Beta-lactam antibiotics exhibit the most common treatment for bacterial infections and continue to be the prominent cause of resistance to beta-lactam antibiotics among Gram-negative bacteria worldwide. The persistent exposure of bacterial strains to a multitude of beta-lactams has induced dynamic and continuous production and mutation of beta-lactamases in these bacteria, expanding their activity against most beta-lactam antibiotics.
Resistance to beta-lactams in Enterobacteriaceae is mainly conferred by beta-lactamases. These enzymes inactivate beta-lactam antibiotics by hydrolysis. Beta-lactamases are commonly classified according to two systems: the Ambler molecular classification and the Bush–Jacoby–Medeiros functional classification. The Ambler scheme classifies beta-lactamases into four classes according to the protein homology of enzymes. Beta-lactamases of class A, C, and D are serine beta-lactamase and class B enzymes are metallo-beta-lactamases. The Bush–Jacoby–Medeiros functional scheme is based on functional properties of enzymes and on their ability to hydrolyze specific beta-lactam classes. This classification was updated in 2010. The updated system includes group 1 (class C) cephalosporinases; group 2 (classes A and D) broad-spectrum, inhibitor-resistant, extended-spectrum beta-lactamases and serine carbapenemases; and group 3 (class B) metallo-beta-lactamases.
Group 1 enzymes are cephalosporinases belonging to molecular class C. They are more active on cephalosporins than benzylpenicillin. It includes AmpC beta-lactamases. AmpC-hyperproducing mutants are resistant to penicillins, aztreonam, third generation cephalosporins including cefotaxime, ceftazidime, ceftriaxone and even ertapenem when the enzyme is massively expressed. Cefepime, a fourth-generation cephalosporin with broader spectrum activity compared to ceftriaxone, is a poor inducer of AmpC beta-lactamase. Many AmpC-producing organisms are susceptible to cefepime because cefepime is poorly hydrolyzed by the AmpC beta-lactamase enzyme. However, the role of cefepime in treating infections caused by AmpC-producing organisms is controversial because of the inoculum effect.
Group 2 (classes A and D) represent the largest group of beta-lactamases, it includes ESBL producing Enterobacteriaceae and carbapenemases (class A) and OXA beta-lactamases (class D).
ESBL are enzymes capable of hydrolyzing and inactivating a wide variety of beta-lactams, including third-generation cephalosporins, penicillins, and aztreonam. Most ESBLs of clinical interest are encoded by genes located on plasmids. These plasmids may also carry genes encoding resistance to other multiple drug classes including aminoglycosides and fluoroquinolones. The main ESBL enzymes imparting antibiotic resistance are TEM-, SHV-, and CTX-M. Although hyperproduction of beta-lactamases or additional resistance mechanisms may hamper the antibiotic effectiveness, most TEM, SHV and CTX-M variants remain susceptible in vitro to the “old” beta-lactam/beta-lactam inhibitor combinations such as piperacillin-tazobactam. However, the efficacy of piperacillin-tazobactam for treating serious ESBL infections is controversial. Yet, there have been concerns that in vitro susceptibility may not reliably translate into clinical efficacy. This has been based largely on concerns over inoculum effects, the co-location of other beta-lactamase enzymes (which may not be well inhibited by beta-lactamase inhibitors) on acquired plasmids and the potential for additional resistance mechanisms such as alterations in outer membrane proteins. Furthermore, in critically ill patients the pharmacokinetic properties of beta-lactam agents are modified and these patients may have adverse outcomes as a result of sub-optimal antibiotic exposure. Rates of CTX-M infections have increased during the last decade compared with rates of TEM- and SHV- infections. The diffusion of CTX-M-producing Enterobacteriaceae are common in Southeast Asia and Eastern Mediterranean countries.
The OXA-type beta-lactamases are so named because of their oxacillin-hydrolyzing abilities. OXA beta-lactamases have resistance limited to the penicillins, but some became able to confer resistance to cephalosporins. OXA-1 and OXA-10 beta-lactamases have only a narrow hydrolytic spectrum. However, other OXA beta-lactamases including OXA-11, -14, -15, -16, -28, -31, -35 and -45 confer resistance to cefotaxime, ceftazidime and aztreonam. OXA-23 and OXA-48 are classes of carbapenemases that belong to OXA-type beta-lactamases with carbapenem-hydrolyzing activities. While OXA-23 appears most frequently in A. baumannii, OXA-48 enzymes have now become widespread in the Enterobacteriaceae, especially in Mediterreanean countries.
K. pneumoniae carbapenemases (KPCs) are beta-lactamases produced by Gram-negative bacteria. They efficiently hydrolyse penicillins, all cephalosporins, monobactams, beta-lactamase inhibitors, and even carbapenems. KPCs are becoming an increasingly significant problem worldwide. KPC-producing K. pneumoniae pose a serious threat in clinical situations where administration of effective empiric antibiotics is essential to prevent mortality following bacteraemia and infections in immunocompromised patients including organ transplant recipients and those with cancer.
Group 3 (Class B) metallo-beta-lactamases (MBLs) differ structurally from the other beta-lactamases by their requirement for a zinc ion at the active site. They are all capable of hydrolysing carbapenems. In contrast to the serine beta-lactamases, the MBLs have poor affinity or hydrolytic capability for monobactams and are not inhibited by clavulanic acid or tazobactam. The most common metallo-beta-lactamase families include the IMP, VIM and NDM.
Two new cephalosporin beta-lactamase inhibitor combinations, ceftolozane/tazobactam and ceftazidime/avibactam, have been approved recently for the treatment of patients with complicated intra-abdominal infections. Ceftolozane/tazobactam is active in vitro against many ESBL-producing Enterobacteriaceae, It is also active against many strains of P. aeruginosa and appears to be the most potent currently available beta-lactam or beta-lactam-beta-lactamase inhibitor combination against this organism. Ceftazidime/avibactam has activity against most strains of Enterobacteriaceae, including ESBL-producing strains and AmpC beta-lactamase-producing strains. Ceftazidime/avibactam is the only currently available beta-lactam-beta-lactamase inhibitor combination with substantial in vitro activity against KPC-producing Enterobacteriaceae. Both ceftolozane/tazobactam and ceftazidime/avibactam are not active against MBL-producing micro-organisms.
Reference
Sartelli M, Weber DG, Ruppé E, Bassetti M, Wright BJ, Ansaloni L, et al. Antimicrobials: a global alliance for optimizing their rational use in intra-abdominal infections (AGORA). World J Emerg Surg. 2016 Jul 15;11:33.
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