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Beta-lactamases and Beta-lactamase Inhibitors: What does the Intensivist Need to Know?

Updated: Apr 9, 2023

Multidrug-resistant (MDR) organisms have become a major concern in Intensive Care Units (ICUs) worldwide. These organisms are bacteria that have developed resistance to multiple antibiotics, making it difficult to treat infections they cause. The increase in MDR organisms in ICUs has led to higher mortality rates and increased healthcare costs.


Mechanism of Antibiotic Resistance

Antibiotic resistance occurs when bacteria evolve mechanisms to protect themselves from the action of antibiotics. The mechanisms of antibiotic resistance in bacteria are complex and varied. Understanding these mechanisms is important for the appropriate use of antibiotics by the clinician and for the effective treatment of infections caused by antibiotic-resistant bacteria. There are several mechanisms of antibiotic resistance against beta-lactam agents, including beta-lactamases, porins, efflux pumps, and alterations in penicillin-binding proteins (PBPs).

Beta-lactamases are enzymes produced by some bacteria that destroy beta-lactam antibiotics, such as penicillins and cephalosporins, making it difficult to treat infections caused by these bacteria. Porins are channels in the bacterial cell membrane that allow the entry of antibiotics into the bacterial cell. Some bacteria have evolved mechanisms to reduce the size or number of porins, making it harder for antibiotics to penetrate the cell and kill the bacteria. Efflux pumps are cellular pumps that actively transport antibiotics out of the bacterial cell, reducing the concentration of antibiotics inside the cell and reducing their effectiveness. PBPs are enzymes responsible for synthesizing the bacterial cell wall, and antibiotics such as penicillins work by inhibiting their activity. Some bacteria have evolved mutations in their PBPs that reduce the affinity of antibiotics for these enzymes, reducing the effectiveness of these antibiotics.


What is the most common multidrug-resistant (MDR) organism encountered in your ICU?

  • Methicillin-resistant Staphylococcus aureus (MRSA)

  • Extended-spectrum beta-lactamase (ESBL)-producing Escherichi

  • carbapenem-resistant Enterobacterales (CRE)

  • Carbapenem-resistant Acinetobacter baumannii (CRAB)



Beta-lactamases Classification

Beta-lactamase is an enzyme produced by some bacteria that destroys the beta-lactam rings in the beta-lactam antibiotics. Beta-lactamase acts by cleaving the beta-lactam ring, which is a crucial structure of the beta-lactam antibiotics and is responsible for their antibacterial activity. Once the beta-lactam ring is cleaved, the antibiotics become inactive and cannot bind to and inhibit bacterial cell wall synthesis.


The Ambler classification is a system for categorizing beta-lactamases based on their molecular structure and function. There are four classes in the Ambler classification: Class A, Class B, Class C, and Class D.


The most frequent form of beta-lactamases are Class A beta-lactamases. These enzymes, which are serine β-lactamases, encompass penicillinases that act against penicillins, cephalosporinases that target first and second generation cephalosporins, and extended-spectrum beta-lactamases (ESBLs) that are effective against most beta-lactam agents including penicillins, cephalosporins, and monobactam with the exception of cefomycins (i.e. cefoxitin) and carbapenems. This class also encompass certain carbapenemases, such as KPC, and are capable of attacking most beta-lactam agents, except for advanced cephalosporins like cefiderocol. A diverse array of bacteria are capable of producing these enzymes, with the most common being Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Haemophilus influenzae, and Proteus mirabilis.

Class B beta-lactamases are also known as the metallo-β-lactamases because they require zinc for activity. These enzymes are capable of hydrolyzing a wide range of beta-lactam antibiotics, including carbapenems, and are often associated with multidrug-resistant organisms. They are found in a wide range of organisms including Escherichia coli, Klebsiella pneumoniae, other enterobacteriacae, pseudomonas aeruginosa, and acinetobater species.


