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β - lactam antibiotics

This entry is made by Project of Compilation and Application of Scientific Terms in "Popular Science China" Encyclopedia to examine.

β - lactam antibiotics (β - lactams) refer to a large class of antibiotics with a β - lactam ring in their chemical structure, including penicillin and cephalosporins, which are most commonly used in clinical practice, as well as other atypical β - lactam antibiotics such as cephalosporins, Thiamphenicols, and monocyclic β - lactams. Such antibiotics have the advantages of strong bactericidal activity, low toxicity, wide indications and good clinical efficacy. The chemical structure of this kind of drugs, especially the change of side chain, has formed many antibiotics with different antibacterial spectrum, antibacterial effect and various clinical pharmacological characteristics.

Chinese name: β - lactam antibiotics
Foreign name: β-lactams
Type: antibiotic

Action mechanism: Inhibition of cell wall mucin synthase
Include: penicillin And its derivatives
Features: Strong bactericidal activity, low toxicity, wide indications, etc

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brief introduction

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Beta lactam antibiotics are a wide variety of antibiotics, including penicillin And its derivatives cephalosporin 、 Monoamide ring 、 Carbapenems And penicillene enzyme inhibitors. β - lactams refer to those antibiotics with β - lactam ring A major class of antibiotics, basically all of which include Beta lactam Nuclear antibiotics belong to β - lactam antibiotics, which are the most widely used category of existing antibiotics, including penicillin and cephalosporins, which are the most commonly used in clinical practice, and other atypical β - lactam antibiotics such as cephalosporins, thiomycetins, monocyclic β - lactams, which are newly developed. Such antibiotics have the advantages of strong bactericidal activity, low toxicity, wide indications and good clinical efficacy. The chemical structure of this kind of medicine, especially the change of side chain, forms many differences Antibacterial spectrum Antibiotics with antibacterial effect and various clinical pharmacological characteristics.

Action mechanism

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Enzyme function of PBPs from Escherichia coli

The mechanism of action of various β - lactam antibiotics is similar, which can inhibit cell wall mucopeptide synthetase, namely penicillin Penicillin binding proteins (PBPs), which hinder the synthesis of cell wall mucopeptides, cause bacterial cell wall defects, cell expansion and lysis. In addition, the lethal effect on bacteria should also include triggering the activity of autolytic enzymes of bacteria. Mutants lacking autolytic enzymes show resistance. Animals have no cell wall and are not affected by β - lactam drugs, so this kind of drugs has selective bactericidal effect on bacteria and is less toxic to the host. In recent ten years, it has been confirmed that the special protein PBPs on the bacterial plasma membrane are the target of β - lactam drugs. The function of PBPs and their combination with antibiotics are summarized in Figure 38-1. The number, molecular weight and sensitivity to β - lactam antibiotics of PBPs on the cell membrane of various bacteria are different, but the types and physiological functions of PBPs of bacteria with similar taxonomy are similar. For example, there are 7 kinds of PBPs in Escherichia coli, PBP1A and PBP1B, which are related to bacterial prolongation. Penicillin ampicillin , Cefothiophene, etc. have high affinity with PBP1A and PBP1B, which can inhibit the growth, reproduction and extension of bacteria, and dissolve and die. PBP2 is related to the shape of tubules. Mexillin, clavulic acid and thiomycin (imipenem) can selectively combine with them, making bacteria form large round cells, stable to osmotic pressure, and can continue to grow for several generations before dissolving and dying. PBP3 has the same function as PBP1A, but its amount is small. It is related to the formation of the septum and bacterial division. Most penicillin or Cephalosporins It mainly combines with PBP1 and (or) PBP3 to form filamentous and spherical bodies, causing bacteria to deform and shrink, and gradually dissolve and die. PBP1, 2 and 3 are necessary for the survival, growth and reproduction of bacteria. PBP4, 5 and 6 are related to the activity of carboxypeptidase, and are not important for the survival and reproduction of bacteria. When antibiotics are combined with them, they have no effect on bacteria.

influence factor

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Factors influencing the antibacterial activity of β - lactam

Gram positive bacteria The structure of β - lactam differs greatly from that of negative bacteria, and different side chains connected to the mother nucleus can affect the lipophilicity or hydrophilicity of β - lactam drugs. Effective drugs must be able to enter the target PBPs on the cell membrane. The main factors affecting the antibacterial effect are:

① It is difficult for drugs to penetrate the cell wall of gram-positive bacteria or the outer membrane of lipoproteins of negative bacteria (the first barrier);

② Yes Beta lactamase (the second enzyme hydrolysis barrier);

③ Affinity to antibacterial target PBPs.

According to these factors, there are six types of effects of β - lactams currently used clinically on gram-positive and negative bacteria.

Class I: penicillin And oral penicillin V can easily penetrate the mucopeptide layer of the cell wall of gram-positive bacteria, but they cannot penetrate the outer membrane of glycoprotein phospholipid of gram-negative bacteria, so they belong to narrow spectrum and are only effective for gram-positive bacteria.

