Clinical application of macrolide antibiotics, these contents must be clear!

Author: Chen Quanfeng Chief Physician Zhumadian Sixth People's Hospital Department of Internal Medicine Macrolides are a class of drugs with the basic structure of a macrolide ring.
Since their discovery and clinical application in 1952, they have played an important role in the field of anti-infection and has an antibacterial effect
.

There are many varieties of such drugs, so what are their characteristics and how should they be selected clinically? What are the common problems in use? The author makes a summary of these drugs in the references, hoping to help everyone better grasp the clinical application of such drugs
.

1 Pharmacological effects of macrolides Macrolides act on the 50s subunit of bacterial ribosomal protein, hinder bacterial protein synthesis, and belong to growth phase inhibitors
.

2 Characteristics of macrolide antibiotics (1) The antibacterial spectrum is narrow, covering aerobic G+ and G- bacteria, some anaerobic bacteria, and atypical pathogens; there is cross-resistance among different varieties
.

(2) The blood drug concentration is low, but in tissues, such as the prostate, the concentration is relatively high; the intracellular concentration is greater than the extracellular concentration, which is conducive to killing the pathogens that multiply in the cells; the drug is not easy to penetrate the blood-brain barrier; the alkaline environment It has strong antibacterial activity, so it is necessary to alkalize urine when urinary tract infection occurs
.

(3) The toxicity is low and the main adverse reactions are gastrointestinal reactions and liver function damage; it is mainly excreted through the bile, and is circulated by the enterohepatic circulation; it is not acid-resistant during oral administration, and enteric-coated tablets or esterified derivatives are often used
.

3 Main varieties of macrolide drugs According to the chemical structure and research and development sequence of macrolide drugs, clinical can be divided into three generations
.

The first generation: mainly including erythromycin, erythromycin ethylsuccinate,
etc.

In addition, there are josamycin and acetylspiramycin.
Compared with erythromycin, although these types have improved drug resistance, their liver toxicity is still obvious, and their clinical use is easy to cause poisoning, so they are rarely used at present
.

Second generation: This type of antibacterial drug is currently the most clinically used variety, mainly including clarithromycin, roxithromycin, and azithromycin
.

These drugs have the same characteristics as erythromycin, but further enhance the antibacterial activity, expand the antibacterial spectrum, and are easily absorbed orally, are stable to acid, and have fewer adverse reactions
.

The third generation: This type of drug introduces a ketone group on the 3rd carbon of erythromycin to obtain a 14-membered ring macrolide derivative, which successfully removes the induced drug resistance of the previous two generations, such as the common Terry erythromycin, and erythromycin
.

It is mainly used for the treatment of infections caused by erythromycin-resistant Streptococcus pneumoniae with low drug resistance
.

4 Characteristics of commonly used macrolide antibiotics (1) Erythromycin: widely used in respiratory, skin, soft tissue and other infections, is an alternative drug for patients allergic to β-lactam antibiotics, and is the first choice for the treatment of Legionella pneumonia ; Due to its relatively narrow antibacterial spectrum, easy to produce drug resistance, low bioavailability, large application dose, and common adverse reactions, especially gastrointestinal reactions are relatively serious, which limits its clinical application
.

(2) Erythromycin ethylsuccinate: ethyl succinate of erythromycin, which is more stable than erythromycin and releases erythromycin after oral administration
.

In addition to cerebrospinal fluid and brain tissue, it is widely distributed in various tissues and body fluids, especially in liver, bile and spleen.
10 to 40 times the concentration of the drug, it can pass through the placental barrier and can also enter breast milk
.

The antibacterial spectrum and antibacterial effect are similar to those of erythromycin, and liver toxicity is more common than other erythromycin preparations.
Patients may experience fatigue, nausea, vomiting, abdominal pain, rash, and fever after taking the drug for several days or 1 to 2 weeks
.

Jaundice can sometimes occur, which can be recovered after stopping the drug
.

(3) Clarithromycin: rapid and complete absorption, excellent tissue penetration, and high intracellular concentration
.

Compared with erythromycin, clarithromycin enhanced the antibacterial activity, expanded the antibacterial spectrum, and had better antibacterial activity against Staphylococcus aureus and Streptococcus than erythromycin
.

And its metabolite 14-hydroxyclarithromycin and clarithromycin have synergistic antibacterial activity
.

It is easily absorbed by oral administration, stable to acid, prolongs half-life, and reduces adverse reactions
.

