scholarly journals 700. Identification and Whole-Genome Sequencing (WGS) of Meropenem-Vaborbactam (MV) Resistant Klebsiella pneumoniae (MVRKP) Among Patients Without Prior Exposure to MV: Collateral Damage

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S252-S252
Author(s):  
Mohamad Yasmin ◽  
Liang Chen ◽  
Steven H Marshall ◽  
Barry N Kreiswirth ◽  
Federico Perez ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Efflux System ◽  
Class A ◽  
Carbapenem Resistant ◽  
Class D ◽  
Outer Membrane Porin ◽  
Historical Database ◽  
Tract Infections ◽  
Inhibitor Combination ◽  
Random Screening

Abstract Background MV is a newly approved β-lactam/β-lactamase inhibitor combination (BLIC) for the treatment of complicated urinary tract infections (cUTI). Vaborbactam is a cyclic boronic acid BLI that was mainly developed as a potent inhibitor of KPC carbapenemases and other Ambler class A&C enzymes. Vaborbactam is inactive against metallo-β-lactamases (MBL) and certain Class D enzymes (e.g. OXA-2 and OXA-48). We encountered a case of MV-resistant Klebsiella pneumoniae (MVRKP)and sought to explore the various mechanisms of MV resistance within KP. Methods A 65-year-old nursing home resident with multiple prior hospitalizations and recent exposure to antibiotics (Timeline) developed sepsis secondary to carbapenem-resistant Klebsiella pneumoniae (CRKP) cUTI. WGS of the patient’s isolate was performed. This was followed by random screening for MV resistance and WGS of other isolates from a historical database. Results Results of WGS are seen in the table below. Sequencing of our patient’s isolate revealed strain ST258 with a premature stop in aa89 of OmpK35 as well as insertions at Gly134 and Asp135 (i.e., the GD repeat) of OmpK36. Furthermore, the KPC plasmid’s copy number was approximately five times higher than the chromosome. No mutations encoding efflux system AcrAB-TolC were found. Conclusion Resistance to MV in KP was found in isolates that predate the drug’s availability. Notably, resistance occurred in the absence of MBLs and OXAs. The mechanism seems to involve outer membrane porin mutations in OmpK35 and/or OmpK36. WGS is a useful tool in identifying the mechanism of resistance especially for newer agents. Disclosures All authors: No reported disclosures.

scholarly journals 610. Meropenem-vaborbactam (MV) In Vitro Activity Against Carbapenem-Resistant Klebsiella pneumoniae (CRKP) Isolates with Outer Membrane Porin Gene Mutations

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S285-S285 ◽  
Author(s):  
Mohamad Yasmin ◽  
Steven Marshall ◽  
Michael Jacobs ◽  
Daniel D Rhoads ◽  
Laura J Rojas ◽  
...  
Keyword(s):  
Klebsiella Pneumoniae ◽  
Outer Membrane ◽  
Gene Mutations ◽  
Underlying Mechanism ◽  
Clinical Isolates ◽  
Historical Cohort ◽  
Carbapenem Resistant ◽  
Outer Membrane Porin ◽  
Tract Infections

