scholarly journals In vitro emergence of carbapenem resistance in extended-spectrum β-lactamase-producing Klebsiella pneumoniae clinical isolates

2015 ◽  
Vol 9 (02) ◽  
pp. 218-221
Author(s):  
Hugo E Villar ◽  
Gabriela Santana ◽  
Monica B Jugo ◽  
Patricia Perren ◽  
Mariana Hidalgo ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Full Text ◽  
Carbapenem Resistance ◽  
Clinical Isolates ◽  
Extended Spectrum

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scholarly journals Sigmoid E max Modelling to Define the Fixed Concentration of Enmetazobactam for MIC Testing in Combination with Cefepime

2021 ◽  
Author(s):  
Philipp Knechtle ◽  
Stuart Shapiro ◽  
Ian Morrissey ◽  
Cyntia De Piano ◽  
Adam Belley
Keyword(s):  
Antibacterial Activity ◽  
Minimum Inhibitory Concentration ◽  
Klebsiella Pneumoniae ◽  
Inhibitory Concentration ◽  
Carbapenem Resistance ◽  
Clinical Isolates ◽  
Extended Spectrum ◽  
Fixed Concentration

Use of carbapenem antibiotics to treat infections caused by Enterobacterales expressing increasingly aggressive extended-spectrum β-lactamases (ESBL) has contributed to the emergence of carbapenem resistance. Enmetazobactam is a novel ESBL inhibitor being developed in combination with cefepime as a carbapenem-sparing option for infections caused by ESBL-producing Enterobacterales . Cefepime-enmetazobactam checkerboard minimum inhibitory concentration (MIC) profiles were obtained for a challenge panel of cefepime-resistant ESBL-producing clinical isolates of Klebsiella pneumoniae . Sigmoid E max modelling described cefepime MIC as a function of enmetazobactam concentration with no bias. A concentration of 8 μg/ml enmetazobactam proved sufficient to restore >95% of cefepime antibacterial activity in vitro against >95% of isolates tested. These results support a fixed concentration of 8 μg/ml of enmetazobactam for MIC testing.

scholarly journals In Vitro Activities of the Potent, Broad-Spectrum Carbapenem MK-0826 (L-749,345) against Broad-Spectrum β-Lactamase-and Extended-Spectrum β-Lactamase-Producing Klebsiella pneumoniae and Escherichia coli Clinical Isolates

1999 ◽  
Vol 43 (5) ◽  
pp. 1170-1176 ◽  
Author(s):  
Joyce Kohler ◽  
Karen L. Dorso ◽  
Katherine Young ◽  
Gail G. Hammond ◽  
Hugh Rosen ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Broad Spectrum ◽  
Bacterial Resistance ◽  
Clinical Isolates ◽  
Inoculum Level ◽  
E Coli ◽  
Extended Spectrum ◽  
Group 1

ABSTRACT An important mechanism of bacterial resistance to β-lactam antibiotics is inactivation by β-lactam-hydrolyzing enzymes (β-lactamases). The evolution of the extended-spectrum β-lactamases (ESBLs) is associated with extensive use of β-lactam antibiotics, particularly cephalosporins, and is a serious threat to therapeutic efficacy. ESBLs and broad-spectrum β-lactamases (BDSBLs) are plasmid-mediated class A enzymes produced by gram-negative pathogens, principallyEscherichia coli and Klebsiella pneumoniae. MK-0826 was highly potent against all ESBL- and BDSBL-producingK. pneumoniae and E. coli clinical isolates tested (MIC range, 0.008 to 0.12 μg/ml). In E. coli, this activity was associated with high-affinity binding to penicillin-binding proteins 2 and 3. When the inoculum level was increased 10-fold, increasing the amount of β-lactamase present, the MK-0826 MIC range increased to 0.008 to 1 μg/ml. By comparison, similar observations were made with meropenem while imipenem MICs were usually less affected. Not surprisingly, MIC increases with noncarbapenem β-lactams were generally substantially greater, resulting in resistance in many cases. E. coli strains that produce chromosomal (Bush group 1) β-lactamase served as controls. All three carbapenems were subject to an inoculum effect with the majority of the BDSBL- and ESBL-producers but not the Bush group 1 strains, implying some effect of the plasmid-borne enzymes on potency. Importantly, MK-0826 MICs remained at or below 1 μg/ml under all test conditions.

scholarly journals Diversity of mucoid to non-mucoid switch among carbapenemase-producing Klebsiella pneumoniae

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Adriana Chiarelli ◽  
Nicolas Cabanel ◽  
Isabelle Rosinski-Chupin ◽  
Pengdbamba Dieudonné Zongo ◽  
Thierry Naas ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Phenotypic Variation ◽  
Point Mutations ◽  
Carbapenem Resistance ◽  
Selective Advantage ◽  
Clinical Isolates ◽  
Phenotypic Characterization ◽  
Colony Development ◽  
Genome Comparison

