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1. Molecular and clinical epidemiology of carbapenem-resistant Enterobacterales in the USA (CRACKLE-2): a prospective cohort study

Author

van Duin, David, Arias, Cesar A, Komarow, Lauren, Chen, Liang, Hanson, Blake M, Weston, Gregory, Cober, Eric, Garner, Omai B, Jacob, Jesse T, Satlin, Michael J, Fries, Bettina C, Garcia-Diaz, Julia, Doi, Yohei, Dhar, Sorabh, Kaye, Keith S, Earley, Michelle, Hujer, Andrea M, Hujer, Kristine M, Domitrovic, T Nicholas, Shropshire, William C, Dinh, An, Manca, Claudia, Luterbach, Courtney L, Wang, Minggui, Paterson, David L, Banerjee, Ritu, Patel, Robin, Evans, Scott, Hill, Carol, Arias, Rebekka, Chambers, Henry F, Fowler, Vance G, Kreiswirth, Barry N, Bonomo, Robert A, and Investigators, Multi-Drug Resistant Organism Network

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Prevention, Infectious Diseases, Clinical Research, Lung, Infection, Good Health and Well Being, Aged, Carbapenem-Resistant Enterobacteriaceae, Cohort Studies, Enterobacteriaceae Infections, Female, Humans, Male, Middle Aged, Phylogeny, Prospective Studies, United States, Multi-Drug Resistant Organism Network Investigators, Public Health and Health Services, Microbiology, Clinical sciences, Medical microbiology, Epidemiology
Abstract

BackgroundCarbapenem-resistant Enterobacterales (CRE) are a global threat. We aimed to describe the clinical and molecular characteristics of Centers for Disease Control and Prevention (CDC)-defined CRE in the USA.MethodsCRACKLE-2 is a prospective, multicentre, cohort study. Patients hospitalised in 49 US hospitals, with clinical cultures positive for CDC-defined CRE between April 30, 2016, and Aug 31, 2017, were included. There was no age exclusion. The primary outcome was desirability of outcome ranking (DOOR) at 30 days after index culture. Clinical data and bacteria were collected, and whole genome sequencing was done. This trial is registered with ClinicalTrials.gov, number NCT03646227.Findings1040 patients with unique isolates were included, 449 (43%) with infection and 591 (57%) with colonisation. The CDC-defined CRE admission rate was 57 per 100 000 admissions (95% CI 45-71). Three subsets of CDC-defined CRE were identified: carbapenemase-producing Enterobacterales (618 [59%] of 1040), non-carbapenemase-producing Enterobacterales (194 [19%]), and unconfirmed CRE (228 [22%]; initially reported as CRE, but susceptible to carbapenems in two central laboratories). Klebsiella pneumoniae carbapenemase-producing clonal group 258 K pneumoniae was the most common carbapenemase-producing Enterobacterales. In 449 patients with CDC-defined CRE infections, DOOR outcomes were not significantly different in patients with carbapenemase-producing Enterobacterales, non-carbapenemase-producing Enterobacterales, and unconfirmed CRE. At 30 days 107 (24%, 95% CI 20-28) of these patients had died.InterpretationAmong patients with CDC-defined CRE, similar outcomes were observed among three subgroups, including the novel unconfirmed CRE group. CDC-defined CRE represent diverse bacteria, whose spread might not respond to interventions directed to carbapenemase-producing Enterobacterales.FundingNational Institutes of Health.

Published
2020

2. Rapid Molecular Diagnostics to Inform Empiric Use of Ceftazidime/Avibactam and Ceftolozane/Tazobactam Against Pseudomonas aeruginosa: PRIMERS IV

Author

Evans, Scott R, Tran, Thuy Tien T, Hujer, Andrea M, Hill, Carol B, Hujer, Kristine M, Mediavilla, Jose R, Manca, Claudia, Domitrovic, T Nicholas, Perez, Federico, Farmer, Michael, Pitzer, Kelsey M, Wilson, Brigid M, Kreiswirth, Barry N, Patel, Robin, Jacobs, Michael R, Chen, Liang, Fowler, Vance G, Chambers, Henry F, and Bonomo, Robert A

Subjects
Infectious Diseases, Biodefense, Vaccine Related, Emerging Infectious Diseases, Prevention, Antimicrobial Resistance, 4.1 Discovery and preclinical testing of markers and technologies, Detection, screening and diagnosis, Infection, Good Health and Well Being, Anti-Bacterial Agents, Azabicyclo Compounds, Ceftazidime, Cephalosporins, Drug Combinations, Drug Resistance, Multiple, Bacterial, Genotype, Humans, Microbial Sensitivity Tests, Molecular Diagnostic Techniques, Pseudomonas Infections, Pseudomonas aeruginosa, Sensitivity and Specificity, Tazobactam, beta-Lactam Resistance, beta-Lactamase Inhibitors, ceftolozane, tazobactam, ceftazidime, avibactam, antimicrobial resistance, Antibacterial Resistance Leadership Group, Pseudomonas aeruginosa, ceftazidime/avibactam, ceftolozane/tazobactam, Biological Sciences, Medical and Health Sciences, Microbiology
Abstract