Abstract Background Vaborbactam is a cyclic boronic acid β-lactamase inhibitor (BLI) developed to potently inhibit Ambler class A&C enzymes, including KPC carbapenemases. Metallo-β-lactamases (MBL) and some Class D oxacillinases (OXA) are not inactivated by vaborbactam. Meropenem-vaborbactam (MV) was recently approved for the treatment of carbapenem-resistant Enterobacteriaceae complicated urinary tract infections. Recent studies have identified outer membrane porin (Ompk35 and -36) mutations in Klebsiella pneumoniae (KP) as a mechanism of decreased susceptibility to MV. We evaluated the activity of MV against a historical cohort of KP clinical isolates with these porin gene mutations. Methods WGS of carbapenem-resistant KP clinical isolates was performed and those harboring mutations in Ompk35 or Ompk36 were selected for testing. Strain KP ATCC BAA-1705 was used as a positive control. Meropenem and MV minimum inhibitory concentrations (MIC) were determined by broth microdilution (BMD) in custom 96-well plates (ThermoFisher Scientific) with a constant 8 µg/mL vaborbactam concentration. The MIC of ceftazidime–avibactam (CZA) was determined by standard BMD reference methods and interpreted according to CLSI criteria. Results A total of 105 KP isolates with either partial or complete mutations in outer membrane porin genes were included in the analysis. All isolates were resistant to Meropenem. The median MV MIC was 0.03 µg/mL (range, 0.015 to >16 µg/mL). Eleven isolates (10.4%) were resistant to MV. Sixteen additional isolates (16.1%) demonstrated higher than expected MV MICs ranging from 1 to 4 µg/mL. Only 1/11 resistant isolates harbored a gene for MBL production. Gene mutations in blaKPC were not detected. See Table 1 for characteristics of resistant isolates. Conclusion Resistance and decreased susceptibility to MV is demonstrated in a historical cohort of KP clinical isolates dating back to 2013. WGS reliably identifies porin variants secondary to gene mutations in Ompk35 and Ompk36 as the underlying mechanism of decreased susceptibility. CZA appears to retain activity against these isolates. Caution should be exercised regarding the empiric use of MV against increasingly resistant KP as a result of non-β-lactamase-mediated mechanisms. Disclosures All authors: No reported disclosures.

scholarly journals Molecular Epidemiology and Characterization of Carbapenem-Resistant Klebsiella pneumoniae Isolated from Urine at a Teaching Hospital in Taiwan

2021 ◽  
Vol 9 (2) ◽  
pp. 271
Author(s):  
Yuarn-Jang Lee ◽  
Chih-Hung Huang ◽  
Noor Andryan Ilsan ◽  
I-Hui Lee ◽  
Tzu-Wen Huang
Keyword(s):  
Klebsiella Pneumoniae ◽  
Teaching Hospital ◽  
Efflux Pump ◽  
Resistance Mechanisms ◽  
Pcr Analysis ◽  
Carbapenem Resistant ◽  
High Prevalence ◽  
Antimicrobial Susceptibility Tests ◽  
Susceptibility Tests ◽  
Tract Infections

Urinary tract infections (UTIs) are common in clinics and hospitals and are associated with a high economic burden. Enterobacterium Klebsiella pneumoniae is a prevalent agent causing UTIs. A high prevalence of carbapenem-resistant K. pneumoniae (CRKP) has emerged recently and is continuing to increase. Seventeen urinary CRKP isolates collected at a teaching hospital in Taiwan from December 2016 to September 2017 were analyzed to elucidate their drug resistance mechanisms. Two-thirds of the isolates were obtained from outpatients. Antimicrobial susceptibility tests demonstrated multidrug resistance in all the isolates. Multilocus sequence typing analysis showed high diversity among the isolates. PCR analysis demonstrated the presence of carbapenemases in three isolates. All isolates carried at least one other extended-spectrum β-lactamase, including TEM, DHA, and CTX-M. Fifteen isolates contained mutations in one of the outer membrane porins that were assessed. The expression levels of the acrB and/or oqxB efflux pump genes, as determined by qRT-PCR, were upregulated in 11 isolates. Six isolates might have utilized other efflux pumps or antimicrobial resistance mechanisms. These analyses demonstrated a highly diverse population and the presence of complex resistance mechanisms in urinary isolates of K. pneumoniae.

scholarly journals Comparative Effectiveness of Aminoglycosides, Polymyxin B, and Tigecycline for Clearance of Carbapenem-Resistant Klebsiella pneumoniae from Urine

2011 ◽  
Vol 55 (12) ◽  
pp. 5893-5899 ◽  
Author(s):  
Michael J. Satlin ◽  
Christine J. Kubin ◽  
Jill S. Blumenthal ◽  
Andrew B. Cohen ◽  
E. Yoko Furuya ◽  
...  
Keyword(s):  
New York ◽  
Klebsiella Pneumoniae ◽  
Urine Culture ◽  
Active Agent ◽  
Polymyxin B ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Tract Infections

