incidence of erythromycin is higher than other drugs.

2. Liver damage and allergic dermatitis

The liver damage is small at the normal dose, and long-term large-scale application can cause cholestatic hepatitis. After esterification, drugs such as roxithromycin, erythromycin ethylsuccinate, and azithromycin are more prone to cholestatic jaundice, so they should be used for a short time. Avoid or stop using it when serum transaminase rises more than three times the normal limit.

3. Arrhythmia

Macrolides can cause the QT interval to be prolonged, and may lead to torsades de pointes, and even ventricular fibrillation or sudden death. Although this adverse reaction is rare, it is fatal. In 2013, the US Food and Drug Administration also issued a warning that azithromycin has a potentially fatal arrhythmia risk. Therefore, patients with high risk of arrhythmia should weigh the pros and cons before medication.

4. Ototoxicity

Long-term medication may cause hearing loss, poor balance, and tinnitus, which are rare and dose-dependent. It usually occurs within 1-2 weeks of medication, and it is prone to occur at high doses. It can be recovered after stopping or reducing the dose.

5. Others

Allergic reactions, neurological side effects, etc.

Conclusion

It should be noted that the long-term application of macrolides has brought about the problem of antibiotic resistance. The drug resistance rate has doubled in the past 10 years, and the number of prescriptions of drugs is significantly related to the drug resistance rate in the region. So use drugs rationally and avoid abuse.

References

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