Evaluation of β-Lactamase Inhibitors in Disk Tests for Detection of Plasmid-Mediated AmpC β-Lactamases in Well-Characterized Clinical Strains of
            <i>Klebsiella</i>
            spp

Black, Jennifer Ann; Thomson, Kenneth S.; Buynak, John D.; Pitout, Johann

doi:10.1128/jcm.43.8.4168-4171.2005

Cited by 38 publications

(28 citation statements)

References 22 publications

(16 reference statements)

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“…Syn 2190 has also shown utility for the challenging clinical task of identifying production of plasmid-mediated AmpC ␤-lactamase in Klebsiella spp. In combination with cefotetan, Syn 2190 achieved 100% specificity and 91% sensitivity for AmpC producers (28). However, Syn 2190 has lower affinity than tazobactam for class A enzymes and could not restore susceptibility to cephalosporins in bacteria expressing these enzymes.…”

Section: Monobactam Derivativesmentioning

confidence: 99%

Three Decades of β-Lactamase Inhibitors

Drawz¹,

2010

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SUMMARYSince the introduction of penicillin, β-lactam antibiotics have been the antimicrobial agents of choice. Unfortunately, the efficacy of these life-saving antibiotics is significantly threatened by bacterial β-lactamases. β-Lactamases are now responsible for resistance to penicillins, extended-spectrum cephalosporins, monobactams, and carbapenems. In order to overcome β-lactamase-mediated resistance, β-lactamase inhibitors (clavulanate, sulbactam, and tazobactam) were introduced into clinical practice. These inhibitors greatly enhance the efficacy of their partner β-lactams (amoxicillin, ampicillin, piperacillin, and ticarcillin) in the treatment of seriousEnterobacteriaceaeand penicillin-resistant staphylococcal infections. However, selective pressure from excess antibiotic use accelerated the emergence of resistance to β-lactam-β-lactamase inhibitor combinations. Furthermore, the prevalence of clinically relevant β-lactamases from other classes that are resistant to inhibition is rapidly increasing. There is an urgent need for effective inhibitors that can restore the activity of β-lactams. Here, we review the catalytic mechanisms of each β-lactamase class. We then discuss approaches for circumventing β-lactamase-mediated resistance, including properties and characteristics of mechanism-based inactivators. We next highlight the mechanisms of action and salient clinical and microbiological features of β-lactamase inhibitors. We also emphasize their therapeutic applications. We close by focusing on novel compounds and the chemical features of these agents that may contribute to a “second generation” of inhibitors. The goal for the next 3 decades will be to design inhibitors that will be effective for more than a single class of β-lactamases.

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Section: Monobactam Derivativesmentioning

confidence: 99%

Three Decades of β-Lactamase Inhibitors

Drawz¹,

2010

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“…Another approach for AmpC detection is the use of an inhibitor for this ␤-lactamase class analogous to the use of (36,37). Unfortunately, these inhibitors are not commercially available.…”

Section: Ampc Detectionmentioning

confidence: 99%

AmpC β-Lactamases

2009

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SUMMARY AmpC β-lactamases are clinically important cephalosporinases encoded on the chromosomes of many of the Enterobacteriaceae and a few other organisms, where they mediate resistance to cephalothin, cefazolin, cefoxitin, most penicillins, and β-lactamase inhibitor-β-lactam combinations. In many bacteria, AmpC enzymes are inducible and can be expressed at high levels by mutation. Overexpression confers resistance to broad-spectrum cephalosporins including cefotaxime, ceftazidime, and ceftriaxone and is a problem especially in infections due to Enterobacter aerogenes and Enterobacter cloacae, where an isolate initially susceptible to these agents may become resistant upon therapy. Transmissible plasmids have acquired genes for AmpC enzymes, which consequently can now appear in bacteria lacking or poorly expressing a chromosomal blaAmpC gene, such as Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis. Resistance due to plasmid-mediated AmpC enzymes is less common than extended-spectrum β-lactamase production in most parts of the world but may be both harder to detect and broader in spectrum. AmpC enzymes encoded by both chromosomal and plasmid genes are also evolving to hydrolyze broad-spectrum cephalosporins more efficiently. Techniques to identify AmpC β-lactamase-producing isolates are available but are still evolving and are not yet optimized for the clinical laboratory, which probably now underestimates this resistance mechanism. Carbapenems can usually be used to treat infections due to AmpC-producing bacteria, but carbapenem resistance can arise in some organisms by mutations that reduce influx (outer membrane porin loss) or enhance efflux (efflux pump activation).

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“…producing plasmidmediated AmpC β-lactamases have been involved in several worldwide outbreaks of infection. Often, genes encoding plasmidmediated AmpC beta-lactamases coexist in the same plasmid with genes encoding mechanisms of resistance to other classes of antibiotics, leaving clinicians with limited therapeutic options [29]. Of the twelve Enterobacteriaceae strains with positive results on the initial screening test for ESBL, eleven were resistant to cefotaxime and three to ceftazidime.…”

Section: Discussionmentioning

confidence: 99%