A summarized version of my presentation on penicillins for my pharmacology course. Penicillins are β-lactams antibacterial drugs that inhibit bacterial cell wall synthesis, thus categorized as bactericidal.
History
Discovered by Alexander Fleming, in 1928. Accidentally observed that staphylococci did not grow around the mold of Penicillium rubens.
However, it wasn’t until 1941 the Australian pathologist Howard Florey and German-born British biochemist Ernst Boris Chain successfully developed a method to produce a pure form of penicillin on a large scale. This breakthrough eventually led to mass production, with penicillin becoming widely available by the end of World War II.
It revolutionized the medical world, providing an effective treatment for many bacterial infections, and earning Fleming, Florey, and Chain the 1945 Nobel Prize in Physiology of Medicine.
Fun fact:
Amalia Fleming, the wife of Alexander Fleming, was a Greek physician & politician that aided the Greek Resistance against the occupation of Axis powers.
Overview
Structure
Structurally, this class of beta-lactams particularly possesses a distinct 4-membered beta-lactam ring, in addition to a thiazolide ring and an R side chain.
The main distinguishing feature between variants within this family is the R substituent. This side chain is connected to the 6-aminopenicillanic acid residue and results in variations in the antimicrobial spectrum, stability, and susceptibility to beta-lactamases of each individual bactericidal drug.
Mechanism of Action
The mechanism of action for Penicillins primarily focuses on inhibiting bacterial cell wall synthesis, an essential process for bacterial growth and survival. The beta-lactam ring in penicillins mimics the D-Alanyl-D-Alanine terminal structures found in the precursors of bacterial cell walls. This mimicry allows penicillins to bind to penicillin-binding proteins (PBPs), which are enzymes involved in cell wall synthesis.
Upon binding, the normal function of the PBPs is disrupted, leading to faulty cell wall production. As a result of these alterations in cell wall integrity, bacteria can undergo lysis due to imbalances in cellular osmotic pressure, thus achieving the bactericidal effect of penicillins.
Moreover, the R side chain of penicillin allows for its diverse range of action against different types of bacteria, due to variations affecting the antimicrobial spectrum, stability, and resistance to beta-lactamases.
Antibacterial Spectrum & Types
Naturally occurring
Obtained from fermentations of the fungus Penicillum chrysogenum
Penicillin G
Penicillin G is a crucial member of the penicillin family due to its unique characteristics. It doesn’t absorb well through the gastrointestinal tract, so it is predominantly used intravenously. Due to its selectivity, most species of Streptococci show sensitivity towards it, leading to effective infection control in most cases.
However, it is worth noting that the majority of Staphylococcus aureus species have developed resistance to it, rendering the penicillin G less effective in such situations.
Despite this, penicillin G is the drug of choice when it comes to the treatment of gas gangrene brought about by Clostridium perfringens. Similarly, its efficacy is demonstrated in the treatment of infections like syphilis caused by Treponema.
Penicillin G is effective in treating syphilis, one essential thing to note is the potential occurrence of the Jarisch-Herxheimer reaction. This is a systemic reaction, often observed within the first few hours of therapy in patients treated for syphilis. Symptoms may include fever, chills, headache, and myalgia. While it can be alarming, the reaction is typically self-limiting and can be managed symptomatically.
Penicillin V
Penicillin V, a less potent variant of Penicillin G, is typically administered orally due to its acid-stable properties. This makes it highly effective and safe for gastric administration.
While it delivers a milder impact compared to Penicillin G, it is widely utilized in treating less severe infections, making it an essential component in the spectrum of Penicillins.
Antistaphylococcal penicillins
Also known as penicillinase-resistant penicillins, are a subset of penicillins that are particularly effective against Staphylococcus infections. Unlike regular penicillins, they are resistant to penicillinase (beta-lactamase) enzymes secreted by certain bacteria to nullify penicillins’ bactericidal activity.
Methicillin, although no longer commonly used due to allergic reactions and resistance, was one of the first of these penicillins. It paved the way for other, more robust, antistaphylococcal penicillins.
Flucloxacillin, oxacillin, and dicloxacillin, largely have replaced methicillin.
They all have a similar mechanism of action, they inhibit bacterial cell wall synthesis by binding to penicillin-binding proteins, ultimately leading to bacterial cell death. These medications are primarily used for skin and soft tissue infections caused by Staphylococcus aureus, including cellulitis and impetigo.
Although they are generally well-tolerated, they can cause side effects like gastrointestinal issues and allergic reactions. These drugs should be used with caution in patients with a history of penicillin allergy and kidney disease. Oxacillin and dicloxacillin are often more desirable due to their ability to be administered orally compared to flucloxacillin, which is typically given parenterally.
Aminopenicillins
They are classified as broad-spectrum antibiotics due to their utility against both gram-negative and gram-positive bacteria. Amoxicillin and Ampicillin are common examples of Aminopenicillins.
Ampicillin
Ampicillin, exhibits similar antibacterial spectrum as amoxicillin but differs crucially in its pharmacokinetics and mode of administration.
While it is effective against many Gram-positive and select Gram-negative bacteria, it lacks stability in gastric acid, which can lower its systemic absorption when taken orally.
Therefore, it is frequently administered intravenously or intramuscularly in a clinical setting. Ampicillin’s spectrum can be notably widened by the co-administration of a beta-lactamase inhibitor such as sulbactam.
Amoxicillin
Distinguished by its wide usage in treating a variety of bacterial infections. It is favored for its broad-spectrum antibacterial activity against both Gram-positive and Gram-negative microbes, including H. influenzae, E. coli, and S. pneumoniae. Its enhanced stability against gastric acid ensures a higher systemic absorption when administered orally, a major advantage over its contemporaries.
Additionally, amoxicillin is often prescribed in combination with clavulanic acid, a beta-lactamase inhibitor, to tackle bacteria producing beta-lactamase enzymes which can otherwise inactivate amoxicillin.
Extended-spectrum
Piperacillin
Piperacillin is a potent extended-spectrum penicillin developed to counter the rise of resistant bacterial infections.
It has broader antibacterial activity than most other penicillins, particularly effective against Gram-negative bacteria including pseudomonas aeruginosa. Piperacillin also has superior activity against enterococci, however, it remains ineffective against methicillin-resistant Staphylococcus aureus (MRSA). It functions by inhibiting bacterial cell wall synthesis, leading to cell death.
Piperacillin is often combined with tazobactam, a beta-lactamase inhibitor, to overcome resistance caused by beta-lactamase enzymes.
Ticarcillin
Ticarcillin, another extended-spectrum penicillin, has a similar mechanism to piperacillin, targeting bacterial cell wall synthesis. But it differs from piperacillin in its antimicrobial spectrum.
It is less active against Gram-negative bacteria and has minimal activity against pseudomonas aeruginosa. However, it is more effective against staphylococci and streptococci bacteria.
Ticarcillin is frequently used with a beta-lactamase inhibitor, clavulanic acid, to combat beta-lactamase-associated resistance.
Comparison
Comparing both, ticarcillin has a lower sodium load which may be beneficial in patients requiring sodium restriction.