What Are Macrolides?

Macrolide antibiotics (MA) are a general term for a class of antibacterial drugs with 12-16 carbon lactone rings in their molecular structure. They inhibit bacterial protein synthesis by blocking the activity of peptidyltransferase in the 50s ribosome. , Belongs to fast bacteriostatic agent. It is mainly used to treat aerobic Gram-positive and negative cocci, certain anaerobic bacteria, and Legionella, Mycoplasma, Chlamydia and other infections. However, recent studies have shown that besides antibacterial effects, macrolide antibiotics also have a wide range of pharmacological effects.

Macrolide antibiotics are 14 to 16-membered macrolide antibiotics (such as erythromycin derivatives, acetylspiramycin, etc.). In fact, broad-based macrolide antibiotic drugs include: 14 to 16-membered macrolide antibiotics, 24- or 31-membered macrolide lactam antibiotics (such as tacrolimus tacorolimus and sirolimus Sirolimus (immunosuppressant), polyene macrolide antibiotics (such as amphotericin B and pentamycin, antifungal antibiotics), and a new 18-membered macrolide antibiotic (fidaxomycin) fidaxomycin, treatment drugs for Clostridium difficile infection) and so on.

Generally speaking, macrolide antibiotics are 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 Mycoplasma, Chlamydia, Legionella, Spirochetes and Rickettsia have strong effects. According to the number of carbons on the nucleus of its lactone structure, it can be divided into 14-, 15-, and 16-membered ring macrolide antibiotics. The macrolide antibiotics on the market are mainly divided into three categories, namely erythromycins, medicillins and spiramycins. Erythromycin and its (ester) derivatives (such as erythromycin succinate, erythromycin, roxithromycin, clarithromycin, erythromycin, and erythromycin) are 14-membered macrolides Antibiotics, but azithromycin derived from erythromycin is the first 15-membered aza macrolide antibiotics (azalides) antibiotics, and medicillin and its derivatives, and spiramycin and its derivatives It belongs to 16-membered macrolides. In addition, ketolides products telithromycin newly listed abroad also belong to the 14-membered macrolides.

The so-called first-generation macrolide antibiotics refer to erythromycin and its ester derivatives. Products include erythromycin, erythromycin succinate, erythromycin stearate, ethyl carbonate erythromycin, Erythromycin acetate, erythromycin lactate, erythromycin and the like. Second-generation macrolide antibiotics include azithromycin, roxithromycin, clarithromycin, dirithromycin, and fluoroerythromycin. The third generation of macrolide antibiotics currently on the market is only telithromycin.

Erythromycin is a macrolide antibiotic produced by Streptomyceserythreus. It has broad-spectrum antibacterial activity against upper respiratory pathogens such as Mycoplasma, Chlamydia, and Legionella pneumophila, and has been widely used to treat upper respiratory infections for more than forty years. The decrease in erythromycin activity is considered to be the result of the interaction between the 6-position hydroxyl group, the 9-position carbonyl group, and the 8-position hydrogen. Therefore, it is unstable in gastric acid and quickly degrades into inactive by-products. This acid instability causes erythromycin to lose its antibacterial activity and greatly reduces its bioavailability. Therefore, the structural modification of these sites and overcoming their acid instability became a hot research topic in the 1880s. Therefore, the second generation of macrolide antibiotics-clarithromycin, azithromycin, roxithromycin, Dierythromycin and fluoroerythromycin were born and came into being in the 1990s. Compared with erythromycin, the second-generation macrolide antibiotics have the following characteristics:

(1) Stable to gastric acid and high oral bioavailability;

(2) Plasma drug concentration, interstitial fluid and intracellular drug concentration are high and durable;

(3) The plasma half-life is prolonged. Except that the half-life of roxamycin and miocomycin is close to that of erythromycin, the rest are longer than erythromycin. The plasma half-life of roxithromycin and azithromycin are 8.4 ~ 15.5 h and 48-72 h, enhance patient compliance;

(4) The gastrointestinal side effects caused by it are also mild. ^[1]

