scholarly journals Genetic Diversity, Biochemical Properties, and Detection Methods of Minor Carbapenemases in Enterobacterales

2021 ◽  
Vol 7 ◽  
Author(s):  
Rémy A. Bonnin ◽  
Agnès B. Jousset ◽  
Cécile Emeraud ◽  
Saoussen Oueslati ◽  
Laurent Dortet ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Multidrug Resistant ◽  
Biochemical Properties ◽  
Amino Acid Sequences ◽  
Detection Methods ◽  
Gram Negative ◽  
Class A ◽  
Class D ◽  
Class B ◽  
Encoding Genes

Gram-negative bacteria, especially Enterobacterales, have emerged as major players in antimicrobial resistance worldwide. Resistance may affect all major classes of anti-gram-negative agents, becoming multidrug resistant or even pan-drug resistant. Currently, β-lactamase-mediated resistance does not spare even the most powerful β-lactams (carbapenems), whose activity is challenged by carbapenemases. The dissemination of carbapenemases-encoding genes among Enterobacterales is a matter of concern, given the importance of carbapenems to treat nosocomial infections. Based on their amino acid sequences, carbapenemases are grouped into three major classes. Classes A and D use an active-site serine to catalyze hydrolysis, while class B (MBLs) require one or two zinc ions for their activity. The most important and clinically relevant carbapenemases are KPC, IMP/VIM/NDM, and OXA-48. However, several carbapenemases belonging to the different classes are less frequently detected. They correspond to class A (SME-, Nmc-A/IMI-, SFC-, GES-, BIC-like…), to class B (GIM, TMB, LMB…), class C (CMY-10 and ACT-28), and to class D (OXA-372). This review will address the genetic diversity, biochemical properties, and detection methods of minor acquired carbapenemases in Enterobacterales.

scholarly journals Assessment of theIn VitroActivity of Ceftazidime-Avibactam against Multidrug-Resistant Klebsiella spp. Collected in the INFORM Global Surveillance Study, 2012 to 2014

2016 ◽  
Vol 60 (8) ◽  
pp. 4677-4683 ◽  
Author(s):  
Meredith Hackel ◽  
Krystyna M. Kazmierczak ◽  
Daryl J. Hoban ◽  
Douglas J. Biedenbach ◽  
Samuel K. Bouchillon ◽  
...  
Keyword(s):  
Multidrug Resistant ◽  
Surveillance Study ◽  
Gram Negative ◽  
Content Type ◽  
Class A ◽  
Highly Active ◽  
Class D ◽  
Class B ◽  
Klebsiella Spp

ABSTRACTIncreasing resistance in Gram-negative bacilli, includingKlebsiellaspp., has reduced the utility of broad-spectrum cephalosporins. Avibactam, a novel non-β-lactam β-lactamase inhibitor, protects β-lactams from hydrolysis by Gram-negative bacteria that produce extended-spectrum β-lactamases (ESBLs) and serine carbapenemases, including Ambler class A and/or class C and some class D enzymes. In this analysis, we report thein vitroactivity of ceftazidime-avibactam and comparators against multidrug-resistant (MDR)Klebsiellaspp. from the 2012-2014 INFORM surveillance study. Isolates collected from 176 sites were sent to a central laboratory for confirmatory identification and tested for susceptibility to ceftazidime-avibactam and comparator agents, including ceftazidime alone. A total of 2,821 of 10,998 (25.7%)Klebsiellaspecies isolates were classified as MDR, based on resistance to three or more classes of antimicrobials. Among the MDR isolates, 99.4% had an ESBL screen-positive phenotype, and 27.4% were not susceptible to meropenem as an example of a carbapenem. Ceftazidime-avibactam was highly active against MDR isolates, including ESBL-positive and serine carbapenemase-producing isolates, with MIC50/90values of 0.5/2 μg/ml and 96.6% of all MDR isolates and ESBL-positive MDR isolates inhibited at the FDA breakpoint (MIC value of ≤8 μg/ml). Ceftazidime-avibactam did not inhibit isolates producing class B enzymes (metallo-β-lactamases) either alone or in combination with other enzymes. Thesein vitroresults support the continued investigation of ceftazidime-avibactam for the treatment of MDRKlebsiellaspecies infections.