Class II includes ampicillin Carboxybenzyl penicillin Acylurea penicillin, imipenem and some cephalosporins can moderately penetrate the mucopeptide layer of the cell wall of gram-positive bacteria, but have good permeability to the outer membrane of gram-negative bacteria, so they are broad-spectrum antibacterial drugs.

Class III refers to penicillin and other penicillins that are easily destroyed and inactivated by extracellular β - lactamases of gram-positive bacteria, i.e. penicillinase, and often show obvious resistance to enzyme producing bacteria.

Class IV is isoxazole penicillin, cephalosporins I and II and imipenem, which are stable to penicillin enzyme and effective to gram-positive enzyme producing bacteria, but the structure of PBPs changed by chromosome mutation can reduce or disappear the affinity between drugs and PBPs, so it is invalid.

Class V includes acylurea penicillin (aloxicillin and mezlocillin, etc.), carbenicillin and cephalosporins of the first and second generations. When a small amount of β - lactamase in the extracellular space exists, it has antibacterial effect. When a large amount of enzyme exists, it is destroyed and ineffective.

Class VI, including the third-generation cephalosporins, aztreonam, imipenem, etc., is very stable to β - lactamases. Even if a large number of β - lactamases exist, it is still effective, but it is invalid for PBPs changed due to chromosome mutation Aminoglycoside antibiotics It is still invalid.

Drug resistance mechanism

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The mechanism of bacterial resistance to β - lactam antibiotics can be summarized as follows:

① Bacteria produce β - lactamases (penicillin enzyme, cephalosporin enzyme, etc.) to hydrolyze susceptible antibiotics and inactivate them;

② The mechanism of resistance to broad-spectrum penicillin and the second and third generation cephalosporins with stable β - lactamases produced by gram-negative bacteria is not due to the hydrolysis of antibiotics by β - lactamases, but due to the rapid and firm combination of antibiotics with a large number of β - lactamases, which makes them stay in the extracellular space, so they cannot enter the target sites (PBPs) for antibacterial action. The non hydrolytic mechanism of this β - lactamase is also called "trapping mechanism";

③ The decrease of the affinity between the target protein of PBPs and antibiotics, the increase of PBPs or the generation of new PBPs can make antibiotics lose their antibacterial effect. For example, MRSA (methicillin resistant Staphylococcus aureus) has multiple drug resistance, and its production mechanism is the result of the change of PBPs. High drug resistance lines produce a new PBP2 '(PBP2a) between the original PBP2 and PBP3, and low and moderate drug resistance lines produce more PBPs or Methicillin Caused by the decrease of affinity;

④ The permeability of cell wall or outer membrane of bacteria changes, so that antibiotics can not or rarely enter the bacteria to reach the target. The outer membrane of gram-negative bacteria is the first barrier to restrict the penetration of β - lactam antibiotics into the bacteria.

In recent years, it has been confirmed that there are two kinds of non-specific channels and specific channels for antibiotics to penetrate into the outer membrane. The outer membrane of Escherichia coli K-12 has a hydrophilic non-specific porin with a trimer structure. There are two porins, OmpF and OmpC, whose synthesis is regulated by OmpB3 gene. The diameter of OmpF is 1 nm, and many important β - lactam antibiotics are mostly diffused into bacteria through this channel. The permeability of Salmonella typhimurium OmpF and OmpC deficient mutants to cefotaxime is 10 times smaller than that of wild strains, so they are resistant to cefotaxime. The penetration of E. coli mutants containing only trace OmpF and OmpC to cefazolin and cefothiophene was also twice as low as that of wild strains, and their MIC was significantly higher, which also showed resistance. The resistance of Pseudomonas aeruginosa to β - lactam antibiotics has been proved to be caused by the defect of outer membrane non-specific pore protein OprF. The specific channel of Gram negative outer membrane in the imipenem resistant mutant of Pseudomonas aeruginosa has been proved to be due to the absence of an outer membrane protein OprD with a molecular weight of 45-46kD. If this OprD is recombined into the outer membrane protein liposome of the mutant with defective OprD, the penetrability of imipenem can be increased by more than five times, and its MIC is correspondingly reduced, so the bacterial resistance is eliminated.

⑤ Due to the lack of autolytic enzyme, bacteria are resistant to antibiotics, that is, antibiotics have normal bacteriostasis but poor bactericidal effect.

Penicillins

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Basic structure

Penicillin G is the earliest antibiotic used in clinical practice. Because of its strong bactericidal power, low toxicity, low price, convenient use and other advantages, it is still the first choice for treating various infections caused by sensitive bacteria. However, penicillin has some shortcomings, such as acid intolerance, penicillin enzyme intolerance, narrow antibacterial spectrum, and easy to cause allergic reactions, which limit its clinical application. Since 1959, people have used the mother nucleus of penicillin 6-Aminopenicillanic acid (6-APA), chemically modified, connected with different side chains, and synthesized hundreds of“ Semi synthetic penicillin ”There are many penicillins which have been used in clinic.

penicillin

Penicillin G, also known as benzyl penicillin, is a natural penicillin with benzyl as the side chain. Its sodium salt or potassium salt is commonly used. Its crystal powder is stable at room temperature and easily soluble in water. The aqueous solution is unstable at room temperature. When it is kept at 20 ℃ for 24 hours, its antibacterial activity drops rapidly and can generate antigenic degradation products. Therefore, penicillin should be prepared into an aqueous solution before use.

