How did the Cephalosporin family become successful? It can be said that "every generation has its own talents"

The origin of cephalosporins: "friendly forces" among microorganisms

In the 17th century, Leeuwenhoek observed bacteria for the first time through a homemade microscope. Later, Louis Pasteur and Robert Koch successively isolated different pathogenic microorganisms from various diseased animals and plants.

Louis Pasteur Robert Koch

Image source: Internet

But the question is, how to eliminate these pathogenic microorganisms?

Antibiotics came into being, and their tactics were: to fight barbarians with barbarians, to use microbial weapons against microorganisms! This substance is secreted by microorganisms with medicinal value, and can destroy or slow down the growth of another type of pathogenic microorganism. Since the advent of penicillin and streptomycin, antibiotics have become a huge category of drugs, among which one of the most important and widely used antibiotics is the well-known cephalosporin.

The history of ceftriaxone: "Cultivating one's way out of the barrier" from a river

In the 1940s, many cities in Italy suffered from typhoid fever due to poor sanitary conditions, but there was an area in Cagliari where few people got sick even though they swam in a sewage river and ate raw fish from the river. Giuseppe Brotzu, a professor of medicine at the University of Cagliari in Italy, noticed this situation. At that time, he had learned about penicillin and had done some research in microbiology. So he suspected that there were substances in the river that could fight against bacteria, which might be produced by microorganisms in the river. Then he used agarose culture medium to culture river water and obtained a cephalosporin. After 21 years of perseverance, in 1961, Brotzu, Guy Newton and Edward Abraham of Oxford University jointly discovered cephalosporin C, which became the first cephalosporin that could be used clinically - cephalothin was born. [1]

Giuseppe Brotzu

Image source: Internet

How can a tiny molecule burst out such a huge energy to inhibit cell growth?

This has to do with the penicillin-binding protein needed for bacterial cell membrane synthesis. Cephalosporins competitively bind to this protein, snatching away the raw materials needed for bacterial derivation, and ultimately killing the bacteria in the cradle.

However, the initial program of cephalosporin was not fully developed: due to its relatively simple structure, there is an α-amino group on the carbon-7 side chain. This structure makes it easy to be hydrolyzed by its natural enemy, β-lactamase, and has a low affinity for penicillin-binding protein, so the vitality of the drug is greatly reduced.

Molecular structure of cephalosporin Image source: drawn by the author

So scientists began to look for a suitable weapon for this new antibacterial drug - modifying its side chain. Cephalosporins officially started a battle with various drug-resistant bacteria.

The "attacking" cephalosporin grew indomitable while practicing in seclusion to improve its strength. From the second generation to the fifth generation, the stability of cephalosporin has been strengthened generation by generation, and the types of antibacterial agents have been continuously expanded, gradually evolving into the all-round ACE in the antibacterial world today.

Members of the cephalosporin family: each generation has unique skills

As drug research continues to deepen, cephalosporin drugs have been developed one after another, gradually forming a large family of cephalosporins. Cephalosporins started from bronze and have been upgraded for seventy years, going through silver, gold, platinum, and now finally reaching diamond.

The representative drugs of the first generation of cephalosporins are mainly cephalexin and cefradine.

The first generation of cephalosporins, which were just starting out, started out as "bronze-grade, a rotten life, just to die". It was more effective against Gram-positive bacteria than the three generations of cephalosporins that followed, but it was still defeated by Gram-negative bacteria because it had a fatal weakness - it was easily hydrolyzed by β-lactamase. In addition, it was also the most nephrotoxic.

The representative drugs of the second-generation cephalosporins mainly include cefuroxime and cefaclor.

The cephalosporins in the silver stage have a wider range of attack, not only having a significant effect on Gram-negative bacteria, but also a certain effect on anaerobic bacteria, and are very low in toxicity to the kidneys. But God opened a door for it, and at the same time closed a window for it. The antibacterial properties of the last three generations against Gram-positive bacteria cannot compete with the first generation. Perhaps it also knows that "you can't have your cake and eat it too".