scholarly journals In Vitro Activity of Cefiderocol Against Multidrug-Resistant Gram-Negative Clinical Isolates

2020 ◽  
Vol 41 (S1) ◽  
pp. s291-s292
Author(s):  
Sandra Boyd ◽  
Karen Anderson
Keyword(s):  
Dipicolinic Acid ◽  
Underlying Mechanism ◽  
Multidrug Resistant ◽  
Gram Negative ◽  
Class A ◽  
Class D ◽  
Mueller Hinton ◽  
Class B ◽  
Global Threat

Background: New antimicrobials are being developed as a response to the global threat of multidrug-resistant and panresistant bacterial pathogens. Cefiderocol (FDC; Shionogi & Co) is a novel parenteral siderophore cephalosporin with activity against gram-negative rods. Here, we report on the in vitro activity of FDC against multidrug-resistant gram-negative isolates collected by the CDC, including isolates available through the CDC and FDA Antibiotic Resistance Isolate Bank (AR Isolate Bank). Methods: The challenge set of gram-negative isolates (n = 339), most of which were obtained from the AR isolate bank (n = 258), comprised 188 Enterobacteriaceae (ENT), 72 Pseudomonas aeruginosa (PSA), and 79 Acinetobacter baumannii (ACB). Minimum inhibitory concentrations (MICs) for FDC in iron-depleted cation-adjusted Mueller-Hinton broth were determined using frozen reference broth microdilution panels (IHMA, Schaumburg, IL) according to CLSI guidelines. Isolates displaying nonsusceptibility to FDC (MIC >4 µg/mL) underwent additional testing with β-lactamase inhibitors (FDC with 4 µg/mL avibactam, FDC with 100 µg/ml dipicolinic acid (DPA), and FDC with both 100 µg/mL dipicolinic acid (DPA) and 4 µg/mL avibactam). Results: Cefiderocol MICs ranged from ≤0.03 to >64 µg/mL, and 313 (92.3%) isolates displayed susceptibility to FDC (MIC ≤4 μg/mL). The proportions of susceptible ENT, PSA, and ACB were 93.1%, 94.4%, and 88.6%, respectively. Among isolates harboring Ambler class A, class B, or class D carbapenemases, the proportions of susceptible isolates were 96.5%, 79.5%, and 94.0%, respectively. Overall, 26 (7.7%) isolates were categorized as FDC nonsusceptible (MIC ≥ 8 µg/mL); 65% of these were NDM producers. We selected 23 isolates for testing with β-lactamase inhibitors. The combination FDC-avibactam reduced the MIC to susceptible for all isolates harboring an Ambler class A or D carbapenemase, except for 1 OXA-71–producing ACB and 1 KPC-producing Citrobacter farmeri. The combination FDC-DPA reduced the MIC to susceptible for 9 of 13 (69.2%) NDM-producing and 4 of 4 (100%) OXA-23–producing ACB. By combining FDC with both DPA and avibactam, the MIC was reduced to susceptible (91%) for all but 1 KPC-producing and 1 NDM-producing Enterobacteriaceae isolate. Conclusions: Cefiderocol (FDC) demonstrated potent activity against a diverse collection of multidrug-resistant, gram-negative isolates, including producers of Ambler class A, B, and D carbapenemases. Among the 26 FDC nonsusceptible isolates, 65% were NDM positive. Our data indicate that FDC combined with β-lactamase inhibitors may restore susceptibility in FDC nonsusceptible isolates. Additional studies are needed to understand the underlying mechanism(s) of FDC resistance and to further explore the use of β-lactamase inhibitors in combination with FDC.Funding: NoneDisclosures: None

scholarly journals In Vitro Activity of Cefiderocol against Multi-Drug Resistant Carbapenemase-Producing Gram-Negative Pathogens

