Cephalexin: The First Generation Cephalosporin

What are cephalosporins?

Cephalosporium acremonium is a widely used β-lactam antibiotic developed from compounds extracted from the fungus Cephalosporium acremonium. It is prepared by semi-synthesis using natural cephalospin C as raw material. They kill bacteria by inhibiting their cell wall synthesis and are widely used in the treatment of gram-positive and Gram-negative bacterial infections. They are classified according to the anti-microbial spectrum. The first generation of cephalosporin antibiotics showed excellent performance against gram-positive bacteria, while later cephalosporins increased resistance against gram-negative bacteria, but decreased resistance against gram-positive bacteria.

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Cephalosporin structure

The core of cephalosporin is 7-amino-cephalosporin (7-ACA), which is derived from cephalosporin C and has been shown to be similar to the core of penicillin (6-amino-penicillanic acid, 6-APA). Modifications to the 7-ACA side chain resulted in some very useful antibiotics. Cephalosporins has a β-lactam ring (four-membered cyclic amide), which is essential for their antibacterial activity. This ring structure is fused to a six-membered dihydrothiazine ring, forming the core of cephalosporin antibiotics. The substitutions at positions 3 and 7 of this nucleus are critical in modulating the drug's pharmacological properties and antibacterial spectrum. Alterations at position 7 influence antibacterial activity, while changes at position 3 primarily affect pharmacokinetics, such as absorption and excretion.

Structure diagram of cephalosporin C.

Mechanism of action of cephalosporin

Cephalosporins, like all β-lactam antibiotics, exert their bactericidal action by inhibiting bacterial cell wall synthesis. By mimicking the structure of D-Ala-D-Ala, the terminal moiety of the peptidoglycan precursor, cephalosporins irreversibly bind to the PBPs, blocking the crosslinking of peptidoglycan. This inhibition causes an accumulation of non-crosslinked strands, leading to cell wall instability and ultimately bacterial cell death.

The integrity of the bacterial cell wall relies on the proper crosslinking of peptidoglycan layers. Cephalosporins disrupt this process, causing osmotic imbalance and cell lysis. This bactericidal action is particularly effective against actively dividing bacterial cells, which are constantly synthesizing new cell wall material.

Cephalosporin classification

Cephalosporins are divided into five generations according to their discovery time and antibacterial spectrum:

First generation: Highly effective against Gram-positive cocci, with limited activity against Gram-negative bacilli. Cefazoli, cephalexin, cefradine and cefaloridine are the first generation of cephalosporins. Cefadroxil antibiotic is a para-hydroxyl derivative of cephalexin and is used to treat strep throat, urinary tract infections, reproductive tract infections, and skin infections.

Second generation: Broader spectrum with enhanced activity against Gram-negative organisms, including Bacteroides fragilis, such as cefaclor and cefuroxime.

Third generation: Improved efficacy against Gram-negative bacilli, including Pseudomonas aeruginosa. Ceftazidime, cefixime, ceftriaxone, cefotaxime, and cefovecin are all third-generation cephalosporins.

Fourth generation: Compared with the commonly used third-generation cephalosporins, the fourth-generation cephalosporins have a wider antibacterial spectrum and enhanced action against gram-negative bacteria, including most aminoglycoside resistant or third-generation cephalosporin strains. It has a lower affinity with β-lactamase, is more stable to some chromosome mediated β-lactamase than the third generation cephalosporins, and has stronger penetration of bacterial cell membranes. Like cefepime and cefpirome.

Fifth generation: Designed for activity against methicillin-resistant Staphylococcus aureus (MRSA). Like ceftobiprole and ceftaroline.

What is cephalexin?

Cephalexin is a semi-synthetic first-generation oral cephalosporin antibiotics, which can effectively inhibit the synthesis of bacterial cell walls and can be used as an antibiotic for several bacterial infections. Cephalexin can be obtained by reacting the cephalosporin parent nucleus (7-amino-cefanoic acid) with side chain amino acids. Cephalexin is metabolized in the body mainly by the liver, and some of it is excreted from the urine in its original form.

The development process of cephalexin originated from the structural optimization of cephalosporin C, and scientists found that by changing its side chain structure, antibacterial activity and stability could be enhanced. The synthesis of cephalexin is mainly through the introduction of benzyl side chain to improve its antibacterial activity against gram-positive and some gram-negative bacteria. The researchers also focused on improving the oral absorption of the drug, so that it can be easily administered through the oral route, filling the shortage of cephalosporins for injection. The success of cephalexin not only marks a great breakthrough in the clinical application of cephalosporin antibiotics, but also represents the arrival of the era of semi-synthetic antibiotics. In the process of its research and development, scientists overcame the problems of poor oral absorption and fast degradation in vivo, and finally synthesized cephalexin, a drug with both broad-spectrum antibacterial and good absorption, through multiple structural modifications. Cephalexin is mainly effective against gram-positive bacteria and some Gram-negative bacteria, and is suitable for the treatment of upper respiratory tract infection, urinary system infection, skin and soft tissue infection. Drug resistance is relatively low, but long-term use can lead to dysbiosis.

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What is cephalexin used for?

Uncomplicated skin and soft tissue infections

Cefalexin is commonly prescribed for uncomplicated skin and soft tissue infections, particularly those caused by Staphylococcus aureus and Streptococcus pyogenes. It is highly effective against these Gram-positive organisms, which are responsible for a wide range of skin infections, including cellulitis, impetigo, and abscesses.

Cephalexin antibiotics for urinary tract infection (UTI)

Due to its activity against Escherichia coli, a common pathogen in urinary tract infections, cefalexin is frequently used to treat uncomplicated UTIs. Cephalexin has good bioavailability and urinary osmosis, but there is little data to support its optimal dose for the treatment of simple urinary tract infection. A recent study published in Open Forum Infect Dis shows that cefalexin applied twice daily is as effective as a four-times daily regimen for women with a uUTI.

Cephalexin for respiratory tract infections

Cefalexin is also employed in the treatment of respiratory tract infections, such as pharyngitis, tonsillitis, and bronchitis, caused by susceptible organisms. Although its use in respiratory infections is more limited than in skin and urinary tract infections, cefalexin remains an option when Gram-positive cocci are implicated.

Resistance mechanisms of cephalexin

With the widespread use of cephalosporins, it has become increasingly common for bacteria to develop resistance to them. Common resistance mechanisms include:

Production of beta-lactam enzymes: Some bacteria produce enzymes that destroy the beta-lactam ring of cephalosporins, rendering the drug inactive.

Changes in cell wall targets: Bacteria alter the structure of cell wall synthetase (PBP) so that cephalosporins cannot bind effectively.

Efflux pump mechanism: Some bacteria use efflux pumps to expel cephalosporins from the cell, reducing the concentration of the drug in the bacteria.

Conclusion

Cephalexin, as a first-generation cephalosporin, remains a cornerstone in the treatment of common bacterial infections. Its effectiveness against Gram-positive organisms, favorable pharmacokinetics, and minimal side effects contribute to its widespread use, particularly in treating uncomplicated skin, soft tissue, and urinary tract infections. However, the growing threat of antibiotic resistance, driven by mechanisms such as beta-lactamase production, necessitates continued vigilance in its use and the development of new strategies to combat resistant strains.

Reference

1. Yetsko, A., et al. Two times versus four times daily cephalexin dosing for the treatment of uncomplicated urinary tract infections in females. In Open Forum Infectious Diseases. 2023, 10(9): ofad430.