scholarly journals CTX-M-33 Is a CTX-M-15 Derivative Conferring Reduced Susceptibility to Carbapenems

2019 ◽  
Vol 63 (12) ◽  
Author(s):  
Laurent Poirel ◽  
José-Manuel Ortiz de la Rosa ◽  
Anaïs Richard ◽  
Marta Aires-de-Sousa ◽  
Patrice Nordmann
Keyword(s):  
Membrane Protein ◽  
Klebsiella Pneumoniae ◽  
Hydrolytic Activity ◽  
Sequence Type ◽  
High Rate ◽  
Mutant Selection ◽  
Content Type ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Lactamase Inhibitor

ABSTRACT CTX-M-type extended-spectrum β-lactamases (ESBLs) are widespread among Enterobacterales strains worldwide. The most common variant is CTX-M-15, which hydrolyzes ceftazidime at a high rate but spares carbapenems. Here, we identified CTX-M-33, a point mutation derivative of CTX-M-15 (Asp to Ser substitution at Ambler position 109) that exhibited low carbapenemase activity. β-Lactamase CTX-M-33 was identified in a Klebsiella pneumoniae isolate, belonging to sequence type 405 and lacking the outer membrane protein OmpK36, that was resistant to broad-spectrum cephalosporins and β-lactam/β-lactamase inhibitor combinations and displayed decreased susceptibility to carbapenems. Comparative hydrolytic activity assays showed that CTX-M-33 hydrolyzed ceftazidime at a lower level than CTX-M-15 but significantly hydrolyzed meropenem. In addition, CTX-M-33 showed higher mutant prevention concentration values and a wider mutant selection window in the presence of meropenem, in accordance with its observed hydrolytic properties. Here, we identified the very first CTX-M enzyme possessing weak carbapenemase activity, which may correspond to an emerging phenomenon, considering its possible evolution from the widespread ESBL CTX-M-15.

scholarly journals Searching for the Optimal Predictor of Ciprofloxacin Resistance in Klebsiella pneumoniae by UsingIn VitroDynamic Models

2015 ◽  
Vol 60 (3) ◽  
pp. 1208-1215 ◽  
Author(s):  
Elena N. Strukova ◽  
Yury A. Portnoy ◽  
Andrey V. Romanov ◽  
Mikhail V. Edelstein ◽  
Stephen H. Zinner ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Area Under The Curve ◽  
Mutant Selection ◽  
Content Type ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Ciprofloxacin Resistance ◽  
Resistant Mutants ◽  
Time Courses ◽  
Selection Of

There is growing evidence of applicability of the hypothesis of the mutant selection window (MSW), i.e., the range between the MIC and the mutant prevention concentration (MPC), within which the enrichment of resistant mutants is most probable. However, it is not clear if MPC-based pharmacokinetic variables are preferable to the respective MIC-based variables as interstrain predictors of resistance. To examine the predictive power of the ratios of the area under the curve (AUC24) to the MPC and to the MIC, the selection of ciprofloxacin-resistant mutants of threeKlebsiella pneumoniaestrains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. ResistantK. pneumoniaemutants were intensively enriched at an AUC24/MIC ratio of 60 to 360 h (AUC24/MPC ratio from 2.5 to 15 h) but not at the lower or higher AUC24/MIC and AUC24/MPC ratios, in accordance with the MSW hypothesis. AUC24/MPC and AUC24/MIC relationships with areas under the time courses of ciprofloxacin-resistantK. pneumoniae(AUBCM) were bell shaped. These relationships predict highly variable “antimutant” AUC24/MPC ratios (20 to 290 h) compared to AUC24/MIC ratios (1,310 to 2,610 h). These findings suggest that the potential of the AUC24/MPC ratio as an interstrain predictor ofK. pneumoniaeresistance is lower than that of the AUC24/MIC ratio.

scholarly journals Nosocomial Outbreak of VIM-1-Producing Klebsiella pneumoniae Isolates of Multilocus Sequence Type 15: Molecular Basis, Clinical Risk Factors, and Outcome