Clarithromycin has strong activity against intracellular Legionella pneumophila, and has good antibacterial activity against Helicobacter pylori; experiments have shown that it has antibacterial activity against Mycobacterium avium, Mycobacterium chelae, Mycobacterium molluscs and leprosy in vitro and in vivo Bacilli also have antibacterial activity
.

(4) Azithromycin: completely absorbed, with long serum and tissue half-life (24-96 h), with post-antibiotic effects
.

Due to the presence of protonated tertiary amino groups in the structure, it has a higher affinity for tissues, and its concentration is higher in leukocytes, macrophages and fibroblasts (including lung, tonsil, prostate, etc.
), and the concentration in tissue is higher than that in blood.
The medium concentration is 10 to 100 times higher
.

Azithromycin, unlike clarithromycin, has no effect on the hepatic drug metabolizing enzyme CYP
.

It has a broad antibacterial spectrum and has stronger antibacterial activity against Gram-positive bacteria, especially Haemophilus influenzae and Enterobacter
.

The intracellular complex (MAC) activity against Chlamydia trachomatis, Legionella pneumophila and Mycobacterium avium is similar to that of clarithromycin, and it has antibacterial activity against Salmonella, Shigella and Escherichia coli
.

(5) Roxithromycin: It has strong permeability and improves the characteristics of pharmacokinetics
.

It can produce long-lasting high concentrations in serum and tissues, and the total plasma concentration is higher than that of other macrolides
.

It can penetrate and enter phagocytic cells, and is effective for the treatment of intracellular infections such as chlamydia and legionella
.

Its antibacterial spectrum is similar to that of erythromycin.
It can be used for infections caused by Legionella, Mycoplasma pneumoniae, Chlamydia trachomatis and Ureaplasma urealyticum in addition to Gram-positive bacteria, some Gram-negative bacteria and anaerobic bacteria
.

Gastrointestinal reactions are less
.

(6) Telithromycin: Oral absorption is good, bioavailability is about 57%, absorption is not affected by food
.

Has broad-spectrum antibacterial activity, low selective resistance and cross-resistance with other macrolides
.

Due to its structural elimination of induced resistance, the application of telithromycin opens up opportunities for the increasing resistance of community-acquired respiratory pathogens to β-lactams and most macrolide antibiotics a new and important treatment avenue
.

5 How to choose macrolide antibiotics clinically? (1) Community-acquired pneumonia: The Chinese Medical Association's guidelines for the diagnosis and treatment of community-acquired pneumonia suggest that macrolides can be used alone for outpatient young adults and those without underlying diseases; Patients with the disease are advised to use macrolides in combination with beta-lactam antibiotics, or beta-lactam/beta-lactamase inhibitors, or quinolones
.

Azithromycin is effective in the treatment of community-acquired pneumonia, and the efficacy of short-course (500 mg/d, treatment for 3 days) treatment is the same as that of clarithromycin (250 mg, 2 times/d, treatment for 10 days)
.

It is worth noting that the blood concentration of azithromycin is low, if the patient is suspected of pneumococcal pneumonia, clarithromycin should be used clinically
.

(2) Streptococcal pharyngitis: For patients allergic to β-lactams, choosing erythromycin has the best cost-effectiveness ratio
.

If the patient cannot tolerate the adverse reactions of erythromycin, clarithromycin or azithromycin can be used as an alternative drug
.

(3) Sinusitis: Acute bacterial sinusitis in adults is usually caused by infection with Streptococcus pneumoniae, Haemophilus influenzae and anaerobic bacteria
.

Tests have confirmed that clarithromycin and azithromycin are equally effective as amoxicillin in the treatment of acute sinusitis
.

(4) Acute otitis media: The most common pathogens of otitis media are Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis
.

In recent years, the number of beta-lactamase-producing strains of these bacteria has increased rapidly, prompting clinicians to use macrolides as an alternative to amoxicillin
.

Both azithromycin and clarithromycin can be used to treat acute otitis media
.

(5) Helicobacter pylori infection: Clarithromycin has good in vitro antibacterial activity against Helicobacter pylori, but the bacterial clearance rate of clarithromycin monotherapy is low
.

Therefore, a proton pump inhibitor or colloidal bismuth agent plus any two of the three antibiotics, clarithromycin, amoxicillin, metronidazole or tinidazole, can be selected to form triple therapy
.