ABSTRACTCarbapenem-resistantKlebsiella pneumoniae(CRKP) is an increasingly common cause of health care-associated urinary tract infections. Antimicrobials within vitroactivity against CRKP are typically limited to polymyxins, tigecycline, and often, aminoglycosides. We conducted a retrospective cohort study of cases of CRKP bacteriuria at New York-Presbyterian Hospital from January 2005 through June 2010 to compare microbiologic clearance rates based on the use of polymyxin B, tigecycline, or an aminoglycoside. We constructed three active antimicrobial cohorts based on the active agent used and an untreated cohort of cases that did not receive antimicrobial therapy with Gram-negative activity. Microbiologic clearance was defined as having a follow-up urine culture that did not yield CRKP. Cases without an appropriate follow-up culture or that received multiple active agents or less than 3 days of the active agent were excluded. Eighty-seven cases were included in the active antimicrobial cohorts, and 69 were included in the untreated cohort. The microbiologic clearance rate was 88% in the aminoglycoside cohort (n= 41), compared to 64% in the polymyxin B (P= 0.02;n= 25), 43% in the tigecycline (P< 0.001;n= 21), and 36% in the untreated (P< 0.001;n= 69) cohorts. Using multivariate analysis, the odds of clearance were lower for the polymyxin B (odds ratio [OR], 0.10;P= 0.003), tigecycline (OR, 0.08;P= 0.001), and untreated (OR, 0.14;P= 0.003) cohorts than for the aminoglycoside cohort. Treatment with an aminoglycoside, when activein vitro, was associated with a significantly higher rate of microbiologic clearance of CRKP bacteriuria than treatment with either polymyxin B or tigecycline.

scholarly journals Nacubactam Enhances Meropenem Activity against Carbapenem-Resistant Klebsiella pneumoniae Producing KPC

2019 ◽  
Vol 63 (8) ◽  
Author(s):  
Melissa D. Barnes ◽  
Magdalena A. Taracila ◽  
Caryn E. Good ◽  
Saralee Bajaksouzian ◽  
Laura J. Rojas ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Klebsiella Pneumoniae ◽  
The United States ◽  
Alternative Mechanism ◽  
Enhancer Activity ◽  
Content Type ◽  
Class A ◽  
Carbapenem Resistant ◽  
Biochemical Analyses ◽  
Molecular Modeling And Docking

ABSTRACT Carbapenem-resistant Enterobacteriaceae (CRE) are resistant to most antibiotics, making CRE infections extremely difficult to treat with available agents. Klebsiella pneumoniae carbapenemases (KPC-2 and KPC-3) are predominant carbapenemases in CRE in the United States. Nacubactam is a bridged diazabicyclooctane (DBO) β-lactamase inhibitor that inactivates class A and C β-lactamases and exhibits intrinsic antibiotic and β-lactam “enhancer” activity against Enterobacteriaceae. In this study, we examined a collection of meropenem-resistant K. pneumoniae isolates carrying blaKPC-2 or blaKPC-3; meropenem-nacubactam restored susceptibility. Upon testing isogenic Escherichia coli strains producing KPC-2 variants with single-residue substitutions at important Ambler class A positions (K73, S130, R164, E166, N170, D179, K234, E276, etc.), the K234R variant increased the meropenem-nacubactam MIC compared to that for the strain producing KPC-2, without increasing the meropenem MIC. Correspondingly, nacubactam inhibited KPC-2 (apparent Ki [Ki app] = 31 ± 3 μM) more efficiently than the K234R variant (Ki app = 270 ± 27 μM) and displayed a faster acylation rate (k2/K), which was 5,815 ± 582 M−1 s−1 for KPC-2 versus 247 ± 25 M−1 s−1 for the K234R variant. Unlike avibactam, timed mass spectrometry revealed an intact sulfate on nacubactam and a novel peak (+337 Da) with the K234R variant. Molecular modeling of the K234R variant showed significant catalytic residue (i.e., S70, K73, and S130) rearrangements that likely interfere with nacubactam binding and acylation. Nacubactam’s aminoethoxy tail formed unproductive interactions with the K234R variant’s active site. Molecular modeling and docking observations were consistent with the results of biochemical analyses. Overall, the meropenem-nacubactam combination is effective against carbapenem-resistant K. pneumoniae. Moreover, our data suggest that β-lactamase inhibition by nacubactam proceeds through an alternative mechanism compared to that for avibactam.

