• First-Generation Cephalosporins

  • "Cephalosporin versus penicillin ring structures. The solid arrows indicate the core four-membered β-lactam ring within both penicillins and cephalosporins. Open arrows indicate the five-and six-member side rings for penicillin and cephalosporins, respectively. R indicates additional side chain sites where substitutions of various chemical groups produce different antimicrobial spectrum, pharmacokinetics, or stability to beta-lactamases." Attribution Harrison C Bratcher D Cephalosporins: A Review. Pediatrics and Review volume 29, Number 8, August 2008. https://renaissance.stonybrookmedicine.edu/sites/default/files/Cephalosporins. PIR 2008 pdf.pdf First-generation cephalosporins are characterized by their β-lactam ring fused to a dihydrothiazine ring, which distinguishes them from penicillins and confers greater resistance to β-lactamase enzymes.2,9 Unlike penicillins, which contain a thiazolidine ring, cephalosporins possess a six-membered dihydrothiazine ring that provides enhanced stability and broader spectrum activity.11  This structural modification is crucial for their antimicrobial efficacy and pharmacological properties.

  • Introduction and History

    • First-generation cephalosporins represent the pioneering class of cephalosporin antibiotics, introduced into clinical practice in the early 1960s.

      • These β-lactam antibiotics, an important advanced in antimicrobial therapy,  were originally derived from the mold Acremonium (previously called Cephalosporium).

        • The first-generation cephalosporins include:

          • Cefazolin

          • Cephalothin

          • Cephapirin

          • Cephradine

             

          • Cefadroxil

          • Cephalexin

             

        • Each of  the agents above offer unique pharmacological properties while sharing a common mechanism of action.

  • Generational Classification

    • To facilitate classification of this antibiotic family, a "generation" system was developed.

      • This classification approach groups cephalosporins based mainly on their spectrum of antimicrobial activity as well as when they were introduced to the market.⁶

        • First-generation cephalosporins are defined by their potent activity against Gram-positive bacteria along with modest but clinically important spectrum against a limited set of community-acquired Gram-negative pathogens.^5,7 

    • The generational system describes a trade-off in cephalosporin development in that as one progresses to higher generations (second, third, and fourth), the spectrum of activity against Gram-negative bacteria generally expands, but this is often accompanied by a decrease in potency against Gram-positive cocci. 

      • This principle explains the continuing utility for first-generation drugs.⁸ 

        • For infections caused by susceptible Gram-positive organisms like methicillin-susceptible Staphylococcus aureus (MSSA), the focused and potent activity of a first-generation cephalosporin is often superior to that of a broader-spectrum but less potent later-generation agent.

          • The principle involves selecting the narrowest-spectrum, most effective drug to treat the pathogen while minimizing damage to the microbiome.

            • The  major drugs of the first generation include parenteral formulations, such as cefazolin and cephalothin, and orally administered drugs, including cephalexin, cefadroxil, and cephradine.^9,10

  • Mechanism of Action

    • First-generation cephalosporins are β-lactam antibiotics that exert bactericidal effects by inhibiting bacterial cell wall synthesis.⁹

      • Like other β-lactams, they contain a β-lactam ring that binds to and inactivates penicillin-binding proteins (PBPs), which are the transpeptidase enzymes responsible for cross-linking peptidoglycan strands in the bacterial cell wall.⁹

        • By blocking the transpeptidation step, cephalosporins prevent peptidoglycan cross-linking, leading to a weakened cell wall and osmotic lysis of the bacterium.⁹  These drugs mimic the D-alanyl-D-alanine terminus of peptidoglycan precursors, irreversibly acylating the active site of PBPs.

          • The result is an inability of bacteria to maintain cell wall integrity, causing cell death which is a time-dependent bactericidal effect.

            • Staphylococcus aureus can acquire resistance by producing altered PBPs (e.g. PBP2a encoded by the mecA gene) that have low affinity for β-lactams .

            • This resistance mechanism is the basis for methicillin-resistant S. aureus (MRSA), against which first-generation cephalosporins are ineffective.⁹ 

              • Another resistance mechanism is bacterial production of β-lactamase enzymes that cleave the β-lactam ring; first-generation cephalosporins are susceptible to some β-lactamases produced by Gram-negatives, limiting their spectrum.⁸

              • First generation drugs are stable to staphylococcal penicillinase, allowing them to kill methicillin-susceptible S. aureus (MSSA) where penicillin G would be inactivated.⁹

September, 2025