First, the concept and classification of the fourth generation cephalosporins
The fourth generation cephalosporin is a new generation cephalosporin developed from the third generation cephalosporin, but it is obviously different from the third generation cephalosporin. Structurally, on the basis of the molecular structure of the third generation cephalosporin, a C-3' quaternary ammonium substituent was introduced into the C-3 position of the mother nucleus of 7- aminocephalosporin (7-ACA). From the mechanism of action, the above structural changes enable it to penetrate the outer membrane of Gram-negative bacilli faster, have higher affinity for pbps and are more stable for bacterial β -lactamases. From the antibacterial spectrum, it has strong antibacterial activity against Gram-positive cocci [1]. According to the different side chains at C-7 position in the molecular structure, it can be divided into two subclasses: 2- amino -5- thiazole subclasses and 5- amino -2- thiazole subclasses. See table 1 [2] for the classification and varieties of the fourth generation cephalosporins.
Table 1 classification of the fourth generation cephalosporins
2- amino -5- thiazole subclass
Cefpirox (Cefpirox)
Cefepime (Cefepime)
Cefodil cefprozil
Cefoquinone FK-5 18
CP6679 YM-40220
CS-46 1 L-640876
DN9550 L-642946
DW-75 1 L-65283 1
MT520
TOC-39
Among them, cefpirome and cefepime have been listed abroad and applied in clinic. Characteristics of the second and fourth generation cephalosporins
1. The antibacterial spectrum is wider: cefpirome and cefepime have stronger antibacterial activities against Enterobacteriaceae than ceftazidime and cefotaxime, and their antibacterial activities against Pseudomonas aeruginosa are better than 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 penicillin-resistant Streptococcus pneumoniae, is significantly enhanced compared with that of the third generation cephalosporins. According to the available data, among the fourth generation cephalosporins, cefpirome has the strongest antibacterial effect on gram-positive cocci. It should be pointed out that the effect of the fourth generation cephalosporins on anaerobic bacteria and methicillin-resistant Staphylococcus aureus (MRSA) is still not ideal [3 ~ 5].
2. Better stability to β-lactamases: Compared with the third generation cephalosporins, the fourth generation cephalosporins have better stability to β -lactamases mediated by Richmond-Sykes chromosome I [6 ~ 8]. Notably, they also have good stability to β -lactamase mediated by AmpC gene [9]. AmpC gene is a structural gene encoding β -lactamase and exists in almost all gram-negative bacilli. In some bacteria, such as Escherichia coli, the expression of AmpC gene is too low to cause bacterial drug resistance, but in other bacteria, such as Enterobacter cloacae, Citrobacter freundii, Serratia and Pseudomonas aeruginosa, the expression of AmpC gene can be induced, and various β -lactam antibacterial drugs can induce its expression. It can increase the enzyme level by hundreds of times and produce cross-resistance to a variety of β -lactam antibiotics, especially to the third generation cephalosporins, so the bacterial resistance caused by it is quite difficult in clinical treatment [10]. Because the fourth generation cephalosporin is stable to β -lactamase mediated by AmpC gene, it can be tried when gram-negative bacilli are resistant to the third generation cephalosporin. It should be pointed out that the fourth-generation cephalosporins are still unstable to TEM-4, SHV-2, SHV-3, SHV-4 and other extended-spectrum enzymes, so they are ineffective to all gram-negative bacteria resistant to the third-generation cephalosporins [4, 1 1].
3. Pharmacokinetic characteristics: As shown in Table 2, the pharmacokinetic characteristics of the fourth generation cephalosporins are almost the same. Although the fourth-generation cephalosporin has a short half-life, its peak blood concentration is high. After 4 hours, 2 grams of cefepime was injected intravenously, and it still had bactericidal effect on Pseudomonas aeruginosa, Staphylococcus aureus, Enterobacteriaceae and Streptococcus after 8 hours. It has been reported that cefpirome can effectively penetrate the blood-brain barrier, and the drug concentration in tracheal mucosa and lung tissue is 56% and 36% of its blood drug concentration respectively [12, 13].
Pharmacokinetic parameters of the fourth generation cephalosporin in healthy volunteers after a single intravenous injection
Drug name: intravenous dosage (g) peak blood concentration (g/L) half-life (h) renal excretion rate (%) protein binding rate (%)
20.1751.970 ~ 90 <10.
