infectious diseases
Beta Lactams
Beta Lactamases
Beta-lactamases are a diverse class of enzymes produced by bacteria that break open the beta-lactam ring, inactivating the beta-lactam antibiotic. Some beta-lactamases are encoded on mobile genetic elements (eg, plasmids); others are encoded on chromosomes. Beta-lactamase production is among the most clinically important mechanisms of resistance for gram-negative bacterial pathogens. Understanding the most common types of beta-lactamases produced by different pathogens can help with susceptibility interpretation, therapeutic decision making, and infection control practices. There are thousands of different types of beta-lactamases; multiple classification schemes exist, but the Ambler classification scheme is the most widely used. It groups beta-lactamases by class on the basis of molecular homology. Classes A, C, and D have a serine residue at the active site, whereas class B enzymes have zinc at the active site, ie, metallo-beta-lactamases (MBLs). Class A includes extended-spectrum BLs (ESBLs) andKlebsiella pneumoniaecarbapenemases (KPCs), class B includes the MBLs (NDM, IMP, and VIM), class C includes AmpC, and class D includes the oxacillinases (OXAs). Extended-spectrum beta-lactamases (ESBLs), including TEM, SHV, CTX-M, and GES enzymes, are plasmid-encoded enzymes primarily found inKlebsiellaspecies,Escherichia coli, and other Enterobacterales. ESBLs can hydrolyze extended-spectrum penicillins (eg, piperacillin), most cephalosporins (cephamycins are not hydrolyzed by most ESBLs), and monobactams. Klebsiella pneumoniaecarbapenemases (KPCs) are similar to ESBLs except that they also hydrolyze carbapenems. These enzymes first emerged inK. pneumoniaebut have spread to other Enterobacterales. Metallo-beta-lactamases (MBLs), including VIM, IMP, and NDM, use a zinc ion to hydrolyze all beta-lactams, including carbapenems, except the monobactamaztreonam. MBLs can be chromosomally encoded in some organisms, such as the L1 MBL ofStenotrophomonas maltophilia, or can be acquired as can occur with a variety of gram-negative organisms includingKlebsiella,Pseudomonas, andAcinetobacterspecies. These enzymes are not inhibited by currently available beta-lactamase inhibitors. AmpC enzymes hydrolyze most cephalosporins (except forcefepime), cephamycins (eg,cefoxitin,cefotetan), monobactams (eg,aztreonam), and penicillins. AmpC beta-lactamase may be chromosome- or plasmid-encoded. Chromosomal AmpC expression can become induced by certain antibacterials or may become constitutively expressed (ie, overproduced) in de-repressed mutants. Plasmid-encoded AmpC expression is also constitutive and may be spread among bacteria usually lacking this beta-lactamase, such asEscherichia coli,Klebsiella pneumoniae, andProteus mirabilis. Isolates with inducible AmpC expression may initially test as susceptible to 3rd-generation cephalosporins, which can complicate treatment decisions, especially for Enterobacterales.Enterobacter cloacae,K. aerogenes, andCitrobacter freundiishould be regarded as harboring inducible AmpC, and 3rd-generation cephalosporins should be avoided regardless of susceptibility results.Proteus vulgaris,Morganella morganii,Serratia marcescens,Providenciaspecies may also overproduce AmpC, but clinically significant expression is less common. OXA beta-lactamases primarily hydrolyze narrow spectrum penicillins but certain OXA variants such as the plasmid encoded OXA 48 can hydrolyze carbapenems, even while leaving many cephalosporins active. 