Class C beta-lactamases belong to the serine β-lactamase family, with AmpC being the dominant enzyme in this group. AmpC is typically found on the chromosome and frequently produced by members of the Enterobacteriaceae family, such as Enterobacter, Citrobacter, and chromosomal Serratia. In some cases, the encoding of AmpC can also occur on a plasmid, as seen in species like Salmonella and Escherichia coli. This enzyme is active against all the beta-lactam agents with the exception of cefepime and carbapenems.


Class D beta-lactamases, also known as oxacillinases (OXA), are primarily present in enterobacteriaceae, Acinetobacter baumannii, and Klebsiella pneumoniae. These beta-lactamases are effective against nearly all beta-lactam agents, including carbapenems, with a few exceptions among third and fourth generation cephalosporins.


Beta-lactamase Inhibitors

The first generation of β-lactamase inhibitors clavulanic acid, sulbactam, and tazobactam are widely used to enhance the activity of beta-lactam agents. These are β-lactam compounds that function by creating permanent, covalent bonds with the catalytic serine β-lactamases, causing inactivation of the enzyme by staying attached to the active site serine residue. They are referred to as 'suicide inactivators'. These inhibitors are highly effective against class A serine beta-lactamases but typically have limited efficacy against enzymes in classes B, C, or D. Over time, some class A beta-lactamases have developed resistance through mutations, while others, such as KPC, exhibit reduced susceptibility to inhibition. Tazobactam has varying levels of effectiveness against class C beta-lactamases. None of these compounds are markedly active against the current carbapenemases.


The second generation of β-lactamase inhibitors consists of non-β-lactam compounds, such as avibactam and relebactam, which belong to the class of diazabicyclooctanones. Avibactam is combined with either ceftazidime or aztreonam, while relebactam is combined with imipenem. These compounds serve as reversible inhibitors for class A carbapenemases (e.g. KPC-2), extended-spectrum β-lactamases (e.g. CTX-M), class C cephalosporinases (e.g. AmpC, Enterobacter cloacae complex, and P aeruginosa), and some class D enzymes, particularly the OXA-48 carbapenemase (mainly with avibactam). Unfortunately, these compounds do not effectively block metallo-β-lactamases in a manner that produces significant clinical results.


The third generation of β-lactamase inhibitors are non-β-lactam compounds featuring a cyclic boronic acid structure. These inhibitors target class A serine carbapenemases, but do not possess any antibacterial properties on their own. Vaborbactam, in particular, was designed to inhibit serine β-lactamases like KPC, by forming a covalent bond with the catalytic serine side chain through its boronate component. Vaborbactam is highly effective against serine β-lactamases, particularly KPC-2, but has no impact on metallo-β-lactamases


Overall, there are six approved serine β-lactamase inhibitors in different combinations with antibiotics, but none of these inhibitors work against metallo-β-lactamases. Newer boronic acid beta-lactamase inhibitors are in development and will have activity against metallo-β-lactamases.


Conclusion

Multidrug-resistant (MDR) organisms are bacteria that have developed resistance to multiple antibiotics, causing concern in Intensive Care Units (ICUs) worldwide. The mechanisms of antibiotic resistance in bacteria are complex and varied. The most frequent forms of beta-lactamases, which destroy beta-lactam antibiotics, are Class A beta-lactamases. Class B beta-lactamases, also known as metallo-β-lactamases, are capable of hydrolyzing a wide range of beta-lactam antibiotics, including carbapenems, and are often associated with multidrug-resistant organisms. Class C beta-lactamases belong to the serine β-lactamase family, with AmpC being the dominant enzyme in this group, and class D beta-lactamases are primarily present in enterobacteriaceae, Acinetobacter baumannii, and Klebsiella pneumoniae. The first generation of β-lactamase inhibitors, such as clavulanic acid, sulbactam, and tazobactam, are highly effective against Class A serine beta-lactamases but have limited efficacy against other classes of beta-lactamases. The second generation of β-lactamase inhibitors consists of non-β-lactam compounds, such as avibactam and relebactam, and the third generation features cyclic boronic acid structure inhibitors, such as vaborbactam. None of these inhibitors work against metallo-β-lactamases but newer agents are in development and active against metallo-β-lactamases.







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