Antibacterial effect ：

Penicillin mainly acts on gram-positive bacteria, gram-negative cocci, haemophilus and various pathogenic spirochetes.

Penicillin pair Streptococcus hemolyticus Streptococcus viridis, pneumococcus, etc. have strong effects, but enterococcus is less sensitive. Staphylococcus aureus that does not produce penicillinase and most of the staphylococcus epidermidis are sensitive to penicillin, but the staphylococcus aureus that produces penicillinase is highly resistant to it. Gram positive bacilli, diphtheria bacilli, anthrax bacilli and gram-positive anaerobic bacilli such as Clostridium perfringens , Tetanus, Clostridium difficile, Propionibacterium, Eubacterium and Lactobacillus are all sensitive to penicillin. Meningococci in Gram negative bacteria are highly sensitive to penicillin, and drug resistance is rare. Neisseria gonorrhoeae sensitive to penicillin is increasingly rare. Bordetella pertussis is sensitive to penicillin. Pathogenic spirochetes, such as Treponema pallidum and Leptospira interrogans, are highly sensitive to them.

Internal process ：

Penicillin is easy to decompose in case of acid, and the oral absorption is poor. After intramuscular injection of 1 million units, the absorption is fast and complete, reaching the peak blood concentration in 0.5 hour, about 20U/ml, and the elimination half-life (t1/2) is 1/2 hour. Intravenous drip of 5 million units of penicillin sodium within 6 hours can obtain a blood concentration of 20~30U/ml after 2 hours. The serum protein binding rate of penicillin was 46%~58%. Penicillin is mainly distributed in extracellular fluid, lymph, placenta, liver, kidney, lung, striated muscle, middle ear fluid, etc. The lipid solubility of penicillin is low, and the amount of penicillin entering cells is reduced; The content of aqueous humor and cerebrospinal fluid is also low, but the amount of penicillin penetrating into cerebrospinal fluid and eyes during inflammation can be slightly increased to reach the effective concentration. Penicillin is almost all rapidly excreted in urine in its original form, and about 10% is filtered through the glomerulus. 90% of them are secreted through renal tubules. The elimination half-life of penicillin in anuria patients can be prolonged up to 10 hours. Probenecid can compete with penicillin for the secretion of renal tubules. When the two drugs are used together, the blood concentration of penicillin can be increased and its half-life can be prolonged.

In order to prolong the action time of penicillin, insoluble preparations can also be used Procaine penicillin (procaine penicillin) and benzathine penicillin (long-acting penicillin, bicillin). A single injection of 400000 units of procaine penicillin can last for 24 hours, and a single injection of 120000 units of benzathine penicillin can last for 15 days. The blood concentration of these two preparations is very low, and they are only used for mild patients or to prevent infection.

clinical application ：

Penicillin is used to treat hemolytic streptococcal infection and sensitivity in Group A and Group B Staphylococcal infection Gas gangrene, syphilis, rat bite fever, etc. Pneumococcal infection It can also be used with meningitis. When the pathogen is relatively resistant, vancomycin or rifampicin can be used instead. Penicillin is also the first choice for the treatment of grass green streptococcal endocarditis. It can also be used as an actinomycosis Leptospirosis , syphilis, relapsing fever, etc. and prevention Infective endocarditis The first drug to occur. Penicillin should be used in combination with antitoxin for patients with tetanus and diphtheria.

Adverse reactions ：

Penicillin has very low toxicity. In addition to its large amount of potassium salt which is easy to cause hyperkalemia and intramuscular injection pain, the most common is anaphylactic reaction, including anaphylactic shock, drug eruption, serotype reaction, hemolytic anemia and granulocytopenia. Penicillin thiazole protein, penicillenoic acid and other degradation products, penicillin or 6-APA in toxomycin preparations Polymer They can become allergens. In order to prevent various allergic reactions, the medical history should be inquired in detail, including medication history, drug allergy history, family allergy history, and penicillin skin allergy test. When penicillin and skin test are applied, first aid preparations should be made, such as epinephrine, hydrocortisone and other drugs and injection equipment, so that in case of anaphylactic shock, it can be treated in time.

