What are cephalosporin antibiotics?

Members of the beta-lactam antibiotic family, cephalosporins are effective replacement treatments for a wide range of serious to moderate infectious diseases. Owing to their renowned effectiveness, they are frequently prescribed. Based on data from the healthcare database, between 2004 and 2014, the aggregate number of prescriptions for cephalosporins in the United States exceeded that of narrow-spectrum and wide-spectrum penicillins. Semisynthetic cephalosporins provide a wide range of antimicrobial action against both Gram-positive and Gram-negative bacteria. These chemicals are produced by synthesizing a bicyclic nucleus that includes a beta-lactam ring coupled to a six-membered dihydrothiazine ring. The two carbon atoms (C3 and C7) present on the cephalosporin scaffold provide an excellent opportunity for the incorporation of various side chains. In addition to significantly enhancing the compound's antibacterial properties, these side chains also strengthen its structure against beta-lactamases. The antibiotics known as cephalosporins originate from the filamentous fungus Acremonium chrysogenum. Cephalosporin C (CPC) was the first antibiotic compound from the cephalosporin family to be isolated. The molecular composition of the molecule was quickly identified by Italian scientist Giuseppe Brotzu upon its discovery in 1945 (see image below).

The chemical structure of cefiderocol. (Lin X., et al., 2022)

Cephalosporins antibiotics at BOC Sciences

Generations of cephalosporins antibiotics

As a bactericidal agent, cephalosporins work by blocking the formation of bacterial cell walls through a process known as peptidoglycan chain cross-linking. In the last step of peptidoglycan layer production, penicillin-binding proteins (PBP) cross-link linear glycopeptides to create a three-dimensional structure. With their analogous glycopeptide structures, cephalosporins, which are purposefully designed beta-lactam antibiotics, bind to PBPs and irreversibly hinder bacterial cell wall formation. Presently, there are five distinct generations of cephalosporin antibiotics, each with its own set of advantages and disadvantages. These generations are classified according to the order of their discovery and the diverse antibiotic activities they display (see image below).

Classification of Cephalosporin. (Mehta D., et al., 2016)

• 1^st generation cephalosporin antibiotics

The efficacy of first generation cephalosporins is relatively restricted, as they primarily concentrate on gram-positive cocci. Against gram-positive bacteria, including Streptococci, Staphylococci, and Enterococci, they exhibit antibacterial activity. These agents are ineffective against methicillin-resistant bacteria, including Staphylococcus aureus, due to their restricted spectrum of activity. S. pneumoniae strains that have developed resistance to penicillin. Although these antibiotics can effectively target Gram-positive bacteria (e.g., Escherichia coli, Proteus mirabilis, and Klebsiella pneumoniae), their susceptibilities may vary. With limited or no effectiveness against Moraxella catarrhalis and Hemophilus influenzae. Effective against the vast majority of penicillin-sensitive anaerobic bacteria, excluding Bacterioides fragilis groups.

Cephalosporins of the first generation are efficacious in the treatment of straightforward infections affecting the epidermis and soft tissues, Streptococcal pharyngitis, and moderate surgical prophylaxis. It functions as an effective replacement for anti-staphylococcal penicillins. It is, nevertheless, contraindicated for application in instances of otitis media. Cephalosporins of the first generation are regarded as safer due to their inability to penetrate the cerebral spinal fluid. Narrow spectrum antibiotics are contraindicated for infections affecting the central nervous system. In comparison to alternative cephalosporins of the first generation, cefazolin is a more potent molecule.

• 2^rd generation cephalosporin antibiotics

In contrast to their first-generation counterparts, the second-generation cephalosporins are able to combat a broader range of infections. The range of Gram-negative bacteria that second-generation cephalosporins can effectively combat is much broader, with the exception of anaerobes. In addition, their resistance to beta-lactamase enzymes is significantly higher. Cephalosporins of the second generation are effective against Neisseria gonorrheae, Moraxella catarrhalis, Proteus mirabilis, E. coli, and Klebsiella, as well as Hemophilus influenza. Cephamycins, which are classified as second-generation cephalosporins, are distinguished from other cephalosporins by the presence of a 7-alpha-methoxy group that imparts resistance to beta-lactamases. Furthermore, cephamycins, including cefotetan, cefoxitin, and cefmetazole, demonstrate efficacy against bacteroides that do not thrive in oxygen. Efficacy is absent in the treatment of Pseudomonas and enterococci.