Macrolides can irreversibly bind to the 50S subunit of the bacterial ribosome, selectively block protein synthesis by blocking transpeptide action and mRNA shift. It is believed that macrolides can bind to the special target site of the 50S subunit 23SrRNA, prevent the peptide acyl tRNA from shifting from the "A" position to the "P" position of the mRNA, and prevent the aminoacyl tRNA from binding to the "A" position. Synthesis of bacterial proteins; or binding to the L22 protein of the bacterial ribosome 50S subunit, leading to the destruction of the ribosome structure, causing the peptidyl tRNA to dissociate from the ribosome earlier during the peptide bond extension phase. Since the binding point of macrolides on the 50S subunit of bacterial ribosomes is the same as that of clindamycin and chloramphenicol, when combined with these drugs, mutual antagonistic effects can occur.

Bacteria will develop resistance to macrolides, and there is incomplete cross-resistance between the drugs in this class. Resistance is usually encoded by a plasmid, and the mechanism may be:

The amount of antibiotics entering the bacteria is reduced and the efflux is increased. For example, Gram-negative bacteria can enhance the outer membrane barrier effect of lipopolysaccharide, and it is difficult for drugs to enter the bacteria;

The efflux pump of Staphylococcus aureus is enhanced, the drug excretion is increased, or the bacteria produce enzymes that inactivate macrolides, such as esterase, phosphorylase and glucosease; bacteria change the ribosome bound to antibiotics The binding site reduces its binding ability. ^[1]

1. Role in infectious diseases: Recent studies have shown that macrolide antibiotics are effective for cocci, anaerobic bacteria, legionella, mycoplasma, and chlamydia, and can also be used to treat mycobacteria (including tuberculosis). Mycobacterium and atypical mycobacteria), Pseudomonas aeruginosa infection. It can prevent the biofilm formation of Pseudomonas aeruginosa, and has a synergistic bactericidal effect when combined with quinolone drugs. In 2001, the American Thoracic Society revised the "Guidelines for the Management of Adult Community Acquired Pneumonia" and concluded that the previously considered antagonistic combination of reproductive fungicides and rapid bacteriostatic agents is only a possibility, and clinical data indicate that the two are used in combination Helps improve prognosis.

2. Application in the respiratory system: Macrolide antibiotics have good tissue penetration, the concentration in lung tissue can reach several times the blood drug concentration, and the tissue half-life is much higher than the serum half-life, so It has a good clinical effect in the treatment of G ⁺ , G ^- coccus and G ⁺ bacillus lung infections, and because of its high intracellular drug concentration, it is the drug of choice for the treatment of pulmonary mycoplasma, chlamydia, and legionella infections.

3. Application in cardio-cerebrovascular diseases: used for secondary prevention of cardio-cerebrovascular diseases: Many studies have found that Helicobacter pylori and Chlamydia pneumoniae can be detected in atherosclerotic plaques of atherosclerotic patients, so pylorus is currently considered Helicobacter and chlamydia infections are closely related to coronary heart disease. It is suggested that Helicobacter pylori infection is a risk factor for coronary heart disease. This shows that clarithromycin has a secondary prevention effect in this type of patients. However, the secondary prevention of macrolides in cardiovascular and cerebrovascular diseases remains to be further studied.

4. Application in digestive system diseases: Studies on the use of macrolides for the treatment of peptic ulcer have been repeatedly reported, and this therapeutic effect is related to the antibacterial activity of these drugs on Helicobacter pylori. The combination of macrolides and antacids can eradicate Helicobacter pylori in the stomach of patients with gastric ulcers, and it has now become a treatment recommended by many scholars. In addition, many studies have shown that macrolide antibiotics are also a gastrin, which can increase gastric emptying and can be used for the treatment of non-ulcerative dyspepsia. Long-term intravenous injection of erythromycin for gastroparesis is a feasible, safe and effective method. ^[1]