The main representative drugs of the third-generation cephalosporins are: cefixime, cefotaxime, and cefoperazone.

At this time, β-lactamase has become a smaller threat to cephalosporins, which have strong effects on Gram-negative bacteria and a wider antibacterial spectrum, successfully taking down Enterobacteriaceae and Pseudomonas aeruginosa, and are basically non-toxic to the kidneys. However, their manpower is limited, their effect on Gram-positive bacteria is weak, and they cannot be used to control Staphylococcus aureus infections.

The fourth-generation cephalosporin drug is represented by cefpirome.

Based on the third generation, the fourth generation of cephalosporins is extremely stable. Perhaps because they were dissatisfied with their slow attack speed against Gram-negative bacteria, scientists built a "highway" for them, which was 5 to 7 times faster than the third generation of cephalosporins. [2,3] This time, it finally achieved a double breakthrough against Gram-positive and Gram-negative bacteria.

The representative drugs of the fifth generation cephalosporins are mainly cefuroxime and ceftriaxone.

Representatives of the fifth generation of the cephalosporin family. Image source: drawn by the author

In addition to enhanced stability and a wider hunting range, diamond-level cephalosporins can also effectively combine with penicillin-binding protein 2a, the coding gene of methicillin-resistant Staphylococcus aureus (commonly known as "super bacteria"). This greatly enhances the antibacterial activity against drug-resistant Gram-positive cocci, a feature that other cephalosporin drugs did not have in the past.

Contraindications of medication: Beware of a "counterattack" from friendly forces

According to the latest research survey, more than 70,000 people die in my country every year due to the abuse of antibiotics.

Avoid drinking alcohol during the use of cephalosporins to prevent negative effects on the circulatory system and reduce the incidence of adverse reactions such as abnormal blood pressure and arrhythmia.

During World War II, one day, Erik Jacobsen, director of the biological laboratory of a Danish pharmaceutical company in Copenhagen, ate a sandwich for lunch and drank a bottle of beer as usual. After a while, he felt something was wrong, nauseous, dizzy, and the blood vessels in his head were beating violently. At that time, he was testing the effect of disulfiram on intestinal parasites. Strangely, he had never felt this way before, not when he didn't drink, not his family, but his colleagues who tested drugs and drank with him did! Dedicating oneself to science, science also gives back. After a series of analysis and experiments, he finally discovered the disulfiram reaction.

Disulfiram reaction: These drugs cause acetaldehyde accumulation in the blood by inhibiting acetaldehyde dehydrogenase in the liver. Acetaldehyde in the blood will cause vasodilation, increased vascular permeability, plasma extravasation, and reflexive sympathetic nerve excitement. When a person is excited, his face will turn red and his heart will beat faster. People think it is heart palpitations, but in fact it is impending sudden death!

So, just mix cephalexin with alcohol and go!

Patients taking cephalosporins should not drink alcohol during medication and within 5-7 days after stopping medication, because aldehyde dehydrogenase inhibition takes 4-5 days to recover. At the same time, do not use drugs containing ethanol or use ethanol for skin disinfection or wiping to cool down, especially the elderly and patients with cardiovascular diseases. [4]

The co-administration of cephalosporin antibiotics and antacids (such as omeprazole) will reduce the absorption of cephalosporin.

"All medicines are poisonous to some extent." If the patient's liver or kidney infection is mild, oral administration is recommended; if the systemic infection is severe, intravenous drip is used, and push injection is avoided as much as possible.

The future of cephalosporin: strong alliance, a way to defeat the enemy

According to global statistics in 2021, third-generation cephalosporins account for 60% of the market share of all cephalosporins and are currently the most widely used in clinical practice.