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S376-S376 ◽  
Author(s):  
Sandra Boyd ◽  
Karen Anderson ◽  
Valerie Albrecht ◽  
Davina Campbell ◽  
Maria S Karlsson ◽  
...  
Keyword(s):  
Vitro Activity ◽  
Burkholderia Cepacia Complex ◽  
Uptake System ◽  
Drug Resistant ◽  
In Vitro Activity ◽  
Gram Negative ◽  
Class A ◽  
Class D ◽  
Class B

Abstract Background Few options remain for treatment of infections caused by multi-drug resistant (MDR), carbapenemase-producing gram-negative pathogens. Cefiderocol (CFDC; Shionogi & Co. Ltd), is a novel parenteral siderophore cephalosporin that enters the bacterial cell through the iron–siderophore uptake system. Here we report on the in vitro activity of CFDC against a set of well-characterized MDR gram-negative isolates collected by the Centers for Disease Control and Prevention. Methods Minimum inhibitory concentrations (MIC) values for CFDC in iron-depleted cation-adjusted Mueller Hinton broth were determined using reference broth microdilution. Study isolates (n = 315) included Enterobacteriaceae (59%), Pseudomonas aeruginosa (19%), Acinetobacter baumannii (17%), Stenotrophomonas maltophilia (4%), and Burkholderia cepacia complex (1%). Of these, 229 (73%) were carbapenemase-producers including Ambler Class A- (37%), Class B- (29%) and Class D- type (29%) enzymes. The remaining isolates included 51 β-lactam-resistant isolates that were non-carbapenemase-producers, and 35 β-lactam-susceptible isolates. Results were interpreted using suggested CFDC breakpoints of Sensitive ≤4 μg/mL and Resistant ≥16 μg/mL. Results The majority of the isolates (90.8%) were categorized as CFDC susceptible; the percentage of isolates with a CFDC MIC ≤4 μg/mL among Enterobacteriaceae, P. aeruginosa, and A. baumannii was 87.5%, 100%, and 89%, respectively. Percentage of isolates with a CFDC MIC ≤4 μg/mL that harbored a carbapenemase of the Class A-, Class B-, and Class D-type was 91.8%, 74.8%, 98.0%, respectively. By applying suggested breakpoints, 12 isolates were categorized as intermediate and 17 as resistant. The resistant isolates included 11 NDM-, 2 OXA-23- and 4 KPC-positive organisms. Conclusion Cefiderocol showed potent activity against MDR gram-negative pathogens including Class A, B, and D carbapenemase-producing isolates. Of note, all P. aeruginosa, including Class B metallo-β-lactamase producers, were susceptible to CFDC. Disclosures All authors: No reported disclosures.

scholarly journals In Vitro Properties of BAL30072, a Novel Siderophore Sulfactam with Activity against Multiresistant Gram-Negative Bacilli

2010 ◽  
Vol 54 (6) ◽  
pp. 2291-2302 ◽  
Author(s):  
Malcolm G. P. Page ◽  
Clothilde Dantier ◽  
Eric Desarbre
Keyword(s):  
Multidrug Resistant ◽  
Unusual Property ◽  
Gram Negative ◽  
Penicillin Binding Proteins ◽  
High Affinity ◽  
Class A ◽  
Carbapenem Resistant ◽  
Lactam Antibiotic ◽  
Resistant Strains

