• Penicillin G and Penicillin V Pharmacology and Therapeutics

  • Bacterial Resistance

    • Resistance to penicillin G/V is widespread in many bacteria due to several mechanisms.

      • The most common mechanism is bacterial production of β-lactamase enzymes (penicillinases) that hydrolyze the β-lactam ring, inactivating penicillin.¹ 

      • Many Staphylococcus aureus strains evolved a penicillinase shortly after was introduced to clinical practice.

      • Staphylococcus aureus

        "Produced by the National Institute of Allergy and Infectious Diseases (NIAID), this digitally colorize, scanning electron microscopic (SEM) image, depicts numbers of mustard -colored spheroid shaped, methicillin-resistant, Staphylococcus aureus (MRSA) bacteria, which were surrounded by orange -colored cellular debris." Attribution National Institute of Allergy and Infectious Diseases (NIAID) https://phil.cdc.gov/Details.aspx?pid=18133

      • At present >90% of S. aureus are penicillin-resistant, rendering natural penicillins ineffective for routine staph infections.¹

      • Some Gram-negative bacteria (e.g. certain Haemophilus and Bacteroides species) also produce β-lactamases that destroy penicillin.

        • A second resistance mechanism is alteration of the target PBPs so that penicillin binds with less affinity.²

        • For example, penicillin-resistant Streptococcus pneumoniae and Neisseria gonorrhoeae have modified PBPs with reduced β-lactam affinity, requiring higher penicillin concentrations for effect.³ 

        • Methicillin-resistant S. aureus (MRSA) carries a novel PBP (PBP2a) that penicillins cannot effectively bind thus conferring resistance to all β-lactams.⁴

      • The third mechanism is reduced antibiotic permeability or efflux.

        • Gram-negative bacteria with an outer membrane may prevent adequate penetration of penicillin⁵  or actively pump it out.¹

          • This intrinsic barrier makes many Gram-negative rods (e.g. E. coli, Pseudomonas) inherently less susceptible to penicillin G/V.⁶   

            • Subsequently, penicillins (ampicillin, etc.) were developed that penetrate Gram-negative bacteria more effectively.

          • Because of these resistance factors, penicillin is no longer first-line for certain diseases it once cured. 

            • Examples include gonorrhea and meningococcal meningitis which are more likely treated with third-generation cephalosporins due to resistance.¹

        • Similarly, penicillin should not be used for S. aureus infections unless the isolate is confirmed susceptible (such cases are now uncommon).¹

        • To overcome β-lactamase–mediated resistance, penicillins can be combined with β-lactamase inhibitors (e.g. amoxicillin-clavulanate) or modified (e.g. oxacillin, dicloxacillin) to resist staphylococcal penicillinase¹ 

        • However, such approaches apply to other penicillins, not penicillin G or V themselves.

August, 2025