2 Overview and classification Macrolide antibiotics are mainly extracted from Streptomyces culture solution, and their structures are the same as macrolides. Macrolide antibiotics are named because they contain 14 yuan, 15 yuan and 16 yuan macrolide rings, and their molecules contain lactone structures. It has definite curative effect and no serious adverse reaction. It is often used as the first choice drug for aerobic gram-positive bacteria, gram-negative bacteria and anaerobic cocci, and can also be used as a substitute drug for patients allergic to β -lactam antibiotics.
Macrolide antibiotics have the following chemical structures:
1 and1macrolides in 4 yuan, including erythromycin, hypocrellin, clarithromycin, roxithromycin and dirithromycin.
2. 15 yuan macrolides containing azithromycin.
3. Macrolides 16 yuan, including midecamycin, acemidecamycin, kitasamycin, acekitasamycin, josamycin, spiramycin, acetylspiramycin, gyramycin, etc.
3 main varieties 1. Major macrolide antibiotics developed in the early stage:
Its representative varieties are: erythromycin ethylsuccinate (recorded in China, Britain, the United States and Japanese Pharmacopoeia); Erythromycin estolate (recorded in Pharmacopoeia of China, the United States and the United Kingdom); Erythromycin lactate (recorded in Pharmacopoeia of China, the United States and the United Kingdom); Erythromycin ascorbate; Erythromycin thiocyanate and erythromycin gluconate (in British Pharmacopoeia); Erythromycin, ethyl carbonate and so on.
2. Major macrolide antibiotics developed in recent years:
Roxithromycin, azithromycin, clarithromycin, dirithromycin and fluoroerythromycin.
4 Characteristics of Action * * The same characteristics of this kind of drugs are as follows: ① The antibacterial spectrum is narrow, slightly wider than penicillin, and it mainly acts on aerobic gram-positive bacteria, negative cocci, anaerobic bacteria, Legionella, Campylobacter fetus, chlamydia and mycoplasma; ② The cross-resistance of bacteria to these drugs is incomplete; ③ It has strong antibacterial activity in alkaline environment, so it is often necessary to alkalize urine to treat urinary tract infection; ④ It is not acid-resistant after oral administration, and esterified derivatives can increase oral absorption; ⑤ The concentration of blood drug is low, and the concentration in tissue is relatively high, which is obviously higher than that in sputum, subcutaneous tissue and bile; ⑥ It is not easy to penetrate the blood-brain barrier; ⑦ Intestinal and hepatic circulation is mainly excreted by bile; ⑧ Low toxicity. The main side effect after oral administration is gastrointestinal reaction, and intravenous injection is easy to cause thrombophlebitis.
The mechanism of action of macrolide antibiotics is mainly to inhibit bacterial protein synthesis. The mechanism is that it irreversibly binds to the target site of bacterial ribosome 50S subunit. 14 macrolides block the transfer of peptide tRNA, while 16 macrolides inhibit the transfer of peptide and selectively inhibit the synthesis of protein. In the process of protein synthesis in bacterial cells, 70S ribonucleoprotein is divided into 50S and 30S subunits. Macrolide antibiotics bind to the 50S subunit of ribonucleoprotein to inhibit peptide acyltransferase, thus affecting the translocation process of ribonucleoprotein, hindering the growth of peptide chain and inhibiting the synthesis of bacterial protein. These drugs belong to static bacteriostatic agents.
6 Drug resistance and its mechanism There are several ways for bacteria to produce and resist macrolide antibiotics:
1, producing inactivated enzyme? A variety of inactivation enzymes were isolated from bacteria induced by macrolide antibiotics. These enzymes inactivate macrolide antibiotics through hydrolysis, phosphorylation, acetylation or nucleosides.
2. What is the structural change of the target site? Bacteria can produce resistance genes to macrolide antibiotics, thus synthesizing a methylase, which methylates the drug binding sites of ribosomes and produces drug resistance.
3. Decreased intake and increased outflow? Bacteria resistant to macrolide antibiotics can change membrane components or produce new components, resulting in a decrease in the amount of macrolide antibiotics entering bacteria, but the affinity of drugs to ribosomes remains unchanged.
It is worth noting that bacterial drug resistance is developing from single drug resistance to multiple drug resistance. For example, bacteria can simultaneously develop resistance to macrolide lincomycin streptomycin (MLSR).
Clinical application of macrolide antibiotics 7 macrolide antibiotics are mainly used for the following infectious diseases.