ABSTRACT BAL30072 is a new monocyclic β-lactam antibiotic belonging to the sulfactams. Its spectrum of activity against significant Gram-negative pathogens with β-lactam-resistant phenotypes was evaluated and was compared with the activities of reference drugs, including aztreonam, ceftazidime, cefepime, meropenem, imipenem, and piperacillin-tazobactam. BAL30072 showed potent activity against multidrug-resistant (MDR) Pseudomonas aeruginosa and Acinetobacter sp. isolates, including many carbapenem-resistant strains. The MIC90s were 4 μg/ml for MDR Acinetobacter spp. and 8 μg/ml for MDR P. aeruginosa, whereas the MIC90 of meropenem for the same sets of isolates was >32 μg/ml. BAL30072 was bactericidal against both Acinetobacter spp. and P. aeruginosa, even against strains that produced metallo-β-lactamases that conferred resistance to all other β-lactams tested, including aztreonam. It was also active against many species of MDR isolates of the Enterobacteriaceae family, including isolates that had a class A carbapenemase or a metallo-β-lactamase. Unlike other monocyclic β-lactams, BAL30072 was found to trigger the spheroplasting and lysis of Escherichia coli rather than the formation of extensive filaments. The basis for this unusual property is its inhibition of the bifunctional penicillin-binding proteins PBP 1a and PBP 1b, in addition to its high affinity for PBP 3, which is the target of monobactams, such as aztreonam.

scholarly journals Cyclic Boronates Inhibit All Classes of β-Lactamases

2017 ◽  
Vol 61 (4) ◽  
Author(s):  
Samuel T. Cahill ◽  
Ricky Cain ◽  
David Y. Wang ◽  
Christopher T. Lohans ◽  
David W. Wareham ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Bacterial Infections ◽  
Binding Mode ◽  
Gram Negative ◽  
Content Type ◽  
Class A ◽  
Class D ◽  
Dual Action ◽  
The Common ◽  
Continued Use

ABSTRACT β-Lactamase-mediated resistance is a growing threat to the continued use of β-lactam antibiotics. The use of the β-lactam-based serine-β-lactamase (SBL) inhibitors clavulanic acid, sulbactam, and tazobactam and, more recently, the non-β-lactam inhibitor avibactam has extended the utility of β-lactams against bacterial infections demonstrating resistance via these enzymes. These molecules are, however, ineffective against the metallo-β-lactamases (MBLs), which catalyze their hydrolysis. To date, there are no clinically available metallo-β-lactamase inhibitors. Coproduction of MBLs and SBLs in resistant infections is thus of major clinical concern. The development of “dual-action” inhibitors, targeting both SBLs and MBLs, is of interest, but this is considered difficult to achieve due to the structural and mechanistic differences between the two enzyme classes. We recently reported evidence that cyclic boronates can inhibit both serine- and metallo-β-lactamases. Here we report that cyclic boronates are able to inhibit all four classes of β-lactamase, including the class A extended spectrum β-lactamase CTX-M-15, the class C enzyme AmpC from Pseudomonas aeruginosa, and class D OXA enzymes with carbapenem-hydrolyzing capabilities. We demonstrate that cyclic boronates can potentiate the use of β-lactams against Gram-negative clinical isolates expressing a variety of β-lactamases. Comparison of a crystal structure of a CTX-M-15:cyclic boronate complex with structures of cyclic boronates complexed with other β-lactamases reveals remarkable conservation of the small-molecule binding mode, supporting our proposal that these molecules work by mimicking the common tetrahedral anionic intermediate present in both serine- and metallo-β-lactamase catalysis.

scholarly journals Using Molecular Diagnostics to Develop Therapeutic Strategies for Carbapenem-Resistant Gram-Negative Infections

2021 ◽  
Vol 11 ◽  
Author(s):  
Fred C. Tenover
Keyword(s):  
Carbapenem Resistance ◽  
Multidrug Resistant ◽  
Therapeutic Strategies ◽  
Beta Lactam ◽  
Gram Negative ◽  
Molecular Tests ◽  
Negative Results ◽  
Carbapenem Resistant ◽  
Class B ◽  
Global Threat