When penicillin is used to treat syphilis or leptospirosis, symptoms may be aggravated, which is called Herxheimer reaction or treatment contradiction. This reaction generally occurs 6 to 8 hours after the start of penicillin treatment, and disappears in 12 to 24 hours, showing general malaise, chills, fever, sore throat, hypochondriac pain, rapid heartbeat, etc; At the same time, there may be aggravation of pathological changes, even life-threatening. This reaction may be the result of forming immune complex between spirochete antigen and corresponding antibody, or releasing with spirochete Non endotoxin pyrogen of

Notes on medication ：

Intramuscular injection can occur locally Peripheral neuritis Intrathecal injection and systemic high-dose application can cause penicillin brain pain. For severe infection, intravenous drip should be used. For large dose intravenous injection, serum ion concentration should be monitored to prevent hypernatremia and hyperkalemia.

Semi synthetic penicillin

1. Acid resistant penicillin Phenoxypenicillin includes penicillin V and phenoxyethyl penicillin. The antibacterial spectrum is the same as that of penicillin. The antibacterial activity is lower than that of penicillin. It is acid resistant and well absorbed orally, but it is not resistant to enzymes. It is not suitable for severe infection.

2. Enzyme resistant penicillin The chemical structure is characterized by protecting the β - lactam ring through the steric barrier effect of the acyl side chain (R1), making it not easy to be hydrolyzed by enzymes. It is mainly used for infection of penicillin resistant Staphylococcus aureus.

The side chain of isoxazole penicillin is phenyl isoxazole, which is acid resistant, enzyme resistant and can be taken orally. Commonly used are: Oxacillin (oxacillin, neopenicillin II), cloxacillin, Dicloxacillin (dicloxacillin) and Flucloxacillin （flucloxacillin）。

Antibacterial effect : The antibacterial spectrum and effect on drug-resistant Staphylococcus aureus of this kind of drugs are basically similar pneumonia The effect of cocci was the best, but not as good as that of penicillin. The effect of dicloxacillin on resistant Staphylococcus aureus was the strongest, followed by flucloxacillin, cloxacillin and oxacillin. There was no obvious effect on gram-negative enterobacteria or enterococci.

Internal process : Gastrointestinal absorption is good, and food residues will affect its absorption. Therefore, the drug should be taken once on an empty stomach one hour before meals, and the blood drug concentration reaches the peak value about 1-1.5 hours, and the effective concentration can be maintained for 2-3 hours. The absorption of oxacillin was the worst, followed by cloxacillin, and dicloxacillin was the best. Plasma protein binding rate Both are very high (more than 95%). It is mainly excreted from urine in prototype, and the speed is slower than that of penicillin.

Adverse reactions : Gastrointestinal reaction, individual skin rash or urticaria.

clinical application : It is used for various infections caused by drug-resistant Staphylococcus aureus, or chronic infections requiring long-term medication. For severe staphylococcus aureus infection, it is advisable to inject the drug.

3. Broad-spectrum penicillin It has bactericidal effect on both gram-positive and negative bacteria. It is also acid resistant and can be taken orally, but it is not resistant to enzymes.

(1) Ampicillin (ampicillin) is less effective against penicillin sensitive Staphylococcus aureus than penicillin, but is better than enterococcus penicillin 。 It has a strong effect on gram-negative bacteria, similar to or slightly stronger than chloramphenicol, tetracycline, etc., but not as effective as gentamicin and polymyxin against Pseudomonas aeruginosa.

In vivo process: the peak blood concentration is reached 2 hours after oral administration, and the excretion is delayed by probenecid through the kidney. Effective antibacterial concentration can be reached in body fluid, and cerebrospinal fluid concentration is high in meningitis.

Clinical application: mainly used for typhoid, paratyphoid Gram negative bacilli septicemia , lung, urinary tract and biliary tract infections, and in serious cases, aminoglycoside antibiotics should be used together.

Adverse reaction: slight gastrointestinal reaction.

(2) Amoxicillin (amoxycillin) is para hydroxy ampicillin, whose antibacterial spectrum and activity are similar to those of ampicillin, but its bactericidal effect on pneumococcus and proteus is stronger than ampicillin. It is well absorbed through the stomach and intestines, and the concentration in the blood is about 2.5 times of the oral ampicillin of the same amount. Amoxicillin for treatment lower respiratory tract infection (especially caused by pneumococcus) has more effect than ampicillin.

(3) Piamcillin (pivampicillin) is a double ester of ampicillin, which is better in oral absorption than ampicillin, and can be quickly hydrolyzed into ampicillin to play an antibacterial role. Normal people took 250mg orally, and their blood and urine concentrations were 3 and 2 times higher than those of ampicillin at the same dose.

4. Broad-spectrum penicillin against pseudomonas aeruginosa

(1) Carboxybenzyl penicillin The antibacterial spectrum of carbenicillin is similar to that of ampicillin. It is characterized by strong effect on Pseudomonas aeruginosa and Proteus. The oral absorption is poor, and it needs injection. The effect is prolonged when the renal function is damaged. It is mainly used for various infections caused by Pseudomonas aeruginosa and Escherichia coli. When used alone, bacteria are prone to drug resistance, often used with gentamicin, but not mixed with intravenous injection. It has low toxicity and occasionally causes granulocyte deficiency and bleeding.

