Editing Beta-lactamase (section)

==Treatment of ESBL/AmpC/carbapenemases==

===General overview===

In general, an isolate is suspected to be an ESBL producer when it shows ''in vitro'' susceptibility to the [[cephamycin]]s ([[cefoxitin]], [[cefotetan]]) but resistance to the third-generation cephalosporins and to [[aztreonam]]. Moreover, one should suspect these strains when treatment with these agents for gram-negative infections fails despite reported ''in vitro'' susceptibility. Once an ESBL-producing strain is detected, the laboratory should report it as "resistant" to all penicillins, cephalosporins, and aztreonam, even if it is tested (in vitro) as susceptible.{{Citation needed|date=August 2010}} Associated resistance to [[aminoglycosides]] and [[trimethoprim]]-[[sulfamethoxazole]], as well as high frequency of co-existence of [[fluoroquinolone]] resistance, creates problems. Beta-lactamase inhibitors such as [[clavulanate]], [[sulbactam]], and [[tazobactam]] ''in vitro'' inhibit most ESBLs, but the clinical effectiveness of beta-lactam/beta-lactamase inhibitor combinations cannot be relied on consistently for therapy. [[Cephamycins]] ([[cefoxitin]] and [[cefotetan]]) are not hydrolyzed by majority of ESBLs, but are hydrolyzed by associated AmpC-type β-lactamase.  Also, β-lactam/β-lactamase inhibitor combinations may not be effective against organisms that produce AmpC-type β-lactamase.  Sometimes these strains decrease the expression of outer membrane proteins, rendering them resistant to cephamycins. ''In vivo'' studies have yielded mixed results against ESBL-producing ''[[K. pneumoniae]]''. ([[Cefepime]], a fourth-generation cephalosporin, has demonstrated ''in vitro'' stability in the presence of many ESBL/AmpC strains.) Currently, [[carbapenems]] are, in general, regarded as the preferred agent for treatment of infections due to ESBL-producing organisms. Carbapenems are resistant to ESBL-mediated hydrolysis and exhibit excellent ''in vitro'' activity against strains of [[Enterobacteriaceae]] expressing ESBLs.{{Citation needed|date=August 2010}}

=== According to genes ===

====ESBLs====

Strains producing only ESBLs are susceptible to [[cephamycins]] and [[carbapenems]] ''in vitro'' and show little if any [[inoculum effect]] with these agents.

For organisms producing '''TEM''' and '''SHV''' type ESBLs, apparent ''in vitro'' sensitivity to [[cefepime]] and to [[piperacillin/tazobactam]] is common, but both drugs show an inoculum effect, with diminished susceptibility as the size of the inoculum is increased from 10<sup>5</sup> to 10<sup>7</sup> organisms.

Strains with some '''CTX-M'''–type and '''OXA'''-type ESBLs are resistant to [[cefepime]] on testing, despite the use of a standard inoculum.

====Inhibitor-resistant β-lactamases====

Although the inhibitor-resistant TEM variants are resistant to inhibition by [[clavulanic acid]] and [[sulbactam]], thereby showing clinical resistance to the beta-lactam—beta lactamase inhibitor combinations of [[amoxicillin]]-[[clavulanate]] ([[Co-amoxiclav]]), [[ticarcillin]]-[[clavulanate]], and [[ampicillin/sulbactam]], they remain susceptible to inhibition by [[tazobactam]] and subsequently the combination of [[piperacillin/tazobactam]].

====AmpC====

AmpC-producing strains are typically resistant to [[oxyimino-beta lactams]] and to [[cephamycins]] and are susceptible to [[carbapenems]]; however, diminished porin expression can make such a strain carbapenem-resistant as well.

====Carbapenemases====

Strains with '''IMP-, VIM-, and OXA'''-type carbapenemases usually remain susceptible. Resistance to non-beta-lactam antibiotics is common in strains making any of these enzymes, such that alternative options for non-beta-lactam therapy need to be determined by direct susceptibility testing. Resistance to [[fluoroquinolones]] and [[aminoglycosides]] is especially high.

===According to species===

====''Escherichia coli'' or ''Klebsiella''====

For infections caused by ESBL-producing ''[[Escherichia coli]]'' or ''[[Klebsiella]]'' species, treatment with [[imipenem]] or [[meropenem]] has been associated with the best outcomes in terms of survival and bacteriologic clearance. [[Cefepime]] and [[piperacillin/tazobactam]] have been less successful. [[Ceftriaxone]], [[cefotaxime]], and [[ceftazidime]] have failed even more often, despite the organism's susceptibility to the antibiotic ''in vitro''. Several reports have documented failure of [[cephamycin]] therapy as a result of resistance due to porin loss. Some patients have responded to [[aminoglycoside]] or [[Quinolone antibiotic|quinolone]] therapy, but, in a recent comparison of [[ciprofloxacin]] and [[imipenem]] for bacteremia involving an ESBL-producing ''[[K. pneumoniae]]'', [[imipenem]] produced the better outcome

====''Pseudomonas aeruginosa''====

There have been few clinical studies to define the optimal therapy for infections caused by ESBL producing ''[[Pseudomonas aeruginosa]]'' strains.