The research and development of new cephalosporins has not stopped. Due to the abuse of antibiotics and bacterial evolution, multidrug-resistant bacteria have emerged. The detection rate of bacteria is indirectly reflected by investigating the drug resistance of bacteria. From 2014 to 2019, the national resistance rate of Escherichia coli to third-generation cephalosporins decreased from 59.7% to 51.9%, and the rate in Sichuan Province decreased from 55.9% to 50.2%. The overall detection rate is still high, indicating that bacteria have strong drug resistance; the national resistance rate of Klebsiella pneumoniae to third-generation cephalosporins decreased from 36.9% to 31.9%, while the rate in Sichuan Province increased from 27.6% to 28.5%, suggesting that the supervision of the rational use of antimicrobial drugs and hospital infection prevention and control in key areas should be strengthened. According to the above analysis, there is still a great demand for seeking safe and effective new antibiotics. [6,7] (2020-11-19) [2020-10-10].

In 2020, Allecra Therapeutics developed a cephalosporin and β-lactamase inhibitor combination, exblifep (cefepime-enmetazobactam), which is a combination of cefixime and enmetazobactam. Its four phase I, one phase II, and one phase III clinical trials for the treatment of complicated urinary tract infections led to the approval of the U.S. Food and Drug Administration (FDA) in February 2024.

In 2020, a Phase I clinical trial in my country of taniborbactam (VNRX.5133), a bicyclic boronate compound that inhibits both serine and β-lactamases, combined with cefepime to treat multidrug-resistant bacterial infections, showed good safety and tolerability in healthy Chinese volunteers. [5, 8]

References:

【1】https://blog.sciencenet.cn/blog-28871-548363.html

【2】Xu Changsheng, Chen Guohua, Liang Meifeng. Characteristics and application prospects of the fourth-generation cephalosporins[J]. Jiangsu Pharmacy and Clinical Research, 2001, 9(4): 6-7. DOI:10.3969/j.issn.1673-7806.2001.04.002.

【3】Hancock RE, Bellido F. Antibacterial in vitro activity of fourth generation cephalosporins. J Chemother. 1996 Feb;8 Suppl 2:31-6. PMID: 8738844.

【4】Wang Moli, Yu Cuiling, Chen Zhihui, et al. Diagnosis, treatment and nursing of drug-induced disulfiram-like reaction[J]. Digital User, 2017, 23(36): 242. DOI: 10.3969/j.issn.1009-0843.2017.36.222.

【5】Wang X, Zhao C, Wang Q, Wang Z, Liang X, Zhang F, Zhang Y, Meng H, Chen H, Li S, Zhou C, Li H, Wang H. In vitro activity of the novel β-lactamase inhibitor taniborbactam (VNRX-5133), in combination with cefepime or meropenem, against MDR Gram-negative bacterial isolates from China. J Antimicrob Chemother. 2020 Jul 1;75(7):1850-1858. doi: 10.1093/jac/dkaa053. Erratum in: J Antimicrob Chemother. 2020 Jul 1;75(7):2019. doi: 10.1093/jac/dkaa132. PMID: 32154866.

【6】2014 National Bacterial Resistance Monitoring Report[J]. Chinese Licensed Pharmacist, 2016, 13(02): 3-8.

【7】National Health and Family Planning Commission Expert Committee on Rational Drug Use, National Bacterial Resistance Monitoring Network. 2019 National Bacterial Resistance Monitoring Report (Brief Version) [EB/OL].

【8】Kaye KS, Belley A, Barth P, Lahlou O, Knechtle P, Motta P, Velicitat P. Effect of Cefepime/Enmetazobactam vs Piperacillin/Tazobactam on Clinical Cure and Microbiological Eradication in Patients With Complicated Urinary Tract Infection or Acute Pyelonephritis: A Randomized Clinical Trial. JAMA. 2022 Oct 4;328(13):1304-1314. doi: 10.1001/jama.2022.17034. PMID: 36194218; PMCID: PMC9533186.

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