Abstract Background Klebsiella pneumoniae is a leading cause of intractable hospital-acquired multidrug-resistant infections and carbapenemase-producing K. pneumoniae (CPKp) are particularly feared. Most of the clinical isolates produce capsule as a major virulence factor. Recombination events at the capsule locus are frequent and responsible for capsule diversity within Klebsiella spp. Capsule diversity may also occur within clonal bacterial populations generating differences in colony aspect. However, little is known about this phenomenon of phenotypic variation in CPKp and its consequences. Results Here, we explored the genetic causes of in vitro switching from capsulated, mucoid to non-mucoid, non-capsulated phenotype in eight clinical CPKp isolates. We compared capsulated, mucoid colony variants with one of their non-capsulated, non-mucoid isogenic variant. The two colony variants were distinguished by their appearance on solid medium. Whole genome comparison was used to infer mutations causing phenotypic differences. The frequency of phenotypic switch was strain-dependent and increased along with colony development on plate. We observed, for 72 non-capsulated variants that the loss of the mucoid phenotype correlates with capsule deficiency and diverse genetic events, including transposition of insertion sequences or point mutations, affecting genes belonging to the capsule operon. Reduced or loss of capsular production was associated with various in vitro phenotypic changes, affecting susceptibility to carbapenem but not to colistin, in vitro biofilm formation and autoaggregation. Conclusions The different impact of the phenotypic variation among the eight isolates in terms of capsule content, biofilm production and carbapenem susceptibility suggested heterogeneous selective advantage for capsular loss according to the strain and the mutation. Based on our results, we believe that attention should be paid in the phenotypic characterization of CPKp clinical isolates, particularly of traits related to virulence and carbapenem resistance.

High prevalence of metallo-β-lactamase among carbapenem-resistant Klebsiella pneumoniae in a teaching hospital in China

2014 ◽  
Vol 60 (10) ◽  
pp. 691-695 ◽  
Author(s):  
Bin Li ◽  
Xiao-hong Xu ◽  
Zhi-chang Zhao ◽  
Mei-hua Wang ◽  
Ying-ping Cao
Keyword(s):  
Klebsiella Pneumoniae ◽  
Teaching Hospital ◽  
Carbapenem Resistance ◽  
Broth Culture ◽  
Consensus Sequences ◽  
Carbapenem Resistant ◽  
Extended Spectrum ◽  
Screening And Surveillance ◽  
High Prevalence

The aim of this study was to characterize the carbapenemases in carbapenem-resistant Klebsiella pneumoniae (CR-KP) from a Chinese teaching hospital. A total of 40 CR-KPs were screened for the presence of carbapenemases. Minimum inhibitory concentrations were determined by agar dilution. The modified Hodge test was used for the detection of carbapenemase production. Carbapenemase, extended-spectrum β-lactamase, and AmpC genes were detected using polymerase chain reaction (PCR) and sequencing. A conjugation test was performed using a broth culture mating method, transferred plasmids were typed by PCR-based replicon typing, and clonal relatedness was investigated by enterobacterial repetitive intergenic consensus sequences PCR (ERIC–PCR) and multilocus sequence typing (MLST). The results revealed that modified Hodge test was positive for 28 CR-KPs, and CR-KPs exhibited high resistance rates against various antibiotics, except colistin (5.0%) and tigecycline (22.5%). ERIC and MLST profiles showed no clonal outbreak. PCR demonstrated a high prevalence rate (55.0%, 22/40) of metallo-β-lactamases (MBLs) in CR-KPs. IMP-4, IMP-8, NDM-1, and KPC-2 were identified in 14 (35.0%), 7 (17.5%), 2 (5.0%), and 7 (17.5%) isolates, respectively. Notably, 2 CR-KPs coproduced 2 carbapenemases simultaneously (IMP-8/NDM-1 and IMP-4/KPC-2). In vitro transfer of carbapenem resistance was successful for 11 MBL-producing CR-KPs. The extended spectrum β-lactamase genes were detected in 30 (75.0%) of these CR-KPs. To the best of our knowledge, this is the first report focusing on carbapenem resistance in K. pneumoniae due to metalloenzymes in China. Screening and surveillance of MBLs in Enterobacteriaceae is urgently needed in this region to control and prevent the spread of these resistance determinants.

scholarly journals Roles of β-Lactamases and Porins in Activities of Carbapenems and Cephalosporins against Klebsiella pneumoniae

1999 ◽  
Vol 43 (7) ◽  
pp. 1669-1673 ◽  
Author(s):  
Luis Martínez-Martínez ◽  
Alvaro Pascual ◽  
Santiago Hernández-Allés ◽  
Dolores Alvarez-Díaz ◽  
Ana Isabel Suárez ◽  
...  
Keyword(s):  
Membrane Proteins ◽  
Klebsiella Pneumoniae ◽  
Outer Membrane ◽  
Outer Membrane Proteins ◽  
Carbapenem Resistance ◽  
Clinical Isolates ◽  
Extended Spectrum ◽  
Inoculum Effect