(1) respiratory system: used to treat respiratory tract infection caused by staphylococcus; Tonsillitis caused by streptococcus; Oropharyngeal and respiratory tract infections caused by Streptococcus viridis; Oral cavity, pharynx, tonsil and oral cavity infection caused by diphtheria Bacillus; Pertussis caused by Bordetella pertussis; Erythromycin can be used as the first choice for Legionella pneumonia and mycoplasma pneumonia. Oral and pharyngeal infections caused by Bacteroides.
(2) Urogenital system: mainly used for infection of urinary system, genitals and other parts caused by streptococcus faecalis; Gonorrhea caused by gonococcus; Infection of mucous membrane and external genitalia caused by helicobacter pylori.
(3) Other systems: mainly used for Q fever, typhoid fever and typhus caused by rickettsia; Skin anthrax, intestinal anthrax, pulmonary anthrax and meningitis caused by Bacillus anthracis; Gas gangrene caused by tetanus and Clostridium; Diseases caused by leptospira, such as jaundice hemorrhage, pulmonary hemorrhage and influenza typhoid fever; Hepatosplenomegaly and lymphadenopathy caused by Brucella.
There are many examples of diseases in which macrolide antibiotics are used. Its uniqueness is mainly used to treat respiratory tract infection, mycoplasma, chlamydia pneumoniae, Legionellosis, whooping cough, diphtheria carrier, tinea rubrum (dermatitis caused by Corynebacterium) and so on. This kind of antibiotics has definite curative effect and low price, and has become the first choice for diseases caused by sensitive microorganisms.
Midecamycin, spiramycin, acetylspiramycin and josamycin are mainly used for mild patients with respiratory tract, skin and soft tissue, eyes, ears, nose, throat and oral cavity infections caused by Gram-positive bacteria.
In addition to the above indications, azithromycin can be used for Legionellosis, azithromycin and clarithromycin can also be used for community-acquired respiratory infections caused by Haemophilus influenzae and Moraxella catarrhalis, and combined with other antibacterial drugs for the treatment and prevention of Mycobacterium avium combined infection. Clarithromycin combined with other drugs can be used for Helicobacter pylori infection.
8 Adverse reactions of macrolides (1) Gastrointestinal reactions: Gastrointestinal reactions are the fastest and most intuitive adverse reactions after oral administration of these drugs, which can cause nausea, vomiting, loss of appetite, abdominal pain and diarrhea. The symptoms can be alleviated after stopping the drug. You can avoid taking medicine on an empty stomach. If the reaction is serious but this kind of medicine must be used, Smecta can be taken orally half an hour before taking the medicine or vitamin B 6 can be added to relieve the symptoms without affecting the curative effect.
(2) Local * * *: Injection can cause local * * *, so this kind of drug is not suitable for intramuscular injection, and intravenous injection can cause thrombophlebitis, so it should be diluted to below 0.65438 0% when dripping, and the intravenous drip speed should not be too fast.
(3) Influence on vestibule: Tinnitus, hearing impairment and other symptoms may occur when intravenous administration is given, and can be recovered after stopping or reducing the dosage. Therefore, intravenous drip should not be used in large quantities or for a long time.
(4) Allergic reaction: mainly manifested as drug fever, drug eruption, etc. When the reaction is serious, the drug should be stopped.
(5) Toxicity to liver: Less toxicity to liver at normal dose. Long-term and large-scale application can cause cholestasis and increase of liver enzymes. Generally, it can be recovered after stopping the drug. However, roxithromycin, erythromycin ethylsuccinate and azithromycin after esterification are toxic to the liver, so they should be used for a short time, and should be used with caution in patients with liver insufficiency.
(6) Side effects on the central nervous system: It has been reported that clarithromycin and azithromycin have side effects on the central nervous system, including hallucinations, irritability, anxiety, dizziness, insomnia, nightmares or confusion. After stopping the drug, the symptoms gradually decreased to disappear.
(7) Some drugs easily penetrate the placenta, such as clarithromycin and azithromycin. Pregnant women and lactating women should use them with caution and stop breastfeeding when necessary.
(8) These drugs can inhibit the normal metabolism of theophylline, so they should not be combined with aminophylline drugs to prevent theophylline concentration from increasing and causing poisoning or even death. When it is necessary to use it, you should go to the hospital to monitor the plasma concentration of theophylline to prevent accidents.
(9)/kloc-children under 0/2 years old should be cautious when using this kind of drugs, because the safety test indicators for children have not been completely determined.