⑵ Sulfobenzicillin The antibacterial spectrum of (sulbenicillin) is similar to that of carbenicillin, and its antibacterial activity is strong. It is ineffective after oral administration. The drug concentration in bile is three times that in blood, and the concentration in urine is particularly high. It is mainly used to treat urogenital tract and respiratory tract infections. The side effects were gastrointestinal reaction, occasionally rash, fever, etc.

(3) Tecacillin The antibacterial spectrum of (ticarcillin) is similar to that of carbenicillin, and its anti Pseudomonas aeruginosa activity is 2-4 times stronger than that of carbenicillin. The activity against gram-positive cocci was lower than that of penicillin, and it was not absorbed after oral administration. The peak blood concentration was reached 0.5~1.0 hours after intramuscular injection. It is widely distributed, with high concentration of drugs in bile, and most of them are excreted through the kidney. It is mainly used for various infections caused by Pseudomonas aeruginosa.

⑷ Furbenicillin (furbenicillin) is 6~10 times stronger against Pseudomonas aeruginosa than carbenicillin, and also has strong antibacterial effect against Staphylococcus aureus, Streptococcus, Shigella, etc. The side effects are the same as carbenicillin.

(5) Aloxacillin The antibacterial spectrum of azlocillin is similar to that of carbenicillin, and its antibacterial activity is similar to that of piperacillin, but stronger than that of carbenicillin. It has strong effect on most Enterobacteriaceae bacteria, Enterococcus and Pseudomonas aeruginosa. It also has a good effect on Pseudomonas aeruginosa resistant to carbenicillin and gentamicin. It is mainly used to treat infections caused by Pseudomonas aeruginosa, Escherichia coli and other enterobacteriaceae bacteria.

(6) Piperacillin Piperacillin has a broad antibacterial spectrum similar to that of carbenicillin, but its antibacterial effect is strong, and it has a certain effect on various anaerobic bacteria. In combination with aminoglycosides, it has synergistic effect on Pseudomonas aeruginosa, some fragile Bacteroides and Enterobacteriaceae. Except for the penicillin producing staphylococcus aureus, it is very sensitive to other gram-negative cocci and anthrax. There are few adverse reactions, which can be used for intramuscular and intravenous administration. At present, it has been widely used in clinic.

Cephalosporins

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Basic structure

Cephalosporins quickly seize the market

Cephalosporin antibiotics are derived from the mother nucleus of cephalosporin 7-aminocephalosporanic acid (7-ACA) semi synthetic antibiotic made by connecting different side chains. This kind of antibiotics has the advantages of broad antibacterial spectrum, strong bactericidal power, stable to gastric acid and β - lactamase, less allergic reaction (only partial cross allergy with penicillin), etc. According to its antibacterial characteristics and different clinical applications, it can be divided into four generations of cephalosporins.

Classification characteristics

The first generation cephalosporins, such as cefalexin, cefradine, cefazolin, etc

① The antibacterial effect on gram-positive bacteria (including penicillin sensitive or drug-resistant Staphylococcus aureus) is stronger than that of the second and third generations Gram negative bacteria The role of the;

② It is stable to penicillinase, but can still be destroyed by β - lactamase of gram-negative bacteria;

③ It is toxic to kidney.

Second generation cephalosporins such as cefuroxime, cefmendor, cefaclor, etc

① Effect on gram-positive bacteria First generation cephalosporins Similar or slightly worse, the effect on most gram-negative bacteria is significantly enhanced, some are effective on anaerobic bacteria, but ineffective on Pseudomonas aeruginosa;

② It is relatively stable to a variety of β - lactamases;

③ The toxicity to kidney is lower than that of the first generation.

The third generation cephalosporins, such as cefotaxime, ceftazidime, ceftriazine, cefoperazone, cefzoxime, etc

① It has considerable antibacterial activity against gram-positive bacteria, but is inferior to the first and second generation cephalosporins. It has strong effects on gram-negative bacteria, including Enterobacter, Pseudomonas aeruginosa and anaerobic bacteria, such as Bacteroides fragilis;

② Its plasma t1/2 is longer, widely distributed in the body, and has strong tissue penetration, with a certain amount of infiltration into cerebrospinal fluid;

③ It has high stability to β - lactamase;

④ It is basically non-toxic to kidney.

The fourth generation cephalosporins, such as cefepime, cefpirome, etc

1. Compared with third-generation cephalosporins The affinity of β - lactamase is reduced, the stability of AmpC enzyme is higher, and the penetration of bacterial cell membrane is stronger.

2. The antibacterial spectrum is wider. Staphylococcus sensitive to methicillin and some class I enzyme negative bacteria, such as Enterobacteriaceae, Citrobacter freudii, Serratia, Morganella malignificans, have strong antibacterial effects.

3. Its antibacterial activity against Pseudomonas aeruginosa is similar to or slightly worse than that of ceftazidime, and it also has good antibacterial activity against anaerobic bacteria.