ABSTRACT Two clinical isolates of extended-spectrum β-lactamase (ESBL)-producing Klebsiella pneumoniae were noted to be less susceptible than expected to imipenem. Both were missing outer membrane proteins that serve as channels for antibiotic entry. The role of β-lactamase in resistance was investigated by eliminating the original ESBL and introducing plasmids encoding various ESBLs and AmpC β-lactamase types, by studying the effect of an increased inoculum, and by evaluating interactions with β-lactamase inhibitors. The contribution of porin deficiency was investigated by restoring a functional ompK36 gene on a plasmid. Plasmids encoding AmpC-type β-lactamases provided resistance to imipenem (up to 64 μg/ml) and meropenem (up to 16 μg/ml) in strains deficient in porins. Carbapenem resistance showed little inoculum effect, was not affected by clavulanate but was blocked by BRL 42715, and was diminished if OmpK36 porin was restored. Plasmids encoding TEM- and SHV-type ESBLs conferred resistance to cefepime and cefpirome, as well as to earlier oxyimino-β-lactams. This resistance was magnified with an increased inoculum, was blocked by clavulanate, and was also lowered by OmpK36 porin restoration. In addition, SHV-2 β-lactamase had a small effect on carbapenem resistance (imipenem MIC, 4 μg/ml, increasing to 16 μg/ml with a higher inoculum) when porins were absent. In K. pneumoniae porin loss can thus augment resistance provided either by TEM- or SHV-type ESBLs or by plasmid-mediated AmpC enzymes to include the latest oxyimino-β-lactams and carbapenems.

scholarly journals Comparative in vitro activities of carbapenem L-749,345 and other antimicrobials against multiresistant gram-negative clinical pathogens.

1997 ◽  
Vol 41 (8) ◽  
pp. 1830-1831 ◽  
Author(s):  
G Jacoby ◽  
P Han ◽  
J Tran
Keyword(s):  
Klebsiella Pneumoniae ◽  
Antimicrobial Agents ◽  
Clinical Isolates ◽  
Gram Negative ◽  
Beta Lactamases ◽  
Extended Spectrum ◽  
Extended Spectrum Beta Lactamases ◽  
Clinical Pathogens

Carbapenems L-749,345 and imipenem had the lowest MICs at which 90% of isolates were inhibited (0.5 microg/ml) of 14 antimicrobial agents tested against 76 multiresistant gram-negative clinical isolates with TEM- or SHV-type extended-spectrum beta-lactamases and chromosomal or plasmid-determined AmpC beta-lactamases, but the MIC of L-749,345 for one isolate of Klebsiella pneumoniae was 16 microg/ml.

scholarly journals Bactericidal Activities of Meropenem and Ertapenem against Extended-Spectrum-β-Lactamase-Producing Escherichia coli and Klebsiella pneumoniae in a Neutropenic Mouse Thigh Model

2007 ◽  
Vol 51 (4) ◽  
pp. 1481-1486 ◽  
Author(s):  
C. Andrew DeRyke ◽  
Mary Anne Banevicius ◽  
Hong Wei Fan ◽  
David P. Nicolau
Keyword(s):  
Escherichia Coli ◽  
Klebsiella Pneumoniae ◽  
Infection Model ◽  
Bacterial Reduction ◽  
Efficacy Analysis ◽  
Percent Time ◽  
Extended Spectrum ◽  
Wide Range

ABSTRACT The purpose of this study was to examine the in vivo efficacies of meropenem and ertapenem against extended-spectrum-β-lactamase (ESBL)-producing isolates with a wide range of MICs. Human-simulated dosing regimens in mice were designed to approximate the free drug percent time above the MIC (fT>MIC) observed for humans following meropenem at 1 g every 8 h and ertapenem at 1 g every 24 h. An in vivo neutropenic mouse thigh infection model was used to examine the bactericidal effects against 31 clinical ESBL Escherichia coli and Klebsiella pneumoniae isolates and 2 non-ESBL isolates included for comparison at a standard 105 inoculum. Three isolates were examined at a high 107 inoculum as well. Meropenem displayed greater in vitro potency, with a median MIC (range) (μg/ml) of 0.125 (0.03 to 32), than did ertapenem, with 0.5 (0.012 to 128). Seven of the 31 ESBL isolates were removed from the efficacy analysis due to their inability to establish infection in the mouse model. When MICs were ≤1.5 μg/ml for ertapenem (≤0.5 μg/ml for meropenem), similar reductions in CFU (≈ 2-log kill) were observed for both ertapenem (fT>MIC ≥ 23%) and meropenem (fT>MIC ≥ 75%). Ertapenem showed bacterial regrowth for seven of eight isolates, with MICs of ≥2 μg/ml (fT>MIC ≤ 20%), while meropenem displayed antibacterial potency that varied from a static effect to a 1-log bacterial reduction in these isolates (fT>MIC = 30 to 65%). At a 107 inoculum, both agents eradicated bacteria due to adequate exposures (fT>MIC = 20 to 45%). Due to low MICs, no difference in bacterial kill was noted for the majority of ESBL isolates tested. However, for isolates with raised ertapenem MICs of ≥2 μg/ml, meropenem displayed sustained efficacy due to its greater in vitro potency and higher resultant fT>MIC.

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