scholarly journals Carbapenem-Resistant Klebsiella pneumoniae Urinary Tract Infection following Solid Organ Transplantation

2014 ◽  
Vol 59 (1) ◽  
pp. 553-557 ◽  
Author(s):  
Kyle D. Brizendine ◽  
Sandra S. Richter ◽  
Eric D. Cober ◽  
David van Duin
Keyword(s):  
Urinary Tract ◽  
Klebsiella Pneumoniae ◽  
Solid Organ Transplantation ◽  
Organ Transplant ◽  
Carbapenem Resistance ◽  
First Episode ◽  
Solid Organ ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Tract Infections

ABSTRACTCarbapenem-resistantKlebsiella pneumoniae(CRKP) is an emerging pathogen with a devastating impact on organ transplant recipients (OTRs). Data describing urinary tract infections (UTIs) due to CRKP, compared to extended-spectrum β-lactamase (ESBL)-producing and susceptibleK. pneumoniae, are lacking. We conducted a retrospective cohort study comparing OTRs with a first episode of UTI due to CRKP, ESBL-producingK. pneumoniae, or susceptibleK. pneumoniae. We identified 108 individuals; 22 (20%) had UTIs due to CRKP, 22 (20%) due to ESBL-producingK. pneumoniae, and 64 (60%) due to susceptibleK. pneumoniae. Compared to susceptibleK. pneumoniae(27%), patients with UTIs due to CRKP or ESBL-producingK. pneumoniaewere more likely to have a ≥24-hour stay in the intensive care unit (ICU) before or after development of the UTI (64% and 77%, respectively;P< 0.001). Among 105/108 hospitalized patients (97%), the median lengths of stay prior to UTI with CRKP or ESBL-producingK. pneumoniae(7 and 8 days, respectively) were significantly longer than that for susceptibleK. pneumoniae(1 day;P< 0.001). Clinical failure was observed for 8 patients (36%) with CRKP, 4 (18%) with ESBL-producingK. pneumoniae, and 9 (14%) with susceptibleK. pneumoniae(P= 0.073). Microbiological failure was seen for 10 patients (45%) with CRKP, compared with 2 (9%) with ESBL-producingK. pneumoniaeand 2 (3%) with susceptibleK. pneumoniae(P< 0.001). In multivariable logistic regression analyses, CRKP was associated with greater odds of microbiological failure (versus ESBL-producingK. pneumoniae: odds ratio [OR], 9.36, 95% confidence interval [CI], 1.94 to 72.1; versus susceptibleK. pneumoniae: OR, 31.4, 95% CI, 5.91 to 264). In conclusion, CRKP is associated with ICU admission, long length of stay, and microbiological failure among OTRs with UTIs. Greater numbers are needed to determine risk factors for infection and differences in meaningful endpoints associated with carbapenem resistance.

scholarly journals In VitroandIn VivoProperties of BAL30376, a β-Lactam and Dual β-Lactamase Inhibitor Combination with Enhanced Activity against Gram-Negative Bacilli That Express Multiple β-Lactamases

