Resistance to ticarcillin-potassium clavulanate among clinical isolates of the family Enterobacteriaceae: role of PSE-1 beta-lactamase and high levels of TEM-1 and SHV-1 and problems with false susceptibility in disk diffusion tests

Sanders, Christine C.; Iaconis, Joseph P.; Bodey, Gerald P.; Samonis, George

doi:10.1128/aac.32.9.1365

Cited by 88 publications

(71 citation statements)

References 23 publications

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“…Within several years of the introduction of clavulanate combinations for clinical use, resistance to amoxicillin-clavulanate and ticarcillin-clavulanate was observed in isolates of E. coli and K. pneumoniae (247,248,376,446). In 1987, Martinez et al reported resistance rates in E. coli in Madrid hospitals and estimated that of amoxicillin-resistant strains, 20 to 30% were co-amoxicillin-clavulanate resistant (248).…”

Section: Inhibitor-resistant Class a ␤-Lactamasesmentioning

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: Inhibitor-resistant Class a ␤-Lactamasesmentioning

confidence: 99%

Three Decades of β-Lactamase Inhibitors

Drawz¹,

2010

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“…Both strains were isolated from urine. Different kinetics studies have suggested that the amoxicillin (ticarcillin)-clavulanate resistance in these strains is due to the rapid hydrolysis of substrate by the enzyme rather than to any lack of susceptibility of the enzyme for the inhibitor (21). However, the presence of additional mechanisms such as efflux or altered permeability in this and the other strains has not been evaluated, but the detected enzymes have been documented as being responsible for the phenotype.…”

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confidence: 99%

Prevalence of Clinical Isolates of Escherichia coli Producing Inhibitor-Resistant β-Lactamases at a University Hospital in Barcelona, Spain, over a 3-Year Period

Miró

Navarro

Mirelis

et al. 2002

Antimicrob Agents Chemother

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About 7% of 7,252 nonduplicated clinical Escherichia coli strains from a Spanish hospital showed reduced susceptibility to amoxicillin-clavulanate. Of these, 0.37% produced the IRTs TEM-30, TEM-31, TEM-33, TEM-34, TEM-37, TEM-40, TEM-51, and TEM-54; 5.3% were probable class C ␤-lactamase overproducers; 0.8% were probable TEM-1 hyperproducers; 0.18% produced OXA-30; 0.15% overexpressed SHV-1; and 0.03% produced a PSE-1 enzyme.Resistance to ␤-lactam-␤-lactamase inhibitor combinations in Escherichia coli isolates has been reported to be due to hyperproduction of class A ␤-lactamases (such as TEM-1 or SHV-1), class D plasmid-mediated enzyme, or chromosomal or plasmidic class C ␤-lactamase and/or to modified outer membrane permeability (4,15,17,27). Another mechanism, first recognized in 1992, is the production of inhibitor-resistant derivatives of TEM-1, TEM-2, SHV-1, and OXY-2-derived ␤-lactamases (1-4, 9, 16, 22). The most common inhibitorresistant enzymes were derivatives of TEM-1 (IRTs) and have been detected in several members of the Enterobacteriaceae from different European countries (1, 3-11, 23, 26, 28). However, only a few French reports have documented their prevalence (6,10,11,26,28). The aim of this study was to evaluate the prevalence of IRTs in our hospital from a total of 7,252 clinically significant E. coli strains isolated between 1996 and 1998. Based on ␤-lactam resistance patterns by a disk diffusion technique, we detected 499 strains with a zone diameter for amoxicillin-clavulanate of Ͻ17 mm. The susceptibility pattern was confirmed by an agar dilution method according to NCCLS guidelines (13). We characterized the ␤-lactamases implicated in amoxicillin-clavulanate resistance by analytical isoelectric focusing and determination of kinetic constants, as previously described (12,19,20). Finally, according to the isoelectric point (pI), a PCR using primers for bla SHV -, bla TEM -, and bla OXA-1 -related enzymes was done as published elsewhere (12,20). The PCR products of 907, 1,017, and 921 bp, respectively, were further sequenced by the dideoxy method using fluorescent primers and an automatic laser fluorescent DNA sequencer (Pharmacia Biotech). The bla PSE genes were amplified with the primers PSE-1UP (5Ј-TAG CCA TAT TAT GGA GCC TC-3Ј) and PSE-1DN (5Ј-CCT TAT CAG CGC GAC TGT-3Ј). The PCR product of 940 bp was further sequenced by using in addition the internal primers PSE-1F (5Ј-CGC TTC CCG TTA ACA AGT AC-3Ј) and PSE-1B (5Ј-CTG GTT CAT TTC AGA TAG CG-3Ј).Among the 7,252 strains evaluated, 368 were assumed to be AmpC overproducers (due to cefoxitin resistance and decreased susceptibility to broad-spectrum cephalosporins, without synergy between them and clavulanate) and were disregarded. In 1996, we studied isolates that were highly resistant to amoxicillin-clavulanate, cefoxitin, and broad-spectrum cephalosporins, and they have already been reported as AmpC overproducers (20). However, 16 strains susceptible to cefoxitin (MICs were between 8 and 32 g/ml) were also assumed to be AmpC overproducer...

