Penicillin G and Penicillin V Pharmacology and Therapeutics

• Mechanism of Action (Summary)

  • Penicillin G and penicillin V are β-lactam antibiotics that exert a bactericidal effect by inhibiting bacterial cell wall synthesis¹ 

    • Penicillins bind to penicillin-binding proteins (PBPs), the enzymes (e.g. DD-transpeptidase) responsible for the final cross-linking step of peptidoglycan in the bacterial cell wall.^1,2 

    • By acylating the active site of PBPs with their β-lactam ring, penicillins prevent peptidoglycan cross-links from forming, which critically weakens the cell wall.¹

      • The weakened cell wall cannot maintain osmotic integrity; as a result, water influx leads to cell swelling and lysis.¹ 

        • Accumulated cell wall precursors trigger bacterial autolytic enzymes (autolysins) to degrade the existing cell wall, amplifying the bactericidal effect¹

          • This mechanism selectively targets proliferating bacteria and explains penicillin’s synergy with aminoglycosides: inhibition of cell-wall synthesis allows aminoglycosides to better penetrate and reach their intracellular ribosomal targets.¹

    • Penicillins do not affect human cells (which lack peptidoglycan walls), accounting for their high therapeutic index in clinical use.

• Antimicrobial Spectrum and Activity

  • Penicillin G (benzylpenicillin) and Penicillin V (phenoxymethylpenicillin) are natural, first-generation penicillins with a relatively narrow antimicrobial spectrum focused primarily on Gram-positive organisms.²

    • These agents are highly active against Gram-positive cocci such as Streptococcus species (Groups A for example Streptococcal Pharyngitis³, B, C, G, and viridans streptococci)⁴ and many Streptococcus pneumoniae (pneumococcus) strains.²

    • Viridans Streptococci

      "This is a photomicrographs of a blood culture specimen, which revealed the presence of numbers of Gram-positive, α-hemolytic viridans group streptococci (VGB) bacteria, most of which were arranged in long chains, resembling strings of pearls. "The viridans group streptococci bacteria included number of streptococcal species that are either α-hemolytic or non-hemolytic. "The term, Streptococcus viridans, has, and is still used today note the viridans streptococci group, but identifying an entire group using a single species name is inaccurate." Attribution CDC/Dr. Mike Miller, 1978 https://phil.cdc.gov/Details.aspx?pid=2897

    • Enterococcus faecalis is also susceptible, though serious enterococcal infections may be approached with penicillin combined with an aminoglycoside for bactericidal synergy.² 

      • First-choice antibiotics for enterococcal infections have been approached with combinations of aminopenicillins, vancomycin, daptomycin, and linezolid.

        • In approaching endocarditis caused by Enterococcus faecalis, high-dose ampicillin in combination with ceftriaxone may provide optimal treatment in view of nephro-oto-, and vestibular toxicities associated with aminoglycosides.⁵

      • Effective treatment of Enterococcus faecalis infections has  been demonstrated utilizing combination therapy involving bacteriophage (phage) and ß-lactam antibiotics. Further study is required before phage-antibiotic may become implemented clinically.⁶

        • Note that enterococci, Gram-positive, anaerobic bacteria are recognized uropathogens.

          • These bacteria are also the leading cause of variety of infection such as endocarditis, bacteremia, pneumonia, endocarditis as well as UTIs. Enterococci have also been identified as the second-leading pathogen in catheter-associated UTIs.

          • Furthermore, enterococci exhibit highly malleable genes facilitating rapid development and extensive development of resistance to many antibacterials (for example, vancomycin) enterococci also exhibit natural resistance to other antibiotics such as quinolones, oxazolidinone, and cephalosporins.⁶ 

    • Non-penicillinase-producing Staphylococcus aureus are intrinsically susceptible to penicillin, but most staphylococci now produce penicillinase and are resistant.

      • Penicillin G/V also cover certain Gram-positive rods (bacilli) such as Corynebacterium diphtheriae, Bacillus anthracis (anthrax), Erysipelothrix rhusiopathiae, and Clostridial species (e.g. C. perfringens causing gas gangrene).^1,2 

        • Penicillin G/V have limited Gram-negative coverage: notable susceptible organisms include: Neisseria meningitidis (meningococcus) and Pasteurella multocida^1,2

          • Most common cause of infection after a scratch or bite from a domestic pet.⁷

          • Neisseria meningitidis (meningococcus)

            "Scanning electron micrograph owes single N. Meningitidis cell (colorized in blue) with this dense meshwork of Pili (colorized in yellow). The scale bar is 1 µm." Attribution Arthur Charles-Orszag, CC BY-SA 4.0 <https://creativecommons.org/licenses/by-sa/4.0>, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Neisseria_meningitidis_Charles-Orszag_2018.png

          •  

            Pasturella multocida⁸

            "Gram stain of Pasteurella multocida shown as Gram-negative, nonmotile coccobacilli" Attribution Figure 3 from: Pak S Valencia Decker J Valencia V Askaroglu Y Pasteurella multocida pneumonia in an immunocompetent patient: Case report and systematic review of literature. Lung India 2018 May-June;35(3): 237-240. https://pmc.ncbi.nlm.nih.gov/articles/PMC5946557/

      • Historically Neisseria gonorrhoeae (gonococcus) was penicillin-sensitive^1,2 

        • However, gonococcal resistance is now so prevalent that penicillin is no longer used first-line for gonorrhea.¹

          • "This low-resolution photomicrographs reveals the histopathology an acute case of gonococcal urethritis using Gram-stain technique. "This slide is used to demonstrate the non-random distribution of gonococci among polymorphonuclear neutrophils. Note that there both intracellular and extracellular bacteria in the field of view." Attribution CDC/ Joe Millar, Public domain, via Wikimedia Commons https://commons.wikimedia.org/wiki/File:Gonococcal_urethritis_PHIL_4085_lores.jpg

      • Natural penicillins have activity against most anaerobes of the oral flora (e.g. Peptostreptococcus, Actinomyces israelii), but not against Bacteroides fragilis (which produces β-lactamase).

      • Spirochetes are very susceptible: penicillin G is the treatment of choice for Treponema pallidum (syphilis) and remains highly effective, as T. pallidum has never developed significant resistance to penicillin.¹

      • Penicillin G also treats Leptospira and is used in Lyme disease (caused by Borrelia burgdorferi) in certain situations.⁹ 

      • Overall, penicillin G and V retain excellent activity against many Gram-positive aerobes, select Gram-negatives, and other pathogens (spirochetes, anaerobes) if they do not produce β-lactamase.⁹