1 Digestive system

Erythromycin and a new generation of macrolide antibiotics are mainly manifested as gastrointestinal symptoms and liver toxicity. The clinical symptoms of gastrointestinal symptoms are abdominal pain, bloating, nausea, vomiting and diarrhea. At the daily dose, hepatotoxicity is small, but esterified erythromycin has certain hepatotoxicity, so it should only be used in small amounts in the short term. Similar drugs also have hepatotoxic reactions, mainly manifested as cholestasis, abnormal liver function, etc., which can usually be recovered after withdrawal. For example, azithromycin can cause changes in liver function and increase ALT and AST. Application of roxithromycin in a short course of treatment can also cause jaundice and abnormal liver function. It is suggested that hepatotoxicity of drugs should be paid attention to when using such drugs.

2 Allergies

This product can cause drug rash and drug fever, occasionally cause allergies and temporary deafness, as well as dermatitis, perineal erosion, etc., and even shock. This is related to excessive blood concentration, which often occurs in intravenous administration or with renal impairment and / or liver function impairment.

3 Cardiotoxicity

The cardiotoxicity of macrolide antibiotics such as erythromycin, spiramycin and clarithromycin is mainly manifested by prolonged QT interval and apical torsional ventricular tachycardia. It is very dangerous. Clinically, patients may experience coma and sudden death. It is mostly induced by erythromycin, which is a special type of adverse reaction of macrolide antibiotics. The mechanism is to prolong the time of myocardial action potential and induce early post-depolarization of Purkinje fibers in the heart. In order to reduce or avoid the occurrence of cardiotoxicity, clinicians need to understand the possibility of inducing cardiotoxicity before applying this class of drugs, carefully select drugs based on the patient's condition and the combined drug situation, pay attention to observation during the medication, and monitor the ECG if necessary. Cardiotoxicity should take active treatment measures, immediately discontinue this class of drugs and correct risk factors, and apply antiarrhythmic drugs that can shorten the QT interval and stop tip torsional ventricular tachycardia.

4 Blood system

In recent years, there have been reports of rapid decrease in blood cells in patients after erythromycin application. There have also been reports of leukopenia. ^[1]

The rapid emergence of multi-resistant bacteria of ketolactone macrolide antibiotics has greatly restricted the application of first and second generation macrolide antibiotics, so the third generation of macrolide antibiotics -Ketolide came into being. To overcome the problem of drug resistance of erythromycins, macrolides can be further modified by increasing the effective binding site between the drug and the target. ^[1]

The possibility and intensity of drug interaction between erythromycin and clarithromycin are much greater than azithromycin. The possible reason is that the three have different inhibitory strengths on the main metabolic enzyme CYP3A4 activity of the drug, but not the activity of the drug transporter P-GP. Using midazolam as the substrate of CYP3A4 to evaluate the strength of the three drug-mediated interactions, it was found that clarithromycin, erythromycin, and azithromycin caused strong, moderate, and weak interactions, respectively. Azithromycin is a strong, moderate and weak inhibitor of CYP3A4, respectively. ^[1]

1. Forbidden in patients allergic to erythromycin and other macrolides.

2. Erythromycin and clarithromycin are forbidden to be combined with terfenadine, so as not to cause adverse cardiac reactions. In addition, it can inhibit drugs metabolized by P450 enzymes such as astemizole, carbamazepine, cisapride, sildenafil, phenytoin, triazolam, theophylline, and valproic acid. Especially when given intravenously.

3. If the liver function is impaired, if the indication is applied, it should be appropriately reduced and the liver function should be reviewed regularly.

4. Erythromycin esters should not be used in patients with liver disease and patients during pregnancy. Breastfeeding should be suspended during medication.

5. Strong antibacterial activity in alkaline environment, often need to alkalize urine when treating urinary tract infection.

6. The gastrointestinal reaction is obvious. Do not take it on an empty stomach. If you must use it, you can take "Smecta" orally half an hour before the medication or add "Vitamin B6" to reduce the symptoms without affecting the efficacy.

7. Easy to cause local irritation, not easy to intravenous injection.

8. roxithromycin is not allowed to be combined with ergotamine. ^[1]