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“…For plasmid-mediated and class IV chromosomal P-lactamases, activity in sonic extracts was quantified by using 100 ,uM nitrocefin (22 Table 1. The percentages of strains susceptible to each of the study drugs were 82% for cefixime (MIC, < 1 ,ug/ml), 62% for cefuroxime (MIC, <4 pug/ml), 58% for cephalexin (MIC, <8 pug/ml), and 44% for cefaclor (MIC, .8 pLg/ml).…”

Section: Methodsmentioning

confidence: 99%

“…Most were also resistant to multiple P-lactam antibiotics, and the mechanism(s) responsible for the resistance was identified by (i) characterization of the type and amount of 1-lactamase produced by isoelectric focusing and substrate-inhibitor profiles (22,25) and (ii) analysis of outer membrane proteins (OMPs) (24). Many of these strains have been described previously, since they are resistant to ticarcillin-clavulanic acid (22). Overall, only 20% of the 50 isolates were susceptible to ticarcillinclavulanic acid and only 6% were susceptible to amoxicillinclavulanic acid.…”

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beta-Lactamase stability and in vitro activity of oral cephalosporins against strains possessing well-characterized mechanisms of resistance

Sanders

1989

Antimicrob Agents Chemother

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The in vitro activity of four oral cephalosporins was assessed in dilution tests with 50 isolates of the family Enterobacteriaceae possessing well-characterized mechanisms of resistance to Il-lactam antibiotics. The interaction of the drugs with a broad array of 3-lactamases was also determined in spectrophotometric assays and tests for enzyme induction. Overall, the percentages of strains susceptible to each of the study drugs were 82% for cefixime, 62% for cefuroxime, 58% for cephalexin, and 44% for cefaclor. The poor activity of the older cephalosporins was due to a high degree of susceptibility to hydrolysis by both plasmid-mediated and chromosomally mediated P-lactamases. For cefaclor, higher MICs were associated with higher levels of plasmid-mediated 3-lactamases in the strains. Resistance to cefuroxime was seen primarily among strains expressing high levels of class I or IV 1-lactamase. Resistance to cefixime was seen only among strains expressing high levels of class I enzymes. Neither cefixime nor cefuroxime was a strong inducer of class I ,I-lactamases, although enzyme induction did appear to play a role in cefuroxime resistance in a strain of Serratia marcescens. The consistently greater activity of cefixime over cefuroxime was found not to be due to greater drug permeation into the cell. Rather, it appeared to result from the high affinity of the drug for target enzymes.There has recently been intense activity in the development of new orally absorbable cephalosporins. Some of these compounds are directly absorbable in their active forms (2,6,7,10,11,13,16,28,30), while others are esters which must be enzymatically cleaved to their active forms after absoi-ption (3,5,9,17,18,20,27,29). Many of these newer compounds possess expanded antimicrobial spectra compared with spectra of older oral cephalosporins, which is thought to be due in large part to a diminished susceptibility to hydrolysis by 1-lactamases (1-6, 8, 9, 15-17, 19-21, 26, 27, 29). Thus, the purpose of this study was to assess various factors that might influence the activity of oral cephalosporins. To accomplish this, the interactions of four oral cephalosporins with a broad array of 1-lactamases were assessed, as was the activity of the cephalosporins against organisms possessing well-characterized mechanisms of resistance to 3-lactam antibiotics. Cephalexin, cefaclor, cefuroxime, and cefixime were chosen for study, since the two former drugs represent the older compounds and the latter represent two of the most P-lactamase stable of the newer compounds.MATERIALS AND METHODS Strains. Fifty isolates of diverse genera of the family Enterobacteriaceae were examined in this study. They included 23 Escherichia coli, 11 Klebsiella spp., 4 Enterobacter spp., 7 Citrobacter spp., 3 Serratia spp., and one each Providencia stuartii and Morganella morganii isolates. Most were clinical isolates, although three were laboratory-derived mutants from clinical isolates. Most were also resistant to multiple P-lactam antibiotics, and the mechanism(s) resp...

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Resistance to ticarcillin-potassium clavulanate among clinical isolates of the family Enterobacteriaceae: role of PSE-1 beta-lactamase and high levels of TEM-1 and SHV-1 and problems with false susceptibility in disk diffusion tests

Cited by 88 publications

References 23 publications

Three Decades of β-Lactamase Inhibitors

Three Decades of β-Lactamase Inhibitors

Prevalence of Clinical Isolates of Escherichia coli Producing Inhibitor-Resistant β-Lactamases at a University Hospital in Barcelona, Spain, over a 3-Year Period

beta-Lactamase stability and in vitro activity of oral cephalosporins against strains possessing well-characterized mechanisms of resistance

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