4. The half-life of the blood drug was prolonged, and there was no nephrotoxicity.

Antibacterial mechanism

The antimicrobial spectrum is wide, most Gram positive bacteria are sensitive to it, but enterococci are often resistant; Most gram-negative bacteria are extremely sensitive. Except for a few cephalosporins, Pseudomonas aeruginosa and anaerobes are often resistant. This kind of medicine has synergistic antibacterial effect with penicillin and aminoglycoside antibiotics.

Cephalosporins are bactericides. Their antibacterial mechanism is similar to that of penicillin, and they can also bind to different penicillin binding proteins (PBPs) on the cell wall.

There are some cross resistance phenomena between bacteria to cephalosporins and penicillins.

Internal process

More injections are needed. But cefalexin, cefadroxil and cefaclor are acid resistant, well absorbed in the gastrointestinal tract, and can be taken orally.

After absorption, cephalosporins are well distributed, can penetrate into various tissues, and easily penetrate the placenta. High concentration can be obtained in bursal fluid and pericardial effusion. Cefuroxime and the third generation cephalosporins can be distributed in the prostate. The third generation cephalosporins can also penetrate ocular aqueous humor. The concentration in bile is also high. Among them, cefoperazone is the highest, followed by ceftriaxone. Cefuroxime, ceftriaxone, cefotaxime, ceftazidine, cefoperazone, etc. can penetrate the blood brain barrier and reach effective concentration in cerebrospinal fluid. The plasma t1/2 of most cephalosporins is relatively short (0.5~2.0 hours), but the t1/2 of ceftriaxone is the longest, up to 8 hours.

Adverse reactions

Allergic reaction is common, and anaphylactic shock, asthma and rapid rash can be seen occasionally. About 5%~10% of penicillin allergic patients have cross allergic reaction to cephalosporin; Phlebitis may occur after intravenous administration; The first generation of cephalothiophene, ceftazidime and cefalexin can cause nephrotoxicity in large doses, which is related to the damage of proximal tubular cells. Since the sodium content of cephalosporin sodium salt can reach 2.0~3.5Eq/g, attention should be paid to the occurrence of hypernatremia during a large amount of intravenous injection.

Cefmondo, cefoperazone, etc. may appear Disulfiram like reaction The third generation cephalosporins occasionally have double infection or the proliferation of enterococcus, pseudomonas aeruginosa and candida. High dose of cefmendor and cefoperazone may appear Hypoprothrombinemia 。

clinical application

The first generation cephalosporins are mainly used for drug resistant Staphylococcus aureus infection. Cefothiophene, cefradine and cefazolin are commonly used. The latter has the highest intramuscular blood concentration among cephalosporins and is the most widely used variety in the generation. Oral cephalosporins are mainly used for mild to moderate respiratory and urinary tract infections.

The second generation cephalosporins are used to treat pneumonia, biliary tract infection, bacteremia, urinary tract infection and other tissue and organ infections caused by sensitive bacteria such as Escherichia coli, Klebsiella, Enterobacter, Indole positive Proteus. Cefuroxime and cefmendor are widely used.

The third generation cephalosporins can achieve satisfactory results in the treatment of urinary tract infections, life-threatening septicemia, meningitis, pneumonia and other serious infections. The third generation cephalosporins can also be used to treat meningococcal pneumonia. Ceftadine is currently the strongest antibiotic against Pseudomonas aeruginosa in clinical application, and cefoperazone can also be selected. Ceftriaxone and cefotaxime are similar to enterobacteriaceae bacteria, but cefoperazone is slightly worse. The third generation cephalosporins should be selected for neonatal meningitis and adult meningitis caused by enterobacteriaceae bacteria.

Atypical category

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Atypical β - lactam antibiotics

cephamicins

Cephalomycin obtained β - lactam antibiotics from Streptomyces, including type A, B and C, and type C is the strongest. It has a broad antibacterial spectrum, strong effect on gram-negative bacteria, and is stable to a variety of β - lactamases. The chemical structure of cephalosporin is similar to that of cephalosporin, but there is methoxy group on the 7th carbon of cephalosporin mother nucleus. At present, cefoxitin is widely used. Its antibacterial spectrum and antibacterial activity are the same as those of the second generation cephalosporins. It has good effects on anaerobic bacteria, including Bacteroides fragilis, and is suitable for pelvic infection, gynecological infection, abdominal cavity and other aerobic and anaerobic mixed infections.

Laoxycef

Latamoxef, also known as moxalactam, has a chemical structure of oxycephem. The sulfur at position 1 is replaced by oxygen, and the methoxy group at position 7 is also present. It has a wide antibacterial spectrum, and its antibacterial activity is similar to that of cefotaxime. It has a strong effect on gram-positive and negative bacteria and anaerobic bacteria, especially on Bacteroides fragilis. It is extremely stable to beta lactamase, and its blood concentration has been maintained for a long time.

β - lactamase inhibitor

1. Clavulanic acid (clavulanic acid) is a broad spectrum of oxypenicillanes β - lactamase inhibitor The antibacterial spectrum is wide, but the antibacterial activity is low. When combined with a variety of β - lactam antibiotics, the antibacterial effect was significantly enhanced. The clinical use of augmentin (aminothalin) and timentin (timentin) is the preparation of clavulanic acid, amoxicillin and ticarcillin respectively.

