• The Aminopenicillins:  Ampicillin and Amoxicillin

  • Spectrum of Activity

    • Ampicillin was initially developed (in the 1960s) to broaden penicillin’s spectrum to include more Gram-negative organisms and to allow oral administration.2

    • Spectrum

      • The aminopenicillins retain strong activity against many Gram-positive cocci, including Streptococcus pneumoniae, Streptococcus pyogenes (Group A strep), and other streptococci, as well as susceptible Enterococcus faecalis.^3,4

        • Aminopenicilins have no activity against Staphylococcus aureus on their own if the strain produces penicillinase (the vast majority of S. aureus do), because the enzyme rapidly inactivates ampicillin/amoxicillin.

        • Listeria monocytogenes (a Gram-positive bacillus) is notably very susceptible to aminopenicillins which is a distinguishing feature, as these drugs penetrate host cells moderately well and can kill this intracellular pathogen.³

        • Aminopenicillins also cover certain anaerobes such as Clostridium species and Actinomyces (except C. difficile, which is inherently resistant), and they cover Corynebacterium spp. and other miscellaneous Gram-positives.³

      • Where aminopenicillins extended penicillin’s spectrum was in Gram-negative coverage.

        • These agents can penetrate the outer membrane of some Gram-negatives and resist stomach acid.

          • Organisms in the bowel and urinary tract such as non-β-lactamase-producing strains of Escherichia coli and Proteus mirabilis are typically susceptible .³

            •  They also have activity against Salmonella and Shigella species (ampicillin can treat typhoid fever and shigellosis if the isolate is sensitive).⁴

            •  Haemophilus influenzae is another Gram-negative target – ampicillin/amoxicillin can kill H. influenzae, but only if the strain does not produce beta-lactamase.³ 

            • Many wild-type H. influenzae were originally ampicillin-susceptible, but now >30% produce a penicillinase, making them resistant to aminopenicillins unless a β-lactamase inhibitor is added.

            • Aminopenicillins do not reliably cover Klebsiella, Enterobacter, Pseudomonas, Serratia, or Proteus vulgaris, among others – either due to intrinsic penicillinase production or other resistance factors.⁴

              • For instance, Klebsiella pneumoniae inherently produces a penicillinase that destroys ampicillin, so K. pneumoniae is considered intrinsically resistant.⁶ 

              • Pseudomonas aeruginosa is also intrinsically resistant; aminopenicillins cannot penetrate Pseudomonas’s outer membrane effectively and Pseudomonas has multiple efflux pumps and chromosomal AmpC β-lactamase.⁵ 

                • Pseudomonas aeruginosa (multidrug-resistant)⁹

                  The 2019 threat assessment (estimat) for 2019 from the CDC for multidrug-resistant Pseudomonas aeruginosa: 32,600 cases & 2700 deaths. Antibiotic Resistance Threats in the United States 2019. Centers for Disease Control and Prevention (CDC). https://www.cdc.gov/antimicrobial-resistance/media/pdfs/2019-ar-threats-report-508.pdf9,10

                • Therefore, aminopenicillins are ineffective for pseudomonal infections (antipseudomonal penicillins like piperacillin are needed in that context).

    • Resistance Mechanisms

      • The foremost mechanism of resistance to ampicillin/amoxicillin in community pathogens is beta-lactamase enzyme production, which cleaves the beta-lactam ring and inactivates the drug.²

      • Many Gram-negative bacteria (e.g. E. coli, H. influenzae, Moraxella, Proteus) commonly harbor plasmid-mediated beta-lactamases (like TEM-1) that confer resistance. This concern can be circumvented by combining the aminopenicillin with a beta-lactamase inhibitor, as described earlier, effectively extending coverage to beta-lactamase producing strains of those species.³ 

      • Another mechanism is alteration of PBPs: for example, penicillin-resistant Streptococcus pneumoniae has modified PBP structures (e.g. PBP2x and PBP2b changes) that lower affinity for all penicillins, including amoxicillin.⁷ 

        • Higher doses of amoxicillin (e.g. high-dose amoxicillin for otitis media or pneumonia) may still overcome intermediate pneumococcal resistance in some cases by achieving higher tissue concentrations.

        • Enterococcus faecium often exhibits resistance to ampicillin via a modified PBP (PBP5). The majority of E. faecium strains (especially hospital-associated ones) are ampicillin-resistant, whereas E. faecalis is usually ampicillin-susceptible.

        • Porin changes in Gram-negatives can also reduce entry of aminopenicillins into the periplasm.⁸ 

      • In summary, while aminopenicillins have a useful broad spectrum, resistance is now common in many organisms, and local susceptibility patterns must be considered.

        • Clinical use is often guided by whether the likely pathogens are beta-lactamase negative and known to be ampicillin-susceptible.

September, 2025