• 3^rd generation cephalosporin antibiotics

Third-generation cephalosporins expanded the range of antibiotic effectiveness against Gram-negative bacteria, such as Enterobacter, beta-lactamase-producing H. influenzae, and meningococci (which frequently cause meningitis). As a result, these very potent cephalosporins are frequently employed in the treatment of sepsis with an unidentified source. Furthermore, third-generation and second-generation cephalosporins can be administered to individuals who have penicillin allergies. This is because, unlike penicillin antibiotics, first-generation cephalosporins react with each other because their side chains share chemical structures that are comparable to each other, not the beta-lactam ring. Meningitis and other infections of the central nervous system are best treated with third-generation and later cephalosporins because of their high CSF penetration rates.

The wide antibacterial efficacy of third-generation cephalosporins has been compromised by the emergence of growing resistance in bacteria, particularly within the Enterobacteriaceae family. One example is P. aeruginosa, which is a kind of bacteria that is Gram-negative and aerobic. It is a very troublesome pathogen that is connected with serious infections acquired in hospitals, such as ventilator-associated pneumonia and blood infections. Pseudomonas aeruginosa, a pathogen that thrives in healthcare settings, poses a significant threat to those with weakened immune systems. This bacterium has developed resistance to a wide variety of medicines, making the task of treating infections caused by it exceptionally difficult. Ceftazidime and cefoperazone are the only third-generation cephalosporins that are effective in treating P. aeruginosa infections. On the other hand, fourth-generation cephalosporins demonstrate exceptional efficacy against this particular bacterium.

• 4^rd generation cephalosporin antibiotics

Similar to first-generation cephalosporins, fourth-generation cephalosporins have a wide spectrum of action and are effective against gram-positive infections. They also outperform third-generation cephalosporins when it comes to resistance to beta-lactamases. Cefepime and cefpirome have significant efficacy against a broad spectrum of drug-resistant infections that have traditionally presented difficulties in terms of therapeutic intervention. They demonstrate effectiveness against Gram-positive spherical bacteria, especially Streptococcus pneumoniae. Effective against strains of Entero-bacteriaceae and Pseudomonas aeruginosa. They are effective in treating meningitis and other CNS infections that were previously untreatable with prior cephalosporin generations due to their wide range of antimicrobial action.

• 5^rd generation cephalosporin antibiotics

Ceftaroline, a 5th generation cephalosporin, is the recommended medication because to its excellent efficacy against several drug-resistant strains of Staphylococcus aureus, including MRSA, VRSA, and VISA. Ceftaroline is the only beta-lactam antibiotic that is effective against methicillin-resistant Staphylococcus aureus (MRSA). Furthermore, it has efficacy against Enterococcus. Ceftobiprole is a cephalosporin of the 5th generation, with significant efficacy against a broad spectrum of bacteria. It exhibits wide-ranging effectiveness against gram-positive bacteria, including MRSA and MRSE, as well as penicillin-resistant Streptococcus pneumoniae and Enterococcus faecalis. In addition, it has a strong efficacy against a wide range of gram-negative bacteria, including AmpC-producing E. coli and Pseudomonas aeruginosa. It is now under investigation for its possible application in the treatment of intricate skin and skin structure infections.

References

1. Lin X., et al., Cephalosporins as key lead generation beta-lactam antibiotics, Applied Microbiology and Biotechnology, 2022, 106(24): 8007-8020.
2. Mehta D., et al., Cephalosporins: A review on imperative class of antibiotics, Inventi Rapid: Molecular Pharmacology, 2016, 1(3): 1-6.