2. Sulbactam (penicillin sulfone) is a semi synthetic β - lactamase inhibitor, which has a strong and irreversible inhibitory effect on β - lactamases produced by Staphylococcus aureus and Gram negative bacteria. Its antibacterial effect is slightly stronger than clavulanic acid, but it needs to be used together with other β - lactam antibiotics to have obvious antibacterial synergy. Unasyn is a mixture of sulbactam and ampicillin (1:2) for intramuscular or intravenous injection. Sulperazone is a mixture of sulbactam and cefoperazone (1:1), which can be used for intravenous drip.

Monocyclic beta lactams

Aztreonam is the first monocyclic β - lactam antibiotic successfully used in clinical practice. It has a strong bactericidal effect on aerobic gram-negative bacteria, and has the advantages of enzyme resistance, low toxicity, no cross allergy to penicillin, etc. It can be used in patients with penicillin allergy and is often used as a substitute for aminoglycosides.

Carbapenems

Carbapenems Antibiotics are The broadest antibacterial spectrum ， The strongest antibacterial activity Because of its stability to β - lactamase and low toxicity, the atypical β - lactam antibiotics have become one of the most important antibiotics for the treatment of severe bacterial infections. Thienamycin belongs to carbapenems in chemical structure. The thiazole ring has a saturated chain, and the sulfur at position 1 is replaced by carbon. It has a wide antibacterial spectrum, strong antibacterial effect, low toxicity, but poor stability and no practical significance. Imipenem has the characteristics of high efficiency, wide antibacterial spectrum, enzyme resistance, etc. It is easily inactivated by dehydropeptidase hydrolysis in vivo. It is a mixture of this product and cilastatin, a peptidase inhibitor, called Tai Tienam, good stability, for intravenous drip.

Carbapenem antibiotics are a new class of β - lactam antibiotics, which are modified from penicillin structure. They came out in the 1980s. Its structure is similar to the penicillium ring of penicillins, but the difference is that the sulfur atom on the thiazole ring is replaced by carbon, and there is a Unsaturated double bond ； In addition, its 6-position hydroxyethyl side chain is Trans conformation 。 It has been proved that it is this group with special configuration that makes this kind of compound significantly different from the cis conformation of common penicillenes Ultra broad spectrum and strong antibacterial activity , and Beta lactamase High stability. At present, Taineng (imipenem cilastatin) and meropenem are commonly used.

Preparation and usage

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Penicillin G potassium or sodium, penicillin G sodium， Benzicillin potassium or sodium) is prepared into a solution before use, generally 400000-800000 units/time, intramuscular injection, common infection 2 times/day, severe infection 4 times/day, and the daily total can be increased if necessary. In case of severe infection, it can be used as intravenous drip, but potassium salt should not be injected intravenously. The potassium content (39 mg potassium ion per 600000 units of penicillin potassium salt) should also be calculated during drip, and attention should be paid to the drip speed to prevent excessive blood potassium. When the dosage is large or the patient's renal function is not complete, sodium salt infusion should be used instead.

Procaine penicillin (400000 units/time, once/day, intramuscular injection) can produce quick and long-term effects.

Benzathine benzylpenicillin is injected intramuscularly once to twice a month for adults and once a month for children, 600000 to 1.2 million units per time.

Oxacillin sodium (neopenicillin Ⅱ) is 0.5~1.0 g/time for adults, 4~6 times/day, and 50~100 mg/kg/day for children, divided into 4~6 times. It should be taken 1 hour before meals or 2 hours after meals to avoid food interference. The intramuscular injection dose is the same as that of oral administration and intravenous drip, 4~6g/day for adults and 50~100mg/kg/day for children.

Cloxacillin sodium 250~500mg/time for adults, 2~4 times/day; Children: 30~60mg/kg/day, 2~4 times orally. Intramuscular injection dose is the same as oral administration.

Dicloxacillin is given to adults 1 ～ 3g/day and children 30 ～ 50mg/kg/day in four times.

Flucloxacillin is 0.125-0.25g/time for adults, four times a day or 0.5-1.0g three times a day.

Ampicillin for adults 0.25~1g/time, 4 times/day; Children shall take 20 ～ 80mg/kg/day in four times. Intramuscular injection dose is the same as oral administration. Intravenous injection or intravenous drip, 2~6g/day for adults and 50~150mg/kg/day for children.

Amoxicillin (amoxycillin) 0.3~0.6g/time for adults, 3~4 times a day, and 0.15 g/time for children under 10 years of age, 3 times a day.

Pivampicillin is mildly and moderately infected, 1.5~2.0 g/day for adults, 3~4 g/day for severe infection, and 40~80 mg/kg/day for children. It is taken separately for 3~4 times.