2011 ◽  
Vol 56 (1) ◽  
pp. 420-427 ◽  
Author(s):  
Isabel Sánchez-Romero ◽  
Ángel Asensio ◽  
Jesús Oteo ◽  
María Muñoz-Algarra ◽  
Beatriz Isidoro ◽  
...  
Keyword(s):  
Risk Factors ◽  
Klebsiella Pneumoniae ◽  
Molecular Basis ◽  
Hospital Setting ◽  
Sequence Type ◽  
Clinical Risk Factors ◽  
High Rate ◽  
Content Type ◽  
Clinical Risk ◽  
Extended Spectrum

ABSTRACTWe study the epidemiology, molecular basis, clinical risk factors, and outcome involved in the clonal dissemination of VIM-1-producingKlebsiella pneumoniaeisolates in the hospital setting. All patients infected/colonized by carbapenem-nonsusceptibleK. pneumoniae(CNSKP) in 2009 were included. Molecular epidemiology was studied by pulsed-field gel electrophoresis (PFGE) and multilocus sequence typing (MLST). Antibiotic resistance genes were analyzed by PCR and sequencing. Plasmids were studied by PFGE with S1 nuclease digestion and for incompatibility group by a PCR-based replicon typing scheme. Risk factors associated with CNSKP colonization/infection were assessed by an observational case-control study. All 55 patients studied were infected (n= 28) or colonized (n= 27) by VIM-1-producingK. pneumoniae. All but one acquired isolates of a single clone (PFGE cluster 1 [C1], sequence type 15 [ST15]), while another clone (PFGE C2, ST340) was detected in four patients. C1 isolates also produced the new extended-spectrum β-lactamase SHV-134.blaVIM-1was carried in a class 1 integron and an untypeable plasmid of ∼50 bp. The number of days that the patient received mechanical ventilation, the use of parenteral nutrition, previous treatment with linezolid, and treatment with extended-spectrum cephalosporins for more than 7 days were detected to be independent risk factors for CNSKP acquisition. The VIM-1-producingK. pneumoniaeST15 clone has a high capacity to spread among intensive care unit patients with severe underlying conditions. A high rate of associated mortality and great difficulty in controlling the spread of this clone, without permanent behavioral changes in the personnel, were observed.

scholarly journals Extended-Spectrum β-Lactamase CTX-M-15-Producing Klebsiella pneumoniae of Sequence Type ST274 in Companion Animals

2013 ◽  
Vol 57 (5) ◽  
pp. 2372-2375 ◽  
Author(s):  
Laurent Poirel ◽  
Patrice Nordmann ◽  
Sébastien Ducroz ◽  
Henri-Jean Boulouis ◽  
Pascal Arné ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Companion Animals ◽  
Sequence Type ◽  
High Rate ◽  
Gram Negative Bacteria ◽  
Gram Negative ◽  
Content Type ◽  
Extended Spectrum ◽  
Paris Area

ABSTRACTScreening of extended-spectrum β-lactamase (ESBL)-producing Gram-negative bacteria in companion animals living in the Paris area in France identified a high rate of CTX-M-15-producingKlebsiella pneumoniae. Those isolates were recovered during the 2010-2011 period from both infections and asymptomatic colonizations. Sequence typing revealed that most of these isolates belonged to sequence type ST274. Interestingly, theblaCTX-M-15gene was located on a specific and novel plasmid scaffold. These findings highlight that companion animals may be reservoirs for CTX-M-15-producingK. pneumoniaeevolving separately from the human reservoir of CTX-M-15 producers.

scholarly journals Mutant Prevention Concentration and Mutant Selection Window of Micafungin and Anidulafungin in ClinicalCandida glabrataIsolates

2018 ◽  
Vol 62 (3) ◽  
Author(s):  
María Ángeles Bordallo-Cardona ◽  
Laura Judith Marcos-Zambrano ◽  
Carlos Sánchez-Carrillo ◽  
Elia Gómez G. de la Pedrosa ◽  
Rafael Cantón ◽  
...  
Keyword(s):  
Mutation Frequency ◽  
Galleria Mellonella ◽  
Antifungal Susceptibility ◽  
Wild Type ◽  
Resistance Mutations ◽  
Mutant Selection ◽  
Content Type ◽  
Sabouraud Agar ◽  
Selection Window ◽  
Mutant Prevention Concentration

