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Penicillins - Spectrum of Antibacterial Activity

Updated: Sep 9, 2023


This short review is designed for medical students taking boards exams. An attempt was made to be thorough, without including excessive amounts of details. For exact antibiotic coverage, please refer to textbooks of infectious diseases or other reliable sources.


The penicillin antibiotics can be divided into four groups based on their antimicrobial activity:

  • Anti-staphylococcal penicillins (e.g., flucloxacillin, dicloxacillin, nafcillin, oxacillin)

  • Natural penicillins (e.g., penicillin G, penicillin V)

  • Aminopenicillins (e.g., ampicillin, amoxicillin)

  • Anti-pseudomonal penicillins (e.g., carbenicillin, ticarcillin, piperacillin)

Natural Penicillins

The natural penicillins (e.g., penicillin G, penicillin V) are narrow-spectrum antibiotics. Despite their narrow spectrum of activity, they are effective against a large proportion of gram-positive organisms, gram-negative cocci, and many anaerobes.


The efficacy of natural penicillins against Streptococcus pyogenes and syphilis is well documented, and because they also cover oral anaerobes, they are also very useful for odontogenic infections. Penicillin G and its variants, such as penicillin V, remain the agents of choice for a variety of infections. To date, no resistant strains of group A and B streptococci have emerged. Below is a table of some common indications for penicillin therapy.

Common indications for penicillin therapy

Group A streptococcal infections (e.g., strep throat)

Group B streptococcal infections (e.g., neonatal sepsis) Syphilis

Odontogenic infections

Pneumococcal infections (if sensitive)

Meningococcal infections (if sensitive)

This is not a complete list of indications.


Unfortunately, many other bacteria have developed resistance to these agents, including pneumococci, enterococci, meningococci, and Bacteroides spp. Also note that this class of penicillin is not effective against gram-negative rods, and because it is a penicillinase-susceptible drug, it is not effective against most staphylococcal species either.

Anti-staphylococcal penicillins

The penicillinase-resistant penicillins have a very narrow-spectrum activity and are primarily used to treat methicillin-sensitive staphylococcal aureus (MSSA). These antibiotics also have activity against streptococcal species but less so than the natural penicillins. Thus, a natural penicillin (e.g., penicillin V) is preferable to an anti-staphylococcal penicillin (e.g., oxacillin) for treating a group A beta-hemolytic Streptococcus pyogenes throat infection.

Skin Infections

Anti-staphylococcal penicillins can be used empirically for certain skin infections (e.g., impetigo) as they are active against both MSSA and streptococci. Penicillin V, however, would be a poor choice for the empiric treatment of such skin infections since they do not have staphylococcal coverage.

Severe MSSA Infections

The anti-staphylococcal penicillins are the most effective antibiotics for treating MSSA. They provide even better coverage against MSSA than antibiotics that treat MRSA (e.g., vancomycin). So for severe MSSA infections, anti-staphylococcal penicillins are a better choice than vancomycin.


These penicillins are ineffective against enterococci, anaerobes, gram-negative organisms, and methicillin-resistant staphylococcus aureus (MRSA).


The aminopenicillins have a broader spectrum of activity than the natural penicillins. This group of antibiotics retains the gram-positive coverage of penicillin G, while adding greater activity against gram-negative organisms.


The enhanced antibacterial activity of aminopenicillins allows for the treatment of a variety of different infections. For example, amoxicillin can be effective for middle ear infections caused by non-beta-lactamase-producing strains of Haemophilus influenza. It can also treat urinary tract and enteric infections if the pathogens detected are sensitive to the antibiotic. In combination with inhibitors of beta-lactamase (e.g., clavulanic acid), even wider coverage is obtained, including against MSSA, Moraxella catarrhalis, anaerobes (including Bacteroides fragilis), and gram-negative organisms (e.g., Pasteurella multocida).


Even with the addition of a beta-lactamase inhibitor, the aminopenicillins are not active against MRSA, penicillin- resistant S. pneumoniae or vancomycin-resistant enterococci.

Anti-pseudomonal penicillins

The anti-pseudomonal penicillins have extended coverage against gram-negative rods and can be used to treat infections due to Pseudomonas aeruginosa and Enterobacter species. They are also active against anaerobes, including Bacteroides fragilis, and thus can be used to treat intraabdominal infections. These antipseudomonal penicillins are also used in combination with a beta-lactamase inhibitor.


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