Carbenicillin was injected intramuscularly for 4 g/day in adults and 100 mg/kg/day in children. Intravenous injection or intravenous drip is used for Pseudomonas aeruginosa infection, 10~20g/day for adults and 100~400mg/kg/day for children.

Furbenicillin is administered intravenously or intravenously 4 times a day for adults (4-8 g/day) and 50-150 mg/kg/day for children (50-150 mg/day).

Sulbenicillin is 2~4g/day for adults, 8~13g/day for severe cases, intramuscular injection, intravenous injection or intravenous drip in batches, 40~160mg/kg/day for children.

Ticarcillin is injected intramuscularly or intravenously in the same dose as carbenicillin or sulfabenzylpenicillin.

Piperacillin is 4-8 g/day for adults and 100-150 mg/kg/day for children; Intravenous injection, 8~16g/day for adults and 100~300mg/kg/day for children, all in four times.

Mexillin (1.6 ～ 2.4 g/day for adults and 30 ～ 50 mg/kg/day for children) was injected intravenously or intramuscularly four times.

Cephalothin sodium (Cephalosporin I) 0.5g/time, 4 times/day, intramuscular injection for adults; In case of severe infection, 2~4g per day, intravenous injection or intravenous drip.

Cephaloridine is 0.5~1.0 g/time for adults, 2-3 times/day, intramuscular injection, and the daily dose does not exceed?? Take it 3-4 times.

For adults, cefazolin is 500 mg/time, 2-4 times/day, intramuscular injection or intravenous injection, and the dose can be increased to 3-5 g/day if the disease is serious or drug resistant strains. The dosage for children is 20-100mg/day.

Cefradine is taken by adults 1~4g/day, four times. For severe patients, it can be injected intravenously, not exceeding 8g/day, and children 50~100mg/kg/day, four times.

Cefadroxil (cefadroxil) 2 g/day for adults, taken twice; Children shall take 30~60mg/kg/day, divided into 2~3 times.

Cefamandole was given intramuscularly for 2-4 g/day in adults and 50-100 mg/kg/day in children. Intravenous injection of 8~12g/day for adults and 100~200mg/kg/day for children, divided into 2~4 times.

Cefuroxime was injected intramuscularly for 3 to 4 times, 2 to 2.5 g/day for adults and 30 to 60 mg/kg/day for children. Intravenous injection, 4.5~6g/day for adults and 50~100mg/kg/day for children, divided into 2~4 times.

Cefaclor is given to adults 2-4g/day in four doses.

Cefotaxime is injected intramuscularly for adults 2~6g/day and children 50~100mg/kg/day for 3~4 times; Intravenous injection, 2~8g/day for adults and 50~150mg/kg/day for children, divided into 2~4 times.

Ceftriaxone was injected intramuscularly, 1g/day, dissolved in 3.5ml lidocaine injection, and injected deeply. For intravenous drip, 0.5~2g/day for adults, dissolve in normal saline or 5% glucose solution at one time, and drip for 30 minutes.

Ceftazidime is 1.5~6g/day for adults and 50~100mg/kg/day for children. It is injected intravenously three times, fast intravenous drip or intramuscular injection. The latter is generally dissolved in 0.5ml of 1% lidocaine and injected deeply.

Cefoperazone is given by intravenous drip, intravenous injection or intramuscular injection 2-3 times for adults 2-4g/day and children 50-150mg/kg/day.

Cefoxitin is administered intravenously 3 to 8 g/day for adults, 3 to 4 times, and 45 to 120 mg/kg/day for children, 4 to 6 times, or intramuscularly.

Latamoxef (latamoxef) is administered intravenously twice, intravenously or intramuscularly, 1-2 g/day in adults, and 4 g/day or higher in severe cases. 40~80mg/kg/day for children, and 150 mg/kg/day for serious cases, which can be injected in 2~4 times.

Imipenem is given intravenously to adults 1~2g/day in four times, and should be combined with dehydropeptidase inhibitors, such as Tylenol.

Aztreonam is 1.5~6g/day for adults, divided into three times, intramuscular injection, intravenous injection or intravenous drip (the drug is added to 100ml normal saline, and the drip is completed within 30 minutes).

Harmful effects

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side effect

Side effects of β - lactam antibiotics include diarrhea, dizziness, rash Urticaria , overlapping infection (including Candida ）(Rossi, 2004) Occasionally, β - lactam antibiotics can also cause fever, vomiting, erythema, dermatitis Angioedema and Pseudomembranous enteritis (Rossi, 2004)

When β - lactam antibiotics and β - lactamase inhibitors are used together, the injection site will often be painful and inflamed.

allergy

About 10% of patients are allergic to β - lactam antibiotics. About 0.01% of patients will have Anaphylactic reaction (Rossi, 2004). About 5-10% of patients have cross sensitivity to penicillin derivatives, cephalosporins and carbapenems. However, different scholars question this conclusion.

Nevertheless, if a patient has already shown severe allergic reaction to one β - lactam antibiotic, it must be carefully considered when giving him other β - lactam antibiotics.

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