Infections caused by multidrug-resistant Gram-negative organisms have become a global threat. Such infections can be very difficult to treat, especially when they are caused by carbapenemase-producing organisms (CPO). Since infections caused by CPO tend to have worse outcomes than non-CPO infections, it is important to identify the type of carbapenemase present in the isolate or at least the Ambler Class (i.e., A, B, or D), to optimize therapy. Many of the newer beta-lactam/beta-lactamase inhibitor combinations are not active against organisms carrying Class B metallo-enzymes, so differentiating organisms with Class A or D carbapenemases from those with Class B enzymes rapidly is critical. Using molecular tests to detect and differentiate carbapenem-resistance genes (CRG) in bacterial isolates provides fast and actionable results, but utilization of these tests globally appears to be low. Detecting CRG directly in positive blood culture bottles or in syndromic panels coupled with bacterial identification are helpful when results are positive, however, even negative results can provide guidance for anti-infective therapy for key organism-drug combinations when linked to local epidemiology. This perspective will focus on the reluctance of laboratories to use molecular tests as aids to developing therapeutic strategies for infections caused by carbapenem-resistant organisms and how to overcome that reluctance.

Endolymphatic SAC Surgery for Menière's Disease

1983 ◽  
Vol 92 (2) ◽  
pp. 113-118 ◽  
Author(s):  
Gershon J. Spector ◽  
Peter G. Smith
Keyword(s):  
Meniere’S Disease ◽  
Menière’S Disease ◽  
Meniere's Disease ◽  
Ménière’S Disease ◽  
Menière's Disease ◽  
Class A ◽  
Class D ◽  
Class B ◽  
Ménière's Disease

An endolymphatic-mastoid Silastic shunt procedure was performed in 122 cases of Menière's disease having a mean follow-up period of three years. In accordance with American Academy of Ophthalmology and Otolaryngology 1972 criteria, there were 43 % class A, 20% class B, 21% class C, and 17% class D results. Analysis of 35 recent cases having a mean follow-up period of nine months revealed 57% class A, 25% class B, 9% class C, and 9% class D results. Sixteen percent of the patients who experienced classes A, B or C results complained of other fluctuating symptoms which were not relieved by surgery. Moreover, three new eases of otolithic crisis were found in the postoperative group. Seven of ten patients who experienced a class A or B result had either a recrudescence of their vertigo or a significant decrement in hearing in response to a postoperative salt-loading test. It is concluded that the surgical success rate decreases with time and that the procedure appears to alter the symptom complex but does not cure Menière's disease.

Molecular Detection of Carbapenem Resistant Gram Negative Bacterial Isolates from Dogs 

2021 ◽  
Author(s):  
Surya Sankar ◽  
Thresia . ◽  
Anu Bosewell ◽  
M. Mini
Keyword(s):  
Companion Animals ◽  
Multidrug Resistant ◽  
Beta Lactam ◽  
Gram Negative ◽  
Extended Spectrum Beta Lactamase ◽  
Beta Lactam Antibiotics ◽  
Carbapenem Resistant ◽  
Carbapenemase Gene ◽  
Line Of Therapy ◽  
Encoding Genes

Background: Carbapenems are beta-lactam antibiotics that are considered as the last line of therapy against multidrug resistant extended spectrum beta-lactamase. The resistance to carbapenems predominantly through carbapenemase is one of the most important emerging health problems worldwide in the therapy of clinical infections. The objective of the present study is to determine the presence of carbapenemase encoding genes among Gram- negative bacterial spp. associated with clinical infections in dogs. Methods: 30 Escherichia coli, 11 Klebsiella pneumoniae and three Pseudomonas aeruginosa isolated from urine, swabs from lesional skin and anterior vagina of dogs presented with different clinical ailments formed the samples for the study. Polymerase chain reaction was carried out to detect the presence of carbapenemase encoding genes viz., KPC, NDM, OXA, VIM and IMP among the isolates.Result: Out of the 44 Gram- negative isolates tested, 28 (76.3%) were positive for at least one tested carbapenemase gene. The highest frequency of carbapenemase recorded was for NDM followed by OXA-181, KPC, OXA-48 and VIM. Our study identified a high prevalence of carbapenemases among companion animals like dogs which could act as potential source of transmission of these resistance bacteria or their genomes to humans.

scholarly journals Interactions of Ceftobiprole with β-Lactamases from Molecular Classes A to D

