What Is Cephalosporin?

Cephalosporins (Cephalosporins) are a series of semi-synthetic antibiotics obtained by modifying the side chain of cephalosporin C isolated from the cephalosporin culture medium. Its advantages are: a broad antibacterial spectrum, high efficiency against anaerobic bacteria; lower allergic reactions than penicillins; stable to acids and -lactamase produced by various bacteria; the mechanism of action is the same as penicillin, and it also inhibits the cell wall To achieve the purpose of sterilization. Is a breeding period fungicide. Due to its lower adverse reactions and lower toxic and side effects, it is currently a class of antibiotics that are being developed rapidly.

Cephalosporins (Cephalosporins) are a series of semi-synthetic antibiotics obtained by modifying the side chain of cephalosporin C isolated from the cephalosporin culture medium. Its advantages are: a broad antibacterial spectrum, high efficiency against anaerobic bacteria; lower allergic reactions than penicillins; stable to acids and -lactamase produced by various bacteria; the mechanism of action is the same as penicillin, but also inhibits the bacterial cell wall To achieve the purpose of sterilization. Is a breeding period fungicide. Due to its lower adverse reactions and lower toxic and side effects, it is currently a class of antibiotics that are being developed rapidly.

Chinese name

Cephalosporins

Foreign name

Cephalosporins

Advantages

Broad antibacterial spectrum, highly effective against anaerobic bacteria

Clinical application

Respiratory infection, urinary tract infection

Four generations of cephalosporins

It is a new-generation cephalosporin that has been used in clinical practice abroad in recent years. Compared with the third-generation cephalosporin, the antibacterial spectrum is broader, the antibacterial activity is stronger, and the -lactamase produced by bacteria is more stable. At present, it has begun to be applied in China, but it is estimated that it will soon be applied to domestic clinical. This article outlines the concept, classification, and characteristics of the fourth-generation cephalosporins, and looks forward to the application prospects of this class of drugs in clinical departments such as the respiratory department.

Classification of cephalosporins

The fourth-generation cephalosporin was developed from the third-generation cephalosporin, but it is a new-generation cephalosporin that is significantly different from the third-generation cephalosporin. Structurally, based on the molecular structure of the third-generation cephalosporin, it introduced a C-3 quaternary ammonium substituent at the C-3 position of the 7-aminocephalosporanic acid (7-ACA) mother nucleus; from the mechanism of action For example, the above structural changes allow it to pass through the outer membrane of Gram-negative bacteria more quickly, have higher affinity for penicillin-binding proteins, and be more stable to bacterial -lactamase; from the antibacterial spectrum, It has stronger antibacterial activity against Gram-positive cocci [1]. According to the different side chains on the C-7 position of the molecular structure, it can be divided into two subclasses: 2-amino-5thiazole subclass and 5-amino-2-thiazole subclass. The classification and variety of the fourth-generation cephalosporins are shown in Table 1 [2].

Table 1 Classification of fourth-generation cephalosporins

2-amino-5thiazole subclass 5-amino-2-thiazole subclass

cefpirome cefclindin

cefepime cefozopran

cefoselis cefluprenam

cefquinone FK-518

CP6679 YM-40220

CS-461 L-640876

DN9550 L-642946

DW-751 L-652831

MT520

TOC-39

Cefpirome and cefepime have been marketed abroad and used in the clinic.

Cephalosporins Features

Broader antibacterial spectrum

Cefpirome and cefepime have stronger antibacterial activity against Enterobacteriaceae than ceftazidime and cefotaxime. They have better antibacterial activity against cefotaxime but slightly lower than ceftazidime. However, it is worth noting that the bactericidal activity of the fourth-generation cephalosporins against Gram-positive cocci such as Staphylococcus and Streptococcus, especially the penicillin-resistant pneumococcus, was significantly enhanced compared with the third-generation cephalosporins. From the data available, cefpirome has the strongest antibacterial effect on Gram-positive cocci in the fourth-generation cephalosporins. It should be noted that the fourth-generation cephalosporins are still not ideal for anaerobic and methicillin-resistant Staphylococcus aureus (MRSA) [3 to 5].

Better stability to -lactamase

Compared with the third-generation cephalosporins, the fourth-generation cephalosporins have good stability to Richmond-Sykes classification type I chromosome-mediated -lactamase [6-8]. It is worth noting that they also have good stability to -lactamase mediated by AmpC gene [9]. AmpC gene is a structural gene encoding -lactamase found in almost all Gram-negative bacilli. In some bacteria, such as Escherichia coli, the expression of AmpC gene is very low, which is not enough to cause bacterial resistance, but other bacteria such as the gullet AmpC gene expression of Enterobacter, Claude fulvicii, Serratia, and Pseudomonas aeruginosa can be induced, and various -lactam antibiotics can induce it, which can cause hundreds of enzyme levels Thousands of times higher and cause cross-resistance to multiple -lactam antibiotics, especially can cause resistance to third-generation cephalosporins, so the bacterial resistance caused by it is quite significant in clinical treatment Tricky [10]. Because the fourth-generation cephalosporins are stable to AmpC gene-mediated -lactamase, the fourth-generation cephalosporins can be tried when Gram-negative bacteria are resistant to third-generation cephalosporins. It should be noted that the fourth-generation cephalosporins are still unstable to TEM-4, SHV-2, SHV-3, SHV-4 and other broad-spectrum enzymes, so it is not resistant to all third-generation cephalosporin-resistant leathers. Blue-negative bacteria are effective [4,11].

