Macrolidesantibiotic(macrolides antibiotics, MA) is the general name of a class of antibacterial drugs with 12-16 carbolactone rings in the molecular structure, which inhibits bacteria by blocking the activity of peptidyltransferase in 50s ribosomesprotein synthesis, belongs to fastBacteriostatic agent。 It is mainly used for the treatment of aerobic gram-positive and negative cocci, some anaerobic bacteria, legionella, mycoplasma, chlamydia and other infections.Studies have shown that macrolide antibiotics not only have antibacterial effects, but also have other extensive pharmacological effects.
Macrolide antibiotics refer to 14 to 16 membered macrolide antibiotics (such as erythromycin derivativesAcetylspiramycinEtc.).In fact, macrolide antibiotics in a broad sense include 14 to 16 membered macrolide antibiotics, 24 or 31 membered macrolide lactam antibiotics (such asTacrolimusTacorolimus and sirolimus sirolimus,Immunosuppressant）Polyene macrolide antibiotics (such asAmphotericin BAnd pentamycin, antifungal antibiotics, and 18 yuan new macrolide antibiotics (Fidaxomycin,Clostridium difficileInfection treatment drugs), etc.
The macrolide antibiotics usually refer to those produced by StreptomycesBroad-spectrum antibiotic, with basic lactone ring structureGram positive bacteriaandGram negative bacteriaAre effective, especially for mycoplasma, chlamydia, legionella, spirochete andRickettsiaIt has a strong effect.It can be divided into 14 membered, 15 membered and 16 membered rings according to the number of carbon in the parent core of its lactone structuremacrolide antibiotics。The listed macrolide antibiotics are mainly divided into three categories, namely erythromycin, medimycin and spiramycin.Erythromycin and its (ester) derivatives (such asErythromycin ethylsuccinate、Etorubicin、roxithromycin id、ClarithromycinDeerythromycin, Deerythromycin and Fluerythromycin) belong to 14 membered macrolide antibiotics, but are derived from erythromycinAzithromycinIt is the first listed 15 yuan azamacrolide (azalactone) antibiotic, andMedimycinAnd its derivatives, andSpiramycinAnd its derivatives belong to 16 membered macrolides.In addition, the newly marketed ketolides product telithromycin also belongs to 14 membered macrolides.
The so-called first generation macrolide antibiotics refer to erythromycin and its ester derivatives, including erythromycin, erythromycin ethylsuccinateErythromycin stearate, Erythromycin ethyl carbonate, Erythromycin acetateErythromycin Lactate, relying on erythromycin, etc.The second generation macrolide antibiotics include azithromycin, roxithromycin, clarithromycin, dirithromycin and fluroxithromycin.However, the third generation of macrolide antibiotics only have telithromycin on the market.
Erythromycin is produced byStreptomyces erythromycinMacrolide antibiotics produced by Streptomyces erythrius.For pathogens of upper respiratory tract, such as mycoplasma, chlamydiaLegionella pneumophilaIt has broad-spectrum antibacterial activity and has been widely used for treatment for more than 40 yearsupper respiratory tract infection。The decrease of erythromycin activity is considered to be the result of the interaction of 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 andBioavailabilityGreatly reduced.Therefore, structural modification of these sites and overcoming their acid instability became a research hotspot in the 1980s, and the second generation of macrolide antibiotics clarithromycin, azithromycin, roxithromycin, dirithromycin, and fluroxithromycin came into being at the historic moment, and were listed successively in the 1990s. Compared with erythromycin,The second generation macrolide antibiotics have the following characteristics:
(1) Stable to gastric acid, high oral bioavailability;
(2) The drug concentration in plasma, tissue fluid and cells is high and persistent;
(3)Plasma half-lifeThe plasma half-life of roxithromycin and azithromycin was 8.4~15.5h and 48~72h, respectively, which enhanced the compliance of patients;
(4) Gastrointestinal adverse reactions were also mild.[1]
Antibacterial mechanism
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Macrolides can irreversibly bind to bacterial ribosomal 50S subunit, and selectively inhibitprotein synthesis。It is now believed that macrolides can bind to the special target of 23SrRNA of 50S subunit, prevent peptide tRNA from moving from the "A" position to the "P" position of mRNA, make aminoacyl tRNA unable to bind to the "A" position, and selectively inhibit bacterial protein synthesis;Or it can combine with L22 protein of 50S subunit of bacterial ribosome, leading to ribosome structure destruction, which makes peptidyl tRNA dissociate from ribosome earlier in the peptide bond extension stage.Because the binding point of macrolides on bacterial ribosome 50S subunitClindamycinLike chloramphenicol, when used in combination with these drugs, they can antagonize each other.