2011 ◽  
Vol 55 (4) ◽  
pp. 1510-1519 ◽  
Author(s):  
Malcolm G. P. Page ◽  
Clothilde Dantier ◽  
Eric Desarbre ◽  
Bérangère Gaucher ◽  
Klaus Gebhardt ◽  
...  
Keyword(s):  
Clavulanic Acid ◽  
Stenotrophomonas Maltophilia ◽  
Multidrug Resistant ◽  
Triple Combination ◽  
Class A ◽  
Link Type ◽  
Class D ◽  
Class C ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor

ABSTRACTBAL30376 is a triple combination comprising a siderophore monobactam,BAL19764; a novel bridged monobactam,BAL29880, which specifically inhibits class C β-lactamases; and clavulanic acid, which inhibits many class A and some class D β-lactamases. The MIC90was ≤4 μg/ml (expressed as the concentration ofBAL19764) for most species of theEnterobacteriaceaefamily, including strains that produced metallo-β-lactamases and were resistant to all of the other β-lactams tested. The MIC90forStenotrophomonas maltophiliawas 2 μg/ml, for multidrug-resistant (MDR)Pseudomonas aeruginosait was 8 μg/ml, and for MDRAcinetobacterandBurkholderiaspp. it was 16 μg/ml. The presence of the class C β-lactamase inhibitorBAL29880contributed significantly to the activity ofBAL30376against strains ofCitrobacter freundii,Enterobacterspecies,Serratia marcescens, andP. aeruginosa. The presence of clavulanic acid contributed significantly to the activity against many strains ofEscherichia coliandKlebsiella pneumoniaethat produced class A extended-spectrum β-lactamases. The activity ofBAL30376against strains with metallo-β-lactamases was largely attributable to the intrinsic stability of the monobactamBAL19764toward these enzymes. Considering its three components,BAL30376was unexpectedly refractory toward the development of stable resistance.

scholarly journals In VivoEfficacy of Humanized Exposures of Ceftazidime-Avibactam in Comparison with Ceftazidime against Contemporary Enterobacteriaceae Isolates

2014 ◽  
Vol 58 (11) ◽  
pp. 6913-6919 ◽  
Author(s):  
Shawn H. MacVane ◽  
Jared L. Crandon ◽  
Wright W. Nichols ◽  
David P. Nicolau
Keyword(s):  
Gram Negative ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Class D ◽  
Variable Activity ◽  
Resistant Strains ◽  
The Impact ◽  
Inhibitor Combination ◽  
Lactamase Inhibitor

ABSTRACTCeftazidime-avibactam is a β-lactam β-lactamase inhibitor combination under investigation for the treatment of serious Gram-negative infections. When combined with avibactam, a novel non-β-lactam β-lactamase inhibitor, ceftazidime has activity against isolates that produce Ambler class A, class C, and some class D β-lactamases. However, little is known of thein vivoefficacy of the combination against these targeted ceftazidime- and carbapenem-resistantEnterobacteriaceae. Using humanized exposures in the murine thigh model, we evaluated the efficacy of ceftazidime-avibactam againstEnterobacteriaceaeexhibiting MICs of ≥8 μg/ml to aid in the assignment of interpretive susceptibility criteria. Eighteen clinicalEnterobacteriaceaeisolates, including nine carbapenem-resistant strains, were evaluated against ceftazidime-avibactam (2,000 mg/500 mg) as a 2-h infusion every 8 h. To highlight the impact of avibactam, 13 select isolates were tested in the neutropenic model against a humanized regimen of 2,000 mg ceftazidime every 8 h (2-h infusion). Additionally, nine isolates were evaluated in immunocompetent animals. The efficacy was evaluated as the change in log10CFU compared with that of 0-h controls after 24 h. The vast majority (17/18, 94%) of the isolates were resistant to ceftazidime alone. The ceftazidime monotherapy failed to have activity against 10 of 13 isolates, while ceftazidime-avibactam produced reductions in bacterial density against 16 of 18 isolates. Ceftazidime-avibactam (2,000 mg/500 mg) every 8 h (2-h infusion) displayed dependable activity against theEnterobacteriaceaeisolates, exhibiting MICs of ≤16 μg/ml (free drug concentration above the MIC [fT>MIC] of ≥62%) and variable activity was noted at an MIC of 32 μg/ml (fT>MICof 34%). The presence of a functioning immune system enhanced the efficacy for both regimens against all tested isolates. These data support further examination of the use of ceftazidime-avibactam as an effective therapy against infections due to Gram-negative infections, including carbapenem-resistantEnterobacteriaceae.