Precautions: When patients with liver function impairment have indications, they should reduce the dosage appropriately and check the liver function regularly.
Patients with liver disease and pregnant women should not use erythromycin ester.
Erythromycin lactobionate powder for injection must be completely dissolved in water for injection, added to normal saline or 5% glucose solution, and the drug concentration should not exceed 0. 1% ~ 0.5%, and slowly infused intravenously.
10 drug interaction erythromycin and clarithromycin are prohibited from being used with terfenadine to avoid adverse cardiac reactions.
1 1 When pregnant women explicitly use clarithromycin, they should fully weigh the advantages and disadvantages and decide whether to use it. Breastfeeding patients should suspend breastfeeding during medication.
Children's medication 12 12 children under the age of 2 should be cautious when using this kind of drugs!
Treatment of 20 Cases of Asthma with 13 Macrolide Antibiotics
From 200/kloc-0 to 2002, 40 patients with mild to moderate asthma were hospitalized in our hospital, including 20 males, aged 30-50 years. Twenty female patients, aged from 28 to 565 438 0 years old, were randomly divided into azithromycin group (group A) and conventional treatment group (group B). Group A was given azithromycin (Hubei Kangrui Pharmaceutical Co., Ltd.) in addition to routine treatment (inhaling 200 μg of pulmicort respules 1 time, daily 1 time, inhaling 0.5 mg of Chuankangsu aerosol, three times a day). Group B only inhaled pulmicort respules and Chuankangsu aerosol, with the same dosage and usage as Group A, and all patients were treated before treatment (Chestgraph HI, Jester Company, Japan? 70 1 lung function meter). During the treatment, the daily change rate of PEF was monitored twice a day (MICRO SPIROMERT monitoring PEF provided by GlaxoSmithKline, UK), and symptoms such as wheezing, cough and chest tightness were recorded before and after treatment. After 5 days of treatment, the symptoms and signs in group A were relieved and basically disappeared after half a month. The dosage of Chuankangsu aerosol was halved to 0.25 mg per day, and there was no recurrence. Intermittent attacks occurred in group B during and after medication reduction. After two weeks of treatment, the forced vital capacity at 1 sec (FEV 1), the percentage of forced vital capacity at 1 sec (FEV 1%) and the maximum peak airflow (PEF) in group A were significantly higher than those in group B; The FEV 1 and FEV 1% in group a were also significantly higher after PEF treatment (P < 0.0 1,? Table 1). During the course of treatment, the daily change rate of PEF decreased gradually, with the group A being less than 20% on the first day 10, and the group B being in the second week.
Discussion:
Bronchial asthma is a chronic inflammatory disease of airway involving many inflammatory cells and cellular components, which not only makes smooth muscle contract, but also makes some other characteristics, such as changes in cell phenotype, more difficult to reverse. Azithromycin is a new generation of macrolide antibiotics with good curative effect, few adverse reactions, strong antibacterial effect, long half-life and high tissue concentration. Azithromycin plays an immunomodulatory role by influencing the production of inflammatory cytokines, inhibiting the production of iNOS and the expression of COx2 induced by LPS, and can significantly down-regulate the increase of IL-4 and IL-6 mRNA expression in peripheral blood mononuclear cells (PBMC) of patients with bronchial asthma, thus playing a role in treating asthma. This result shows that azithromycin has a significant clinical effect on mild to moderate asthma.
Ketone lactone, 14 The latest research results: A new 14 yuan macrolide, with keto group at position 3 and more than two sites of action. In the past, it had a good effect on macrolide resistant bacteria. Such as A 1957730, ABT773, HMR3562, telithromycin (HMR3647), HMR3787, RU004. TE802, TE8 10, etc. Among them, ABT773 has a strong effect on all major respiratory pathogens (including mycoplasma pneumoniae and Legionella pneumophila). HMR3647, as the first drug developed in ketolactone antibiotics, will be listed soon, and its English name is Telithromycin.
Acylate: Macrocyclic lactone whose hydroxyl group is acylated after 3-position deglycosylation. TEA0769 has twice the anti-gold grape activity as clarithromycin. The anti-faecal cocci is 0/6 times stronger than clarithromycin, and its in vivo kinetics is also better than clarithromycin. FMA 199 and DMA48 1 have excellent antibacterial activities against erythromycin-resistant Streptococcus pneumoniae, similar to HMR3647.