ABSTRACTWe report the mutant prevention concentration (MPC) and mutant selection window (MSW) for micafungin and anidulafungin administered to treatCandida glabrata. We also determine the mutation frequency. We studied 20 echinocandin-susceptible, fluconazole-intermediate, andFKSwild-typeC. glabrataisolates. Adjusted inocula were stroked directly onto Sabouraud agar plates containing different concentrations of micafungin or anidulafungin and visually inspected daily for up to 5 days of incubation. Individual colonies growing on the plates containing echinocandins at 1 mg/liter were selected for antifungal susceptibility testing. TheFKSgenes of the resulting individual phenotypically resistant colonies were sequenced, and the MPC, MSW, and mutation frequency were determined. Biofilm was quantified, and the growth kinetics and virulence (Galleria mellonellamodel) of the resulting individualFKSmutant colonies were studied. For micafungin and anidulafungin, we found similar results for the MPC (0.06 to 2 mg/liter and 0.25 to 2 mg/liter, respectively), MSW (0.015 to 2 mg/liter for both echinocandins), and mutation frequency (3.7 × 10−8and 2.8 × 10−8, respectively). A total of 12 isolates were able to grow at 1 mg/liter on echinocandin-containing plates, yielding a total of 32 phenotypically resistant colonies; however,FKS2mutations (ΔF658, S663P, W715L, and E655A) were observed only in 21 colonies. We did not find differences in biofilm formation, the kinetic parameters studied, or the median survival of larvae infected by wild-type isolates and the resulting individualFKS2mutant colonies. Echinocandin concentrations lower than 2 mg/liter can lead to selection of resistance mutations inC. glabrataisolatesin vitro.

scholarly journals Bacterial Resistance Studies UsingIn VitroDynamic Models: the Predictive Power of the Mutant Prevention and Minimum Inhibitory Antibiotic Concentrations

2013 ◽  
Vol 57 (10) ◽  
pp. 4956-4962 ◽  
Author(s):  
Alexander A. Firsov ◽  
Elena N. Strukova ◽  
Darya S. Shlykova ◽  
Yury A. Portnoy ◽  
Varvara K. Kozyreva ◽  
...  
Keyword(s):  
Predictive Power ◽  
Bacterial Resistance ◽  
Area Under The Curve ◽  
Mutant Selection ◽  
Content Type ◽  
E Coli ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Time Courses ◽  
Selection Of

ABSTRACTIn light of the concept of the mutant selection window, i.e., the range between the MIC and the mutant prevention concentration (MPC), MPC-related pharmacokinetic indices should be more predictive of bacterial resistance than the respective MIC-related indices. However, experimental evidence of this hypothesis remains limited and contradictory. To examine the predictive power of the ratios of the area under the curve (AUC24) to the MPC and the MIC, the selection of ciprofloxacin-resistant mutants of fourEscherichia colistrains with different MPC/MIC ratios was studied. Each organism was exposed to twice-daily ciprofloxacin for 3 days at AUC24/MIC ratios that provide peak antibiotic concentrations close to the MIC, between the MIC and the MPC, and above the MPC. ResistantE. coliwas intensively enriched at AUC24/MPCs from 1 to 10 h (AUC24/MIC from 60 to 360 h) but not at the lower or higher AUC24/MPC and AUC24/MIC ratios. AUC24/MPC and AUC24/MIC relationships of the areas under the time courses of ciprofloxacin-resistantE. coli(AUBCM) were bell-shaped. A Gaussian-like function fits the AUBCM-AUC24/MPC and AUBCM-AUC24/MIC data combined for all organisms (r2= 0.69 and 0.86, respectively). The predicted anti-mutant AUC24/MPC ratio was 58 ± 35 h, and the respective AUC24/MIC ratio was 1,080 ± 416 h. Although AUC24/MPC was less predictive of strain-independentE. coliresistance than AUC24/MIC, the established anti-mutant AUC24/MPC ratio was closer to values reported forStaphylococcus aureus(60 to 69 h) than the respective AUC24/MIC ratio (1,080 versus 200 to 240 h). This implies that AUC24/MPC might be a better interspecies predictor of bacterial resistance than AUC24/MIC.

