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What unique feature do all Beta Lactams have?
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.
What are the four classifications of Beta Lactams?
What is the Mechanism of Action for Beta Lactamases?
They inhibit the Transpeptidation or Cross-Linking Step in Peptidoglycan synthesis of the Gram Positive Bacterial Cell Wall.
What are the Mechanisms of Bacterial Resistance to the Beta Lactam Antibiotics?
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.
Inactivation of Beta Lactam Antibiotics by Beta Lactamases
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
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:
Class I Inhibitors of Beta Lactamases
1) Clavulanic Acid
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.
What are some examples of Antibiotics that use Class I Inhibitors to combat Beta Lactamases?
Class II Inhibitors of Beta Lactamases
This class consists of the Carbapenems
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
Class I versus Class II: Inhibitors of Beta Lactamases
- Class I Inhibitorspotent inhibitors of Beta Lactamases
- weak antibacterial activity
- must be used in combination
- very electronegative chemistrycross-linking happens
- Class II Inhibitorsweak inhibitors of Beta Lactamases
- potent antibacterial activity
- not used in combination
- much less electronegative chemistry
- cross-linking does not happen
Aminoglycoside + Beta Lactam Combination
It is a synergistic
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