scholarly journals 1265. In Vitro Activity of Aztreonam-Avibactam against Klebsiella pneumoniae Isolates Analyzed by Epidemic Lineage and Hypervirulence Factors Collected in China as Part of the ATLAS Global Surveillance Study in 2019

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S721-S721
Author(s):  
Mark Estabrook ◽  
Krystyna Kazmierczak ◽  
Francis Arhin ◽  
Daniel F Sahm
Keyword(s):  
Klebsiella Pneumoniae ◽  
Multidrug Resistant ◽  
Vitro Activity ◽  
Surveillance Study ◽  
In Vitro Activity ◽  
Independent Contractor ◽  
Illumina Hiseq ◽  
Carbapenem Resistant ◽  
Class D

Abstract Background Hypervirulent Klebsiella pneumoniae (hvKp), unlike classical K. pneumoniae (cKp), are often responsible for community-acquired infections in otherwise healthy individuals. The acquisition of hypervirulence genes by sequence type 11 (ST11) carbapenem-resistant (CR) Kp endemic in Asia is a grave threat. Aztreonam-avibactam (ATM-AVI) is a monobactam combined with a β-lactamase inhibitor for the treatment of infections caused by Enterobacterales isolates that carry Class A, B, C and some Class D β-lactamases. Methods 487 K. pneumoniae isolates were collected from 17 sites in China in 2019 as a part of the ATLAS global surveillance study. 220 isolates with MICs &gt;1 µg/ml to meropenem (MEM), ceftazidime or ATM were selected for whole genome sequencing (Illumina Hiseq 2x150 bp reads). Analyses were carried out using the CLC Genomics Workbench (Qiagen). Presence of the aerobactin synthesis locus differentiated hvKp and cKp. Antimicrobial susceptibility was determined by CLSI broth microdilution. Results Of the 487 isolates, MIC90 values for ATM-AVI (0.5 µg/ml; Table) were lower than those for any comparator tested, with only two isolates testing with MIC &gt;4 µg/ml. Of the isolates sequenced, 82/220 (37.3%) were ST11. 53/82 (64.6%) of these ST11 isolates were hvKp (ATM-AVI, MIC90 1 µg/ml; range, 0.25-4 µg/ml) and showed percentages of susceptibility &lt; 90% to three last-line agents (0% MEM-susceptible (S); 18.9% amikacin (AMK)-S; 88.7% tigecycline (TGC)-S). Isolates of other STs (Non-ST11) were less frequently identified as hvKp (24/138, 17.4%) and more Non-ST-11 hvKp and cKp alike were S to MEM and AMK relative to isolates of ST11 (75.0-86.8% MEM-S; 83.3-96.5% AMK-S). Likewise, the ATM-AVI MIC90 value (0.25 µg/ml) was 4-fold lower for Non-ST11 isolates. Results Table Conclusion CR ST11 hvKp represented at least 10.9% of the collected Kp isolates. ATM-AVI retained potent in vitro activity against these isolates which displayed resistance to a range of last-line agents. CST and TGC also displayed some activity but are limited in utility due to nephrotoxicity and poor accumulation in blood, respectively. The spread of virulence factors leading to the complicated clinical presentation of hvKp infection into multidrug-resistant lineages warrants continued surveillance. Disclosures Mark Estabrook, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Krystyna Kazmierczak, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor) Francis Arhin, PhD, Pfizer, Inc. (Employee) Daniel F. Sahm, PhD, IHMA (Employee)Pfizer, Inc. (Independent Contractor)

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