• First-Generation Cephalosporins

  • Antimicrobial Spectrum of Activity

    • Potency Against Gram-Positive Cocci

      • Potency against Gram-positive Cocci is the defining characteristic of first-generation cephalosporins.

        • Drugs belonging to this class exhibit excellent in vitro and in vivo activity against methicillin-susceptible Staphylococcus aureus (MSSA) and coagulase-negative staphylococci like Staphylococcus epidermidis, including strains that produce penicillinase enzymes.^2,3

          •  These strains would otherwise inactivate penicillins.

        • These antibacterials are also highly potent against a wide range of streptococci, including Streptococcus pneumoniae (penicillin-susceptible isolates), Streptococcus pyogenes (Group A streptococcus), and viridans group streptococci.^4,5

    • Activity Against Susceptible Gram-Negative Bacilli

      • The Gram-negative spectrum of first-generation agents is narrow.

        • Their activity is primarily directed against three common, community-acquired urinary pathogens:

          • Escherichia coli

          • Klebsiella pneumoniae

          • Proteus mirabilis

        • Such targeted activity of the first generation cephalosporins makes these drugs an option for treating uncomplicated urinary tract infections.

    • First generation cephalosporins do not exhibit activity against:⁵

      • Methicillin-resistant Staphylococcus aureus (MRSA)

      • Enterococcus species

  • Resistance Mechanisms

    • Bacteria have evolved several mechanisms to evade the action of β-lactam antibiotics.

      • A common mechanism of acquired resistance is the production of β-lactamase enzymes.

        • These enzymes hydrolyze the amide bond in the β-lactam ring, rendering the antibiotic molecule inactive.

          • While first-generation cephalosporins are more stable to the simple penicillinases produced by staphylococci, they are susceptible to degradation by many of the more complex and potent β-lactamases produced by Gram-negative bacteria.^7,8,9

      • The second critical mechanism of resistance involves modification of the target PBPs, which reduces the binding affinity of the drug.⁷  

        • This mechanism is the basis for methicillin resistance in staphylococci, which is conferred by the acquisition of the mecA gene.

          • This gene encodes for a novel PBP, PBP2a, which has a very low affinity for all β-lactam antibiotics except for the newest fifth-generation cephalosporins.

            • This mechanism also underlies the intrinsic resistance of enterococci.

              • In Gram-negative organisms, resistance can also be mediated by decreased permeability of the outer membrane, due to mutations in porin channels that restrict drug entry, or by the action of active efflux pumps that expel the antibiotic from the cell.¹⁰

September, 2025