Cefepime 20.1331.88019
Third, the clinical application prospects Cefpirox and Cefpirome, which have been marketed, have been successfully applied to respiratory tract infections, urinary tract infections and skin and soft tissue infections. The fourth generation cephalosporin seems to be more suitable for serious hospital and social acquired infections. The indications and non-indications of the fourth generation cephalosporins recommended by Carau et al. [1] are shown in Table 3.
Table 3 Indications and non-indications of the fourth generation cephalosporins
Indication and non-indication
Anaerobic infection of pneumonia
Hospital acquired
Severe community-acquired MRSA/MRSE infection.
Granulopenia complicated with infection of extended-spectrum enzyme-producing strains
Hospital infectious septicemia
Bacterial meningitis
The application of the fourth-generation cephalosporin in the treatment of hospital-acquired pneumonia is determined by the characteristics of pathogenic bacteria and the antibacterial spectrum and activity of the fourth-generation cephalosporin. Take patients with tracheal intubation as an example, Staphylococcus aureus and Haemophilus influenzae are the main pathogens in the early stage, and Enterobacteriaceae and Pseudomonas aeruginosa are the main pathogens in the later stage. The fourth-generation cephalosporin can effectively kill these bacteria, so it is appropriate to choose the fourth-generation cephalosporin as an empirical treatment drug before the pathogen is determined [14, 15]. The main pathogens of severe socially acquired pneumonia are Streptococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae and Moraxella catarrhalis. These bacteria are very sensitive to the fourth generation cephalosporins, so some people recommend them as the first-line drugs for empirical treatment of such infections [1]. Studies have shown that the clinical effective rates of cefepime and ceftazidime in the treatment of severe socially acquired pneumonia are 87% and 66% respectively [16].
For various reasons, ceftazidime has been successfully used in empirical anti-infective therapy, such as chemotherapy and leukemia. However, in recent years, the infection of Gram-positive bacteria such as Staphylococcus aureus, coagulase-negative Staphylococcus and hemolytic Streptococcus is on the rise, and ceftazidime is unstable to β -lactamase related to AmpC gene, while the fourth generation cephalosporin just overcomes the above two shortcomings, so it may replace ceftazidime and become the first choice for empirical treatment [1]. In a multicenter randomized clinical trial for the treatment of agranulocytosis complicated with infection, Staphylococcus epidermidis and Staphylococcus aureus were the main pathogens. The clinical effective rates of cefpirome and ceftazidime both reached 74%, but the bacterial clearance rate of cefpirome (89%) was better than that of ceftazidime (74%), and the situation of nosocomial sepsis was similar [17].
75% of bacterial meningitis is caused by meningococcus, Haemophilus influenzae and Streptococcus pneumoniae. Gram-negative bacilli and Staphylococcus aureus can be infected after admission. Because the fourth generation cephalosporins have good bactericidal activity against the above bacteria and can penetrate the blood-brain barrier, it is expected to achieve good curative effect in the treatment of meningitis infection [18].
To sum up, the fourth generation cephalosporins have some characteristics different from those of the first, second and third generations cephalosporins, such as wider antibacterial spectrum, more stable to β -lactamase and high blood drug concentration, and can penetrate the blood-brain barrier. The preliminary clinical application results also prove some advantages of this kind of drugs. It is expected that this kind of drugs will enter China soon, and its application value in clinical departments such as respiratory department needs to be objectively evaluated by clinicians.
3. 1 The structural characteristics of the fourth generation cephalosporins are as follows
3. 1. 1 There is a 2- aminothiazole -a- methoxyiminoacetyl side chain at the 7-position of the main core.
3. The quaternary amine group at the 3-position of1.23 forms an internal salt with the carboxyl group in the molecule.
3.2 Its performance features are as follows
3.2. 1 has a high affinity for PBPS;
3.2.2 It can quickly spread to the periplasm of bacteria through the outer membrane pores of Gram-negative bacteria and maintain a high concentration;
3.2.3 Low affinity and inductivity to β -lactamase and stable to chromosome-mediated and partial plasmid-mediated β -lactamases.
The fourth generation cephalosporins showed broad-spectrum antibacterial activity against gram-positive bacteria, negative bacteria and anaerobic bacteria. Compared with the previous third-generation varieties, the fourth-generation cephalosporins have stronger antibacterial activity against Gram-positive bacteria, especially against Streptococcus pneumoniae, Cefpirox and Cefazolin, which are insensitive to general cephalosporins, and Cefodil also has stronger antibacterial activity against MRSA. These varieties have strong activity against Citrobacter freundii and Enterobacter cloacae, and their anti-Pseudomonas aeruginosa effect is equivalent to that of ceftazidime.
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