Carbamate 4 carbamate:14+04 and 15 yuan macrolide 4 carbamate has strong activity against both gram-positive and gram-negative bacteria in respiratory tract, including pneumococcus resistant to macrolides. The extracellular activity of CP544372 against various gram-positive drug-resistant bacteria is the same as HMR3647, and the animal test results are better than HMR3847. CP 544372 has a high plasma concentration and a long half-life (6.5 hours). It can maintain the same plasma concentration as ketolactone when administered four times a day.
Dehydrolactones: The activity of A 17946 1 with double bonds between 23 groups is lower than that of RU004, but the activities of A 185685 and A 197800 are higher than that of Ru04, which is effective against MLSC-resistant bacteria.
Erythromycin A ring 1 1, 12 carbonate: Erythromycin A ring 1 1, 12 carbonate has good antibacterial activity and high titer (2500U/mg), which is lower than erythromycin, but it is more toxic to the liver.
Polf Pharmaceutical Factory in Poland reformed the triol groups at the positions of erythromycin lactone ring 1 1, 12, and erythromycin reacted with ethylene carbonate to prepare erythromycin A ring 1 1 2 carbonate.
Erythromycin A-ring 1 1, 12 aspartate carbonate: It has strong antibacterial activity and is also active against gram-negative bacteria with low toxicity. It is reported that the therapeutic effect on experimental animal bronchopneumonia is nearly 5 times greater than erythromycin, and it is in acidic medium (pH 1. 1.2). Because of its superiority and curative effect, it is considered as a rare derivative, which deserves further study.
15 market share In China's macrolide antibiotic market, the dosage of erythromycin is gradually decreasing, while a series of derivatives such as roxithromycin, azithromycin and clarithromycin are widely used in clinic because of their good side effects. At present, domestic enterprises are competing to develop these three varieties, and the competition is fierce. It leads to overcapacity and intensified price competition, which is not conducive to the standardized development of the market.
Erythromycin: The national total output of erythromycin in China was 355.8 tons in 1996, increased to 588 tons in 1997, and remained around 550 ~ 660 tons in 1998 ~ 2000, which basically balanced with the market demand. This product 1996 ~ 1997 is active in the domestic market and rarely exported. After entering 1998, new varieties of erythromycin derivatives, such as azithromycin and roxithromycin, were listed one after another, which seized part of the erythromycin market share and cooled down the erythromycin fever. The export price of raw materials is $80/kg.
Azithromycin (azithromycin): The trade name is histamine./kloc-0 was first listed in the UK from Pfizer in September 1990, and/kloc-0 was listed in the US in September 1990. Its sales in the world market in 2000 was $65.438+38.2 million, which was 5.6% higher than that of 654.38+0.999, ranking 25th among the top 200 drugs in the world (265.438+0 among 654.38+0.999). In 2000, the amount of drugs used in domestic hospitals accounted for 1.85 of the total amount of anti-infective drugs. Macrolide antibiotics rank first in the world.
In China, besides histamine produced in Pfizer, Shumeite from Shenzhen Pharmaceutical Factory, Tai Park Jung Su from Beijing Dayang Pharmaceutical Co., Ltd. and Wei Hong from Younuokang Company have also been listed, especially Wei Hong, Yan Di (roxithromycin) and Lijunsha (erythromycin ethylsuccinate) have formed their own brands in the market. Lijunsha has been selling well in the market for many years, and its good brand awareness makes it still maintain good sales potential. Yan Di relies heavily on advertising. In 200 1 year, the sales of anti-infective drugs in the national retail market ranked sixth.
Clarithromycin is one of the macrolide antibiotics to replace erythromycin. 199 1 1 is listed by Abbott Laboratories under the approval of FDA. The product name is Kelaxian, which is listed in China. The dosage forms are tablets, sustained-release tablets, intravenous injection and dry syrup. Its dry syrup is the only oral antibiotic for children that can control major Gram-positive, Gram-negative and atypical pathogens. The global sales of this product in 1995 was10.50 billion US dollars, and in 2000 it was1/0.30 billion US dollars, ranking the best-selling drug in the world 1 1, and its clinical use in China is also expanding. In China, except clapham produced by Shanghai Abbott Pharmaceutical Company. Other brands include "Tian Wenjia New" in Zhumadian, Henan Province, and Kabis in Guangzhou Nanxin Pharmaceutical; Zhuhai Livzon Pharmaceutical, Zibo Xinhua Pharmaceutical's White; Li Maijun of Xi Anlijun Pharmaceutical; Nanjing Changao Pharmaceutical Co., Ltd. has nearly 50 companies including Aofu 'an.