Pharmacokinetics

As shown in Table 2, the pharmacokinetic characteristics of the fourth-generation cephalosporins were roughly the same. Although the fourth-generation cephalosporin has a short half-life, the serum drug peak concentration is high. One intravenous injection of 2 grams of cefepime still has a bactericidal effect on Pseudomonas aeruginosa after 4 hours, and on S. aureus, enterobacteriaceae, and streptococci after 8 hours. It has been reported that cefpirome and the like can effectively penetrate the blood-brain barrier, and the drug concentration in the tracheal mucosa and lung tissue is 56% and 36% of their blood concentration respectively [12, 13].

Table 2 Pharmacokinetic parameters of fourth-generation cephalosporins in a single intravenous injection of healthy volunteers

Drug name Intravenous dose (g) Peak serum drug concentration (g / L) Half-life (h) Renal excretion rate (%) Protein binding rate (%)

Cefpirome 2 0.175 1.9 70 90 <10

Cefepime 2 0.133 1.8 80 19

Clinical application of cephalosporins

Cefpirome and cefepime have been successfully marketed for respiratory infections, urinary tract infections, and skin and soft tissue infections. But the fourth-generation cephalosporins seem to be more suitable for severe hospital and socially acquired infections. The indications and non-indications for the fourth-generation cephalosporins recommended by Carau et al. [1] are shown in Table 3.

Table 3 Indications and non-indications for fourth-generation cephalosporins

Non-indication

Pneumonia anaerobic infection

Hospital acquired

Severe socially-acquired methicillin-resistant Staphylococcus aureus / Epstaphylococcus aureus (MRSA / MRSE) infection

Granulocyte deficiency combined with infection by extended-spectrum enzyme-producing strains (ESBLs)

Nosocomial sepsis

Bacterial meningitis

The fourth-generation cephalosporins are suitable for the treatment of nosocomial pneumonia due to the characteristics of the pathogenic bacteria and the antibacterial spectrum and antibacterial activity of the fourth-generation cephalosporins. Taking tracheal intubation as an example, the early pathogenic bacteria are mainly Staphylococcus aureus and Haemophilus influenzae, while the latter are mostly Enterobacteriaceae and Pseudomonas aeruginosa. These bacteria, so it is advisable to use the fourth-generation cephalosporins as empirical treatment drugs before the pathogens are identified [14, 15]. The main pathogens of severe socially acquired pneumonia are Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Moraxella catarrhalis. These bacteria are all sensitive to the fourth-generation cephalosporins, so it has been recommended as empirical. First-line drugs for treating such infections [1]. Studies have shown that in the treatment of severe socially acquired pneumonia, the clinical effectiveness of cefepime and ceftazidime is 87% and 66%, respectively [16].

Ceftazidime has been successfully used in empirical anti-infective treatment when granulocytes lack co-infection due to various reasons such as chemotherapy and leukemia. However, in recent years, Gram-positive bacteria such as Staphylococcus aureus, coagulase-negative Staphylococcus, and hemolytic streptococcus infections have increased. Ceftazidime is unstable to AmpC gene-related -lactamase, and the fourth-generation cephalosporins It just overcomes the shortcomings of the above two aspects, so it may replace ceftazidime and become the drug of choice for empirical treatment [1]. In a multi-center randomized clinical trial for the treatment of co-infection with agranulocytosis, Staphylococcus epidermidis and Staphylococcus aureus were the main pathogens. Both cefpirome and ceftazidime achieved a clinical effectiveness of 74%, but in terms of bacterial clearance Cefpirome (89%) is better than ceftazidime (74%), and the situation of nosocomial infectious sepsis is similar [17].

75% of bacterial meningitis is caused by meningococcus, Haemophilus influenzae, and Streptococcus pneumoniae. Gram-negative bacilli and Staphylococcus aureus infections may be secondary to hospital admission. Because the fourth-generation cephalosporins have good bactericidal activity against the above bacteria and can penetrate the blood-brain barrier, it is expected that it will achieve better efficacy in the treatment of meningitis infection [18].

In summary, the fourth-generation cephalosporins have certain characteristics that distinguish them from the first, second, and third-generation cephalosporins, such as a broader antibacterial spectrum, more stability to -lactamase, high blood concentration, and permeability. Blood-brain barrier, etc. Preliminary clinical results have also demonstrated some of the advantages of this class of drugs. It is expected that this class of drugs will soon enter China, and its application value in the respiratory department and other clinical departments remains to be objectively evaluated by the majority of clinicians.

Structural features of cephalosporins

3.1.1 At the 7th position of the main core, a 2-aminothiazole-a-methoxyiminoacetyl side chain is attached.

3.1.2 The quaternary amine group at the 3-position forms an internal salt with the carboxyl group in the molecule.

3.2 Its performance characteristics are

3.2.1 Have a high affinity for penicillin-binding protein (PBPS);

3.2.2 It can quickly spread to the periplasm of bacteria and maintain high concentration through the outer membrane channels of Gram-negative bacteria;

3.2.3 has lower -lactamase affinity and inducibility, and is stable to chromosome-mediated and partially plasmid-mediated -lactamase.

Features of cephalosporins

The fourth-generation cephalosporins show broad-spectrum antibacterial activity against gram-positive bacteria, negative bacteria, and anaerobic bacteria. Compared with the previous third-generation varieties, it has enhanced anti-gram-positive bacteria activity, especially for streptococcus and pneumonia chain. Cocci and so on are very active. Cefpirome and cefazolin also have a strong effect on general cephalosporin-insensitive Streptococcus faecalis. Cefotaxil also has a strong resistance to methicillin-resistant Staphylococcus aureus (MRSA). active. These varieties have strong activity against Citrobacter freundii and Enterobacter cloacae, and their resistance to Pseudomonas aeruginosa can rival ceftazidime.