The use of triple therapy to eradicate Helicobacter pylori in the early stage of infection has a good cost-effectiveness and is worthy of clinical recommendation
.

(6) Pediatric Mycoplasma and Chlamydia pneumonia: Macrolides are the most effective drugs for the treatment of Mycoplasma pneumoniae, Chlamydia and Legionella.
Mild patients can be administered orally, while severe patients can be administered intravenously
.

At present, 10 mg/kg of azithromycin is intravenously infused every day in clinical practice for 7-10 days.
After the clinical symptoms and signs of the patient are improved, oral azithromycin is used for 3 days.

.

(7) Genitourinary system infection: Mycoplasma is one of the main pathogens of common genitourinary system infection such as simple and complex urinary tract infection, bacterial prostatitis, cervicitis
.

Studies have shown that azithromycin combined with doxycycline in the treatment of Ureaplasma urealyticum genital tract infection is more effective than doxycycline alone
.

It is also reported that the treatment of female genital tract Mycoplasma infection with azithromycin can achieve ideal therapeutic effect for 14 days
.

(8) Pseudomonas aeruginosa biofilm-related infection: Macrolide antibiotics can inhibit the synthase of polysaccharide-protein complexes, the main components of Pseudomonas aeruginosa biofilms, prevent the formation of polysaccharide-protein complexes, and destroy Pseudomonas aeruginosa Bacteria biofilm structure, promote the penetration of other antibacterial drugs, play a synergistic antibacterial effect
.

Studies have shown that erythromycin and azithromycin can enhance the permeability of anti-Pseudomonas aeruginosa drugs to biofilms, and have a synergistic effect on killing bacteria in biofilms with anti-Pseudomonas aeruginosa drugs
.

6 Adverse reactions of macrolides (1) Gastrointestinal reactions: abdominal pain, bloating, nausea and vomiting
.

(2) Liver damage: mainly cholestasis, liver parenchyma damage can also occur, but if abnormal liver function is caused by the disease, such as Legionella infection, macrolides can still be used
.

(3) Ototoxicity: mainly deafness, hearing loss, and vestibular function impairment.
It is easy to occur when the dose is higher than 4g.
It often occurs within 1-2 weeks of medication, and it occurs more often in elderly patients with poor renal function
.

(4) Thrombophlebitis: Intravenous administration is often seen, and injection into the muscle or subcutaneous can cause severe pain, local induration or even necrosis
.

(5) Cardiotoxicity: abnormal ECG, prolongation of QT interval, malignant arrhythmia, torsades de pointes, especially when combined with other drugs that may prolong cardiac QT interval, may lead to fatal arrhythmias
.

(6) Hypertrophic pyloric stenosis in infants: Clinical studies have shown that the use of macrolides during breastfeeding may increase the risk of hypertrophic pyloric stenosis in infants
.

(7) Myasthenia: Macrolide antibiotics can lead to aggravation of myasthenia symptoms and even induce the occurrence of crisis
.

7 Interactions with other drugs The macrolide antibiotic itself is a substrate of CYP3A4, and its product forms a nitrosoalkane complex with the ferrous iron of hemoglobin in CYP3A4 after liver metabolism, which inactivates the enzyme.
Inhibition is called suicidal inhibition
.

The metabolic activity of CYP450 enzymes is reduced, the substrate metabolism is slowed down, and the blood drug concentration is increased, which can reduce the clearance rate of many drugs.
The common ones are theophylline, digoxin, carbamazepine, cyclosporine, ascite Imidazole, cisapride, warfarin, statins, etc.
, so when combined with such drugs as P450 enzyme metabolism substrates, attention should be paid to monitoring the blood drug concentration and adjusting the dose to avoid increasing the side effects and adverse reactions of the drug
.

Among them, special attention should be paid to erythromycin and clarithromycin which have the strongest inhibitory effect, while azithromycin is relatively weak
.

8 Special attention points in clinical use (1) In order to reduce phlebitis, gastrointestinal reactions and avoid the occurrence of adverse reactions such as acute pulmonary edema in the clinical practice of azithromycin injection, it is advocated that high concentration and high drip rate, and low concentration and low drip rate are recommended.
, first fully dissolve with an appropriate amount of water for injection, prepare a 100mg/ml solution, then add 250ml or 500ml of 0.
9% sodium chloride injection or 5% glucose injection, and finally prepare a 1-2mg/ml intravenous drip Intravenous infusion time of every 500mg of this drug should not be less than 60 minutes, when the concentration of the drug solution is 1mg/ml, the infusion time should be 3 hours, and when the concentration is 2mg/ml, the infusion time should be 1 hour.
The concentration of the injection solution shall not be higher than 2mg/ml
.