2007 ◽  
Vol 51 (9) ◽  
pp. 3089-3095 ◽  
Author(s):  
Anne Marie Queenan ◽  
Wenchi Shang ◽  
Malgosia Kania ◽  
Malcolm G. P. Page ◽  
Karen Bush
Keyword(s):  
Functional Groups ◽  
Hydrolytic Stability ◽  
Enterobacter Cloacae ◽  
Class A ◽  
Extended Spectrum ◽  
Class D ◽  
The Family ◽  
Class B ◽  
The Common ◽  
Antibacterial Spectrum

ABSTRACT The interactions of ceftobiprole with purified β-lactamases from molecular classes A, B, C, and D were determined and compared with those of benzylpenicillin, cephaloridine, cefepime, and ceftazidime. Enzymes were selected from functional groups 1, 2a, 2b, 2be, 2d, 2e, and 3 to represent β-lactamases from organisms within the antibacterial spectrum of ceftobiprole. Ceftobiprole was refractory to hydrolysis by the common staphylococcal PC1 β-lactamase, the class A TEM-1 β-lactamase, and the class C AmpC β-lactamase but was labile to hydrolysis by class B, class D, and class A extended-spectrum β-lactamases. Cefepime and ceftazidime followed similar patterns. In most cases, the hydrolytic stability of a substrate correlated with the MIC for the producing organism. Ceftobiprole and cefepime generally had lower MICs than ceftazidime for AmpC-producing organisms, particularly AmpC-overexpressing Enterobacter cloacae organisms. However, all three cephalosporins were hydrolyzed very slowly by AmpC cephalosporinases, suggesting that factors other than β-lactamase stability contribute to lower ceftobiprole and cefepime MICs against many members of the family Enterobacteriaceae.

scholarly journals Comparative Evaluation of Four Phenotypic Methods for Detection of Class A and B Carbapenemase-Producing Enterobacteriaceae in China

2018 ◽  
Vol 56 (8) ◽  
Author(s):  
Menglan Zhou ◽  
Danchen Wang ◽  
Timothy Kudinha ◽  
Qiwen Yang ◽  
Shuying Yu ◽  
...  
Keyword(s):  
Predictive Value ◽  
Comparative Evaluation ◽  
Detection Sensitivity ◽  
Detection Methods ◽  
Content Type ◽  
Class A ◽  
Carbapenem Resistant ◽  
Class B ◽  
Phenotypic Methods ◽  
Sensitivity Specificity

ABSTRACT The objective of this study was to evaluate the performance of four phenotypic methods in the detection of carbapenemase-producing Enterobacteriaceae (CPE) in China. We evaluated the performance of four carbapenemase detection methods, the modified Hodge test (MHT), the Carba NP test, the meropenem hydrolysis assay (MHA) with 1- and 2-h incubation, and the modified carbapenem inactivation method (mCIM) with meropenem, imipenem, and ertapenem, on 342 carbapenem-resistant Enterobacteriaceae isolates (CRE) in China. PCR was used as the gold standard. The 2-h-incubation MHA performed the best in carbapenemase detection (overall sensitivity, specificity, positive predictive value, and negative predictive value all 100%). Second was the Carba NP test, with a sensitivity of 99.6%. The 1-h-incubation MHA performed poorly in Klebsiella pneumoniae carbapenemase (KPC) detection (sensitivity, 71.3%). For mCIM, the best performance was observed with the meropenem disk. The MHT exhibited the worst performance, with a specificity of 88.8%. All assays except 1-h-incubation MHA, which failed to identify 68 KPC-2s, had a sensitivity of >98% in the detection of 172 KPCs. Likewise, all assays had a sensitivity of >95% in the detection of 70 class B carbapenemases, except for MHT (82.9%). The 2-h-incubation MHA significantly improved the accuracy in CPE detection compared with that for 1-h incubation and performed the best in the detection of class A and B carbapenemases. Our findings suggest that the MHA is the most practical assay for carbapenemase detection. For those who cannot afford the associated equipment, both the Carba NP test and mCIM are good alternatives with regard to the practical requirements of time and cost.

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