scholarly journals Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae Mediated by Chromosomal Integration of Plasmid DNA

2017 ◽  
Vol 61 (8) ◽  
Author(s):  
Astrid V. Cienfuegos-Gallet ◽  
Liang Chen ◽  
Barry N. Kreiswirth ◽  
J. Natalia Jiménez
Keyword(s):  
Klebsiella Pneumoniae ◽  
Plasmid Dna ◽  
Clonal Expansion ◽  
Genetic Alterations ◽  
Sequence Type ◽  
Chromosomal Integration ◽  
Colistin Resistance ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Single Locus Variant

ABSTRACT Here we describe the spread of colistin resistance in clinical isolates of carbapenem-resistant Klebsiella pneumoniae in Medellín, Colombia. Among 32 isolates collected between 2012 and 2014, 24 showed genetic alterations in mgrB. Nineteen isolates belonged to sequence type 512 (ST512) (or its single locus variant [SLV]) and harbored an 8.1-kb hsdMSR insertion corresponding to ISKpn25, indicating a clonal expansion of the resistant strain. The insertion region showed 100% identity to several plasmids, suggesting that the colistin resistance is mediated by chromosomal integration of plasmid DNA.

scholarly journals Doripenem MICs andompK36Porin Genotypes of Sequence Type 258, KPC-Producing Klebsiella pneumoniae May Predict Responses to Carbapenem-Colistin Combination Therapy among Patients with Bacteremia

2014 ◽  
Vol 59 (3) ◽  
pp. 1797-1801 ◽  
Author(s):  
Ryan K. Shields ◽  
M. Hong Nguyen ◽  
Brian A. Potoski ◽  
Ellen G. Press ◽  
Liang Chen ◽  
...  
Keyword(s):  
Amino Acids ◽  
Combination Therapy ◽  
Klebsiella Pneumoniae ◽  
Sequence Type ◽  
Content Type

ABSTRACTTreatment failures of a carbapenem-colistin regimen among patients with bacteremia due to sequence type 258 (ST258), KPC-2-producingKlebsiella pneumoniaewere significantly more likely if both agents were inactivein vitro, as defined by a colistin MIC of >2 μg/ml and the presence of either a majorompK36porin mutation (guanine and alanine insertions at amino acids 134 and 135 [ins aa 134–135 GD], IS5promoter insertion [P= 0.007]) or a doripenem MIC of >8 μg/ml (P= 0.01). MajorompK36mutations among KPC-K. pneumoniaestrains are important determinants of carbapenem-colistin responsesin vitroandin vivo.

scholarly journals Determination of MIC, MPC, and MSW of Ilex paraguariensis Against Non-Typhoidal Salmonella with Identification of the Mechanisms of Resistance and Pathogenicity Factors

2020 ◽  
Author(s):  
Khaled El Khatib ◽  
Ribal Aby Hadeer ◽  
Anis Saad ◽  
Aline Kalaydjian ◽  
Elie Fayad ◽  
...  
Keyword(s):  
Antibacterial Activity ◽  
Inhibitory Concentration ◽  
Ilex Paraguariensis ◽  
Salmonella Spp ◽  
Mutant Selection ◽  
Selection Window ◽  
Mutant Prevention Concentration ◽  
Resistance Patterns ◽  
Different Strains