(2) Instructions for use during pregnancy: erythromycin and azithromycin among macrolides belong to category B drugs during pregnancy; clarithromycin is category C (which can pass through the placenta
.

Animal tests show that this drug has toxic effects on embryos and fetuses), so pregnant women are prohibited! In addition, erythromycin is hepatotoxic and should not be used for a long time, and some data show that long-term use may increase the risk of cardiovascular malformations and may cause pyloric stenosis in infants
.

(3) Erythromycin lactobionate powder injection is particularly likely to cause thrombophlebitis.
When using it, it must be completely dissolved in water for injection and added to normal saline or 5% glucose solution.
The concentration of the drug should not exceed 0.
1% to 0.
5%.
drip
.

9 External antibacterial effects of macrolides In addition to broad-spectrum antibacterial activities, macrolides also have anti-inflammatory and immunomodulatory effects that are independent of antibacterial and non-steroidal activities
.

(1) Anti-inflammatory effect: Macrolides can inhibit inflammatory cells and their cytokines and inflammatory mediators, thereby exerting anti-inflammatory effects
.

(2) Regulation of airway secretion: Hypersecretion of airway mucus is an important feature of many chronic airway diseases, which can lead to airflow limitation, reduced ciliary mucus transport function, and recurrent respiratory tract infections
.

Both in vitro and in vivo experiments confirmed that macrolides can inhibit mucus hypersecretion
.

(3) Antimicrobial effects related to immune regulation: Macrolides can still interfere with bacterial protein synthesis even below the MIC, and Pseudomonas aeruginosa resistant to macrolides also has this activity, indicating that such The antimicrobial effect of a drug is not dependent on its direct antibacterial activity, but is related to its immunomodulatory effect, which is an indirect effect
.

(4) Hormone-saving effect: Many drugs have hormone-saving effect, which can reduce the dosage of hormone-dependent or resistant asthma hormones and reduce the adverse reactions of hormones.
Some studies have found that clarithromycin can inhibit IL-17 and TNFα.
Anti-inflammatory effects in hormone-insensitive allergic airway disease
.

(5) Antiviral effect: Virus infection of upper respiratory tract is an important cause of acute asthma exacerbation, of which about 60% are caused by rhinovirus
.

ICAM-1 is a rhinovirus receptor of airway epithelial cells, and macrolides exert antiviral effects by inhibiting the upregulation of ICAM-1
.

In addition, macrolides also inhibit the production of pro-inflammatory cytokines triggered by viral infection
.

(6) Gastric motility: Studies have shown that macrolide antibiotics such as erythromycin can stimulate motilin receptors and induce a large-scale gastric propulsive contraction, thereby accelerating gastric emptying and promoting gastrointestinal motility
.

Based on the above-mentioned antibacterial effects of macrolides, this class of drugs can be tested for diffuse panbronchiolitis (DPR), chronic rhinosinusitis (CRS), bronchiectasis, cystic fibrosis, severe asthma, chronic Obstructive pulmonary disease (COPD) and cryptogenic organizing pneumonia, respiratory viral infection diseases and gastric motility disorders such as gastroparesis are more suitable, especially when the above diseases are combined with sensitive bacteria infection
.

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Han Qiong.
Evaluation of the pharmacology and non-anti-infective effects of macrolide antibiotics [J].
China Modern Medicine Application, 2019, 13(09): 127-128.
[2].
Zhao Liang, Hou Chao, Zou Jun.
Review of the efficacy of combined β-lactam and macrolide antibiotics in the treatment of severe community-acquired pneumonia[J].
Northern Pharmacy,2019,16(03):72-73.
[3].
Dong Shulan , Song Youchun.
Observation of the effect of sequential therapy of macrolide antibiotics in the treatment of infantile pneumonia and its influence on the occurrence of abdominal pain [J].
China Maternal and Child Health, 2019,34(07):1593-1596.
[4].
Li Jun .
Comprehensive analysis of the adverse reactions of macrolides in 2012-2016 Wu Changgui Wan Huanying Yu Wencheng Dai Yuanrong Expert consensus on the antibacterial effects and clinical application of macrolides[J].
Chinese Journal of Internal Medicine, 2017,56(07): 546-557.