Β-lactam antibiotic

Beta-lactam antibiotics are a type of antibiotics that penicillins and the non-penicillin drugs such as cephalosporins, penems, monobactams.

Betalactam AB

Structure

They share a basic chemical structure that includes a three-carbon, one-nitrogen cyclic amine structure known as the beta-lactam ring. The side chain associated with the beta-lactam ring is a variable group attached to the core structure by a peptide bond; the side chain variability contributes to antibacterial activity. As of the date of this publication, FDA has approved over 34 beta-lactam compounds as active ingredients in drugs for human use.

Antibiotics mechanism of action

Classes

Beta-lactam antibiotics include the following five classes:

• penicillins (e.g., ampicillin, oxacillin)
• cephalosporins (e.g., cephalexin, cefaclor)
• penems (e.g., imipenem, meropenem)
• carbacephems (e.g., loracarbef)
• monobactams (e.g., aztreonam)

Clinical importance

Since the β-lactam ring is part of the core structure of several antibiotic families such as penicillins, cephalosporins, carbapenems, and monobactams, they are an important class of antibiotics.

Mechanism of action

The betalactams work by inhibiting bacterial cell wall biosynthesis. This has a lethal effect on bacteria.

Antibiotic resistance

Many bacteria populations will typically contain a subgroup that is resistant to β-lactam antibiotics

Allergies

• Allergic reactions associated with penicillins and non-penicillin beta-lactams range from rashes to life-threatening anaphylaxis.
• Immunoglobulin E (IgE) antibodies mediate the immediate hypersensitivity reactions that are responsible for the symptoms of hay fever, asthma, hives, and anaphylactic shock.
• IgE-mediated hypersensitivity reactions are of primary concern because they may be associated with significant morbidity and mortality.
• Patients with a history of hypersensitivity to penicillin may also experience IgE-mediated reactions to other beta-lactams, such as cephalosporins and penems.

Cross sensitivity

• All non-penicillin beta-lactams also have the potential to sensitize individuals, and subsequent exposure to penicillin may result in severe allergic reactions in some patients.
• Although the frequency of hypersensitivity reactions due to cross-reactivity between beta-lactam classes can be lower than the risk within a class, the hazard posed is present11 and potentially life-threatening.
• The potential health hazard of non-penicillin beta-lactams therefore is similar to that of penicillins.

No minimum threshold dose known

• It is difficult to define the minimal dose below which allergic responses are unlikely to occur in humans. • There is a lack of suitable animal or receptor testing models that are predictive of human sensitivity. • The threshold dose at which allergenic response could occur is extremely low and difficult to detect with current analytical methods.

Beta-Lactamase Inhibitors

• Beta-lactam compounds such as clavulanic acid, tazobactam, and sulbactam have weak antibacterial activity but are irreversible inhibitors of many beta-lactamases.
• These compounds, which are potential sensitizing agents, are typically used in combination with specific betalactam agents to preserve antibacterial activity (e.g., amoxicillin-clavulanate, piperacillin-tazobactam).
• Because these compounds are almost always used in combination with specific beta-lactam agents, any clinical observations of hypersensitivity reactions likely would be attributed to the beta-lactam antibiotic component rather than the inhibitor.
• Although there have been no case reports confirming anaphylactic reactions to a beta-lactamase inhibitor that is also a beta-lactam, these compounds are potentially sensitizing agents, and manufacturers should implement controls to reduce the risk of cross-contamination with beta-lactamase inhibitors as with all other beta-lactam products.

Beta-Lactam Intermediates and Derivatives

Some beta-lactam intermediate compounds and derivatives also possess similar sensitization and cross–reactivity properties. Beta-lactam intermediate compounds usually are API precursor materials that undergo molecular change or purification before use in the manufacture of betalactam antibiotic APIs. As a result of these changes, the intermediate compounds may develop antigenic characteristics that can produce allergic reactions.

Intermediates

• 6-aminopenicillanic acid (6-APA) serves as the intermediate for the formation of all synthetic penicillins that are formed by attaching various side chains.
• The structure of 6-APA includes unbroken beta-lactam and thiazolidine rings. The beta-lactam ring is relatively unstable, and it commonly breaks open.
• In the case of 6-APA, this breakage leads to the formation of a penicilloyl moiety, which is the major antigenic determinant of penicillin. This moiety is thought to be a common cause of penicillin urticarial reaction.17 Degradation of 6-APA can also result in the formation of minor
• antigenic determinants, including penicilloic acids, penaldic acid, and penicillamine.

Cause of anaphylaxis

Anaphylactic reactions to penicillins usually are due to the presence of IgE antibodies to minor determinants in the body. Although 6-APA is not a true antibiotic, it still carries with it a potential to induce allergenicity.

Derivatives

• Derivatives are unintended by-products that occur during the manufacturing process (i.e., an impurity or degradant).
• Like intermediates, beta-lactam derivatives could have sensitizing properties and may develop antigenic properties that can produce allergic reactions.

Beta-lactam manufacturing

• Beta-lactam chemical manufacturing processes including, but not limited to, fermentation and synthesis, may create beta-lactam intermediates or derivatives with unknown health consequences.
• Although the health risk of sensitization and cross-reaction is difficult to predetermine for beta-lactam intermediates and derivatives and is not always well-defined, manufacturing controls intended to reduce the risk of cross-contamination should be considered for operations that produce beta-lactam intermediates or derivatives.

Β-lactam antibiotic Resources
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