Abstract Objective: This study investigated the antibacterial activity of Ilex paraguariensis extracts against 32 different strains of non-typhoidal Salmonella (NTS) through the determination of the Minimum Inhibitory Concentration (MIC), Mutant Prevention Concentration (MPC), Mutant Selection Window (MSW), and the detection of virulence genes by multiplex PCR assays. Results: The MIC values of Ilex paraguariensis against Salmonella spp. strains varied between 0.78 mg/ml and 6.25 mg/ml with a MIC 90 of 3.12 mg/ml. The highest MPC in this study was 48 mg/ml yielding a Mutant Selection Window of 41.75 mg/ml. The MSW values of the remaining strains varied between 1.56 and 8.87 mg/ml. Genes of pathogenicity detected in Salmonella spp. isolates were most commonly the stn, sdiA, invA, sopB, invH, and sopE genes. The antibacterial activity of Yerba Mate extracts was not affected by the antimicrobial resistance patterns or pathogenicity genes expressed. More work is needed to identify the active antibacterial compound(s) responsible for the antibacterial activity.

scholarly journals Sequence Type 273 Carbapenem-Resistant Klebsiella pneumoniae Carrying bla NDM-1 and bla IMP-4

2018 ◽  
Vol 62 (6) ◽  
Author(s):  
Lu Liu ◽  
Yu Feng ◽  
Haiyan Long ◽  
Alan McNally ◽  
Zhiyong Zong
Keyword(s):  
Klebsiella Pneumoniae ◽  
Southeast Asia ◽  
Human Blood ◽  
Sequence Type ◽  
Whole Genome Sequence ◽  
Whole Genome ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Transmissible Plasmid ◽  
Long Read

ABSTRACT A carbapenem-resistant Klebsiella pneumoniae isolate was recovered from human blood. Its whole-genome sequence was obtained using Illumina and long-read MinION sequencing. The strain belongs to sequence type 273 (ST273), which was found recently and caused an outbreak in Southeast Asia. It has two carbapenemase genes, bla NDM-1 (carried by an ST7 IncN self-transmissible plasmid) and bla IMP-4 (located on a self-transmissible IncHI5 plasmid). Non-KPC-producing ST237 may represent a lineage of carbapenem-resistant K. pneumoniae , which warrants further monitoring.

scholarly journals In Vivo Activity of QPX7728, an Ultrabroad-Spectrum Beta-Lactamase Inhibitor, in Combination with Beta-Lactams against Carbapenem-Resistant Klebsiella pneumoniae

2020 ◽  
Vol 64 (11) ◽  
Author(s):  
Mojgan Sabet ◽  
Ziad Tarazi ◽  
David C. Griffith
Keyword(s):  
Klebsiella Pneumoniae ◽  
Beta Lactamase ◽  
Beta Lactam ◽  
Beta Lactams ◽  
Bacterial Killing ◽  
Clinical Issue ◽  
Content Type ◽  
Beta Lactam Antibiotics ◽  
Carbapenem Resistant ◽  
Lactamase Inhibitor

ABSTRACT Resistance to beta-lactams has created a major clinical issue. QPX7728 is a novel ultrabroad-spectrum cyclic boronic acid beta-lactamase inhibitor with activity against both serine and metallo-beta-lactamases developed to address this resistance for use in combination with beta-lactam antibiotics. The objective of these studies was to evaluate the activity of QPX7728 in combination with multiple beta-lactams against carbapenem-resistant Klebsiella pneumoniae isolates in a neutropenic mouse thigh infection model. Neutropenic mice were infected with strains with potentiated beta-lactam MICs of ≤2 mg/liter in the presence of 8 mg/liter QPX7728. Two strains of carbapenem-resistant K. pneumoniae were tested with aztreonam, biapenem, cefepime, ceftazidime, ceftolozane, and meropenem alone or in combination with 12.5, 25, or 50 mg/kg of body weight of QPX7728 every 2 hours for 24 hours. Treatment with all beta-lactams alone either was bacteriostatic or allowed for bacterial growth. The combination of QPX7728 plus each of these beta-lactams produced bacterial killing at all QPX7728 doses tested. Overall, these data suggest that QPX7728 administered in combination with different partner beta-lactam antibiotics may have utility in the treatment of bacterial infections due to carbapenem-resistant K. pneumoniae.

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