Bacteria are resistant to macrolides, and there is incomplete cross resistance among these drugs.Drug resistance is usually encoded by plasmids, and the mechanism may be:
① The amount of antibiotics entering the bacteria decreases and the efflux increases. For example, gram-negative bacteria can enhance the role of lipopolysaccharide outer membrane barrier, and drugs are difficult to enter the bacteria;
②Staphylococcus aureusThe function of efflux pump is enhanced, and drug excretion is increased, or bacteria produce enzymes that inactivate macrolides, such as esterase, phosphorylase and glucoamylase;The bacteria changed the binding site of ribosomes binding to antibiotics, reducing their binding capacity.[1]
clinical application
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1. Role in infectious diseases: Recent research shows that macrolide antibiotics can be used for treatment in addition to being effective against cocci, anaerobes, Legionella, mycoplasma and chlamydiaMycobacterium(including mycobacterium tuberculosis and atypical mycobacterium)Pseudomonas aeruginosaInfected.It can prevent the formation of pseudomonas aeruginosa biofilm, andQuinolonesThe combination of drugs has synergistic bactericidal effect.According to the view in the Guidelines for the Treatment of Adult Community Acquired Pneumonia revised by the American Thoracic Society in 2001, it is only possible that the combination of bactericides and rapid bacteriostatic agents in reproductive period may be antagonistic, and clinical data show that the combination of the two can help improve the prognosis.
2. Application in the respiratory system: Macrolide antibiotics have good tissue penetration, the concentration in the lung tissue can reach several times of the blood concentration, and the tissue half-life is far higher than the serum half-life, so they are used in the treatment of G+、G-Coccus and G+Bacillus has a good clinical effect in pulmonary infection, and because of its high intracellular drug concentration, it can be used to treat pulmonary mycoplasma, chlamydiaLegionella infectionThe first choice of drugs.
3. OnCardiovascular and cerebrovascular diseasesApplication in: secondary prevention of cardiovascular and cerebrovascular diseases: many research findings inatherosclerosisThe patient's atheromatous plaque can be detectedHelicobacter pyloriandChlamydia pneumoniae Therefore, it is believed that Helicobacter pylori andChlamydia infectionIt is closely related to coronary heart disease.Tipshelicobacter pylori infection It is a risk factor of coronary heart disease.It shows that clarithromycin has secondary prevention effect in this kind of patients.However, the secondary prevention of macrolides in cardiovascular and cerebrovascular diseases needs further research.
4. OnDigestive system diseasesApplication of macrolides in treatmentPeptic ulcerIt has been repeatedly reported that this therapeutic effect is related to thehelicobacter pyloriThe antibacterial activity of the bacteria.Macrolide drugs combined with antacids and other drugs can eradicate Helicobacter pylori in the stomach of patients with gastric ulcer, which has become a treatment recommended by many scholars.In addition, many studies have shown that macrolide antibiotics are also a kind of gastrin, which can increase gastric emptying and can be used forNon ulcer dyspepsiaTreatment.Long term intravenous injection of erythromycin for gastroparesis is a feasible, safe and effective method.[1]
Adverse reactions
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1 Digestive system
Erythromycin and a new generation of macrolide antibiotics are mainly manifested as gastrointestinal symptoms and hepatotoxicity.The clinical symptoms of digestive tract symptoms include abdominal pain, abdominal distention, nausea, vomiting and diarrhea.At daily dose, the hepatotoxicity is small, but erythromycin esterified has a certain hepatotoxicity, so it should be used only in a small amount for a short time.Similar drugs also have hepatotoxic reactions, mainly manifested asCholestasis、Abnormal liver functionGenerally, it can be recovered after drug withdrawal.For example, azithromycin can cause changes in liver function, increase ALT and AST, and the use of roxithromycin in a shorter course of treatment can also lead to jaundice and abnormal liver function.It is suggested that attention should be paid to the hepatotoxicity of these drugs.
2 Allergy
This product can cause drug eruption and drug fever, and occasionally cause allergy and temporary deafness, dermatitis, perineal erosion, and even shock.This is related to the high blood drug concentration, which often occurs in intravenous administration or patients with renal dysfunction and/or liver function damage.