Erythromycin thiocyanate: Erythromycin thiocyanate was all the rage at the Hangzhou meeting in 2000, but times have changed. By 200 1 Wuhan raw materials conference, it was affected by the price limit of erythromycin preparations by the state. The price of erythromycin thiocyanate plummeted to the lowest point in recent years, 400 yuan/100 million. In 2002, the trend of erythromycin thiocyanate declined, and the market situation was dull.
Roxithromycin: This product 200 1 was tight in the first half of the year, and went down with the trend in the second half. For a meeting in Wuhan, the price of roxithromycin is 1050 yuan/kg. This is mainly due to the sharp drop in the price of erythromycin thiocyanate, and roxithromycin preparations rushed into a frenzy. The market is close to saturation, which leads to the shortage of raw materials and the emergence of inventory. However, some manufacturers turned to export, avoiding the vicious competition of domestic low-price competition. In 2002, the price of its raw materials was stable, with the price of 1000 yuan/kg.
16 There are about 20 kinds of macrolide antibiotics commonly used in clinic in the future. They are unique in that they are used to treat respiratory infections when other antibiotics are ineffective or allergic to drugs. Erythromycin is still the first choice for mycoplasma and chlamydia pneumonia, and it has good curative effect on legionnaires' disease, whooping cough, diphtheria carrier and tinea rubrum (dermatitis caused by coryneform bacteria). The export of macrolides in China mainly includes erythromycin, spiramycin and acetylspiramycin. In the era of rapid expansion of synthetic antibiotics and β -lactam antibiotics, macrolides still have their own expansion space. At present, all commonly used macrolides have been produced in China, and erythromycin thiocyanate as an intermediate has become an important export commodity.
Compared with erythromycin thiocyanate, clarithromycin and azithromycin are new macrolides, but their production and marketing scale has not yet formed. However, they have become a new growth point for the export of APIs. At present, their main export destinations are concentrated in Southeast Asia and the European Union. The main export destination of clarithromycin is Spain in the European Union, and the export is mainly trading companies.
According to relevant data, in 2003, the consumption of macrolides in anti-infective drugs in hospitals in China rose to the fourth place, accounting for about 7% of the market, and their raw materials are new export growth points. In view of this, many enterprises have begun to expand their product production capacity. In September, 2004, Ningxia Qiyuan Pharmaceutical Company's 2000-ton erythromycin project was completed and put into operation, Zhejiang Zhenyuan Pharmaceutical Company also achieved the goal of expanding the production of roxithromycin by 350 tons, and Huaxing Pharmaceutical Company transferred part of its production capacity from penicillin production to erythromycin thiocyanate production, which will further expand the production, sales and export markets of macrolides. It can be predicted that the export volume of macrolides will reach a new level in the next few years.
Macrolide antibiotics, including erythromycin and its derivatives, are attracting the attention of medical circles all over the world again. Because of its unique curative effect, continuous development of new products and continuous expansion and development of application fields, it still maintains a high growth rate in the anti-infective drug market despite the upward trend of various β -lactams and quinolones.
There is a big gap between domestic macrolide antibiotics and foreign ones. Therefore, domestic enterprises should pay attention to the development and research of erythromycin derivatives and semi-synthetic antibiotics while actively developing semi-synthetic antibiotics such as penicillin and cephalosporins.
But at the same time, we should realize that there is also a potential crisis behind the best-selling macrolide antibiotics market. According to statistics, the domestic demand for erythromycin is only 60% of the production capacity. 40% of the production capacity is surplus or idle, and the production technology of erythromycin in China is low, the production cost is high, the price is not competitive in the international market, and it is restricted by many factors such as low export sales, low consumption of erythromycin in downstream products and deep-processed products, and slow growth of the domestic market. Facing the present situation of domestic macrolide antibiotic products, people in the industry believe that the introduction of foreign excellent strains: at present, Dalian Pharmaceutical Factory and Taishan Pharmaceutical Factory with high domestic level can only reach about 60 thousand fermentation units. Other foreign countries also have 890 thousand U/mg. It can be seen that the strains are very different.
The development of macrolide antibiotics should try to avoid foreign patents or joint ventures and develop new varieties that are still lacking or not produced in China. Such as telithromycin, azoerythromycin, dirithromycin, etc.
Conditional research institutes with advanced technology can be combined to develop updated macrolide antibiotic products, such as telithromycin, erythromycin derivatives and compound preparations, erythromycin A-ring 1 1, 12-aspartate, some compounds of macrolide antibiotics, new dosage forms, etc.
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