Drug Mech: Antibiotics 3

All b-lactam antibiotics have a unique four-membered lactam ring in their chemical structures.

They share features of chemistry, mechanism of action, pharmacologic and clinical effects, and immunologic characteristics.

Penicillins

Cephalosporins

Carbapenems

Monobactams

They inhibit the Transpeptidation or Cross-Linking Step in Peptidoglycan synthesis of the Gram Positive Bacterial Cell Wall.

1) Inactivation of the b-lactam antibiotic by b-lactamases.

• 2) Modification of target PBPs. Some
• resistant strains produce PBPs that have low
• affinity for binding to the b-lactams.

• 3) Impaired penetration of the antibiotic into the cell. This occurs only in Gram-negative bacteria.
• Absence of membrane protein channels (porins) in the outer membrane of the cell wall of Gram-negative bacteria or down-regulation of their production can prevent or greatly reduce antibiotic entry into the cell.

4) Active efflux. This also occurs in Gram-negative bacteria due to the presence of efflux membrane protein pumps in the outer membrane of the cell wall.

b-Lactamase production by bacterial cells is the most common mechanism of bacterial resistance to the b-lactam antibiotics.

More than 890 different b-lactamases have been identified. They are produced by both Gram-positive and Gram-negative bacteria. Some of them are relatively narrow in substrate specificity and will hydrolyze penicillins but not cephalosporins. Others are much broader in spectrum and will hydrolyze more than one subclass of the b-lactams. Carbapenems, which are highly resistant to hydrolysis by narrow-spectrum b-lactamases, are hydrolyzed by carbapenemases (which are b-lactamases) and metallo-b-lactamases.

• b-Lactamase is a ‘protease’ capable of
• inactivating a b-lactam antibiotic. A small amount of the b-lactamase enzyme can destroy a very large amount of the b-lactam antibiotic.

The synthesis of b-lactamases is R-Factor mediated and, in some cases, induced by the presence of b lactam antibiotics.

• The inactivation of Beta Lactam Antibiotics by Serine Beta Lactamases:
• 

1) Clavulanic Acid

2) Sulbactam

3) Tazobactam

They are suicide substrates for the b-lactamase enzyme.

They are potent inhibitors against Beta Lactamases and cause prolonged inactivation of Group A b-lactamases; other b-lactamase groups are resistant.

They exhibit a very weak antibacterial activity (ie, they are weak inhibitors of PBPs).

They are used in combination with b-lactamase-sensitive penicillins to treat b-lactamase-producing infections. These Beta Lactamase Inhibitors can't kill bacterial cells, which is why we use them in combination with another antibiotic.

Class I are highly electronegative because of the Oxygen, Sulfur and Nitrogen species in the bonds (see below).

• Cross-linking takes place, but there is prolonged inactivation of the Beta Lactamase enzyme, which allows the antibiotic used in combination to go in and do its thing.
• 

This class consists of the Carbapenems (e.g., imipenem, meropenem, doripenem).

The carbapenems are suicide substrates for the b-lactamase enzyme.

Carbapenems are Beta Lactam antibiotics, but as a bonus, they also inhibit Beta Lactamases....which makes them able to kill bacterial cells and inhibit certain Beta Lactamases. Therefore, they are NOT used in combination.

• They are weak inhibitors and cause only transient inhibition of some b-lactamases (including TEM, SHV, CTX-M, and AmpC b-lactamases). However, carbapenems can be hydrolyzed by
• carbapenemases and metallo-b-lactamases (including KPC, VIM, IMP, GIM, SPM, NDM, and OXA b-lactamases). Metallo-b-lactamases are very resistant and some of the nastiest type of beta lactamases.

• Unlike Class I inhibitors, the carbapenems exhibit a very potent antibacterial activity (ie,
• they are potent inhibitors of PBPs).

Class II are also much less electronegative than Class I because there is a Carbon at the chiral center.

Cross-linking does NOT take place, but hydrolysis does.

• Class I Inhibitors
• potent inhibitors of Beta Lactamases
• weak antibacterial activity
• must be used in combination
• very electronegative chemistry
• cross-linking happens

• Class II Inhibitors
• weak inhibitors of Beta Lactamases
• potent antibacterial activity
• not used in combination
• much less electronegative chemistry
• cross-linking does not happen

It is a synergistic antibiotic combination.

DO NOT physically mix an aminoglycoside and a b-lactam antibiotic. When physically mixed together, both b-lactams and the aminoglycosides will be inactivated (see below). This inactivation reaction does not occur in vivo.

• Drawing of inactivated combination
• 

This combination is widely used in the hospital setting, but the pharmacist must know NOT to mix them in the same IV bag because they are chemically incompatible and will render each other inactive.