3 Cardiotoxicity
The cardiac toxicity of macrolide antibiotics such as erythromycin, spiramycin and clarithromycin is mainly manifested by the prolongation of QT interval andTorsade de pointes ventricular tachycardiaIt is dangerous. In clinical practice, patients may experience coma and sudden death, most of which are induced by erythromycin. This is a special type of adverse reaction of macrolide antibiotics.Its mechanism is to prolong the time of myocardial action potential and induce the heartPurkinje fiberEarly post depolarization.In order to reduce or avoid the occurrence of cardiac toxicity, clinicians need to understand the possibility of inducing cardiac toxicity before using this kind of medicine, carefully select the medicine according to the patient's condition and the situation of combined drugs, pay attention to observation during the use of medicine, monitor ECG if necessary, take active treatment measures once cardiac toxicity occurs, immediately stop using this kind of medicine and correct the risk factors,Application of antitoxin that can shorten QT interval and stop torsade de pointes ventricular tachycardiaArrhythmiaDrugs.
4 Blood system
In recent years, it has been reported that the number of blood cells in patients with erythromycin decreased rapidly.alsoLeukopeniaReport of.[1]
New generation antibiotics
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The rapid emergence of a variety of drug-resistant bacteria of ketolactone macrolide antibiotics has greatly limited the application of the first and second generation macrolide antibiotics, so the third generation macrolide antibiotics ketolide came into being.In order to overcome the problem of erythromycin resistance, macrolides can be further modified by increasing the effective binding sites between drugs and targets.[1]
Mechanism of action of ketolactones
The mechanism of action of this product is similar to that of other macrolide antibiotics. It mainly inhibits protein synthesis by directly binding to the 50S subunit of bacterial ribosome.However, it has unique advantages. It has two action targets in the 23SrRNA II region A752 and V region A2058. Ketolactone antibiotics can not only bind to the A2058 target through the aminodeoxyglucose at position 5, but also their C-11 and C-12 carbamate side chains can bind to the second target A752, with stronger binding power, so as to play an anti drug resistance activity.[1]
Telithromycin, a newly marketed macrolide antibiotic
Telithromycin is the first ketolactone drug to be marketed. It was developed by the former Aventis Company and first marketed under the trade name Ketek in 2001β-LactamaseMacrolide resistant strains and potential induced drug-resistant strains all have activity.However, due to its serious adverse reactions (such as hepatotoxicity), the US Food and Drug Administration (FDA) canceled two of the three originally approved indications (acute bacterial sinusitis andchronic bronchitisAcute exacerbation), only mild and moderateCommunity acquired pneumonia(community acquired pneumonia, CAP).[1]
Interaction
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The possibility and intensity of drug interaction between erythromycin and clarithromycin are far greater than azithromycin.This may be due to the different inhibitory intensity of the three drugs on the activity of CYP3A4, the main drug metabolizing enzyme, rather than the activity of P-GP, the drug transporter.withMidazolamIt was found that clarithromycin, erythromycin and azithromycin caused strong, moderate and weak interactions, respectively. Therefore, clarithromycin, erythromycin and azithromycin were strong, moderate and weak inhibitors of CYP3A4, respectively.[1]
matters needing attention
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1. It is forbidden to use in patients with allergy to erythromycin and other macrolides.
2. Erythromycin and clarithromycin are prohibited fromTefenadineUsed together to avoid adverse cardiac reactions.In addition, it can inhibitAstemizole、carbamazepine、Sisapri、、Sildenafil, phenytoin, triazolam, theophylline, valproic acid and other drugs metabolized by P450 enzyme.Especially for intravenous administration.
3. If there are indications for use in patients with liver function damage, the dosage should be appropriately reduced and the liver function should be reviewed regularly.
4. Erythromycin ester should not be used for patients with liver disease and pregnant women, and lactation should be suspended for patients during lactation.
5. Strong antibacterial activity in alkaline environment, treatmenturinary tract infectionIt is often necessary to alkalize urine.
6. The gastrointestinal reaction is obvious. Do not take it on an empty stomach. If it is necessary, take "Smecta" orally half an hour before taking the medicine or add it when taking the medicine“Vitamin B6”To alleviate symptoms without affecting the efficacy.
7. It is easy to cause local irritation and is not easy to be injected intravenously.
8. Roxithromycin shall not be used together with ergotamine.[1]