BackgroundOvercoming β-lactam resistance in pathogens such as Pseudomonas aeruginosa is a major clinical challenge. Rapid molecular diagnostics (RMDs) have the potential to inform selection of empiric therapy in patients infected by P. aeruginosa.MethodsIn this study, we used a heterogeneous collection of 197 P. aeruginosa that included multidrug-resistant isolates to determine whether 2 representative RMDs (Acuitas Resistome test and VERIGENE gram-negative blood culture test) could identify susceptibility to 2 newer β-lactam/β-lactamase inhibitor (BL-BLI) combinations, ceftazidime/avibactam (CZA) and ceftolozane/tazobactam (TOL/TAZO).ResultsWe found that the studied RMD platforms were able to correctly identify BL-BLI susceptibility (susceptibility sensitivity, 100%; 95% confidence interval [CI], 97%, 100%) for both BLs-BLIs. However, their ability to detect resistance to these BLs-BLIs was lower (resistance sensitivity, 66%; 95% CI, 52%, 78% for TOL/TAZO and 33%; 95% CI, 20%, 49% for CZA).ConclusionsThe diagnostic platforms studied showed the most potential in scenarios where a resistance gene was detected or in scenarios where a resistance gene was not detected and the prevalence of resistance to TOL/TAZO or CZA is known to be low. Clinicians need to be mindful of the benefits and risks that result from empiric treatment decisions that are based on resistance gene detection in P. aeruginosa, acknowledging that such decisions are impacted by the prevalence of resistance, which varies temporally and geographically.

Published
2019

3. A γ-lactam siderophore antibiotic effective against multidrug-resistant Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter spp.

Author

Goldberg, Joel A., Kumar, Vijay, Spencer, Elizabeth J., Hoyer, Denton, Marshall, Steven H., Hujer, Andrea M., Hujer, Kristine M., Bethel, Christopher R., Papp-Wallace, Krisztina M., Perez, Federico, Jacobs, Michael R., van Duin, David, Kreiswirth, Barry N., van den Akker, Focco, Plummer, Mark S., and Bonomo, Robert A.

Published
2021
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4. A comprehensive and contemporary “snapshot” of β-lactamases in carbapenem resistant Acinetobacter baumannii

Author

Hujer, Andrea M., Hujer, Kristine M., Leonard, David A., Powers, Rachel A., Wallar, Bradley J., Mack, Andrew R., Taracila, Magdalena A., Rather, Philip N., Higgins, Paul G., Prati, Fabio, Caselli, Emilia, Marshall, Steven H., Clarke, Thomas, Greco, Christopher, Venepally, Pratap, Brinkac, Lauren, Kreiswirth, Barry N., Fouts, Derrick E., and Bonomo, Robert A.

Published
2021
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5. Can Ceftazidime-Avibactam and Aztreonam Overcome β-Lactam Resistance Conferred by Metallo-β-Lactamases in Enterobacteriaceae?

Author

Marshall, Steven, Hujer, Andrea M, Rojas, Laura J, Papp-Wallace, Krisztina M, Humphries, Romney M, Spellberg, Brad, Hujer, Kristine M, Marshall, Emma K, Rudin, Susan D, Perez, Federico, Wilson, Brigid M, Wasserman, Ronald B, Chikowski, Linda, Paterson, David L, Vila, Alejandro J, van Duin, David, Kreiswirth, Barry N, Chambers, Henry F, Fowler, Vance G, Jacobs, Michael R, Pulse, Mark E, Weiss, William J, and Bonomo, Robert A

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Microbiology, Clinical Sciences, Medical Microbiology, Infectious Diseases, Antimicrobial Resistance, Vaccine Related, Emerging Infectious Diseases, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Infection, Animals, Anti-Bacterial Agents, Azabicyclo Compounds, Aztreonam, Ceftazidime, Colony Count, Microbial, Cyclophosphamide, Drug Administration Schedule, Drug Combinations, Drug Therapy, Combination, Enterobacteriaceae, Enterobacteriaceae Infections, Female, Gene Expression, Humans, Klebsiella Infections, Klebsiella pneumoniae, Mice, Microbial Sensitivity Tests, Neutropenia, Plasmids, Soft Tissue Infections, Thigh, beta-Lactam Resistance, beta-Lactamases, ceftazidime, avibactam, aztreonam, disk diffusion, metallo-beta-lactamases, metallo-β-lactamases, Pharmacology and Pharmaceutical Sciences, Medical microbiology, Pharmacology and pharmaceutical sciences
Abstract

Based upon knowledge of the hydrolytic profile of major β-lactamases found in Gram-negative bacteria, we tested the efficacy of the combination of ceftazidime-avibactam (CAZ-AVI) with aztreonam (ATM) against carbapenem-resistant enteric bacteria possessing metallo-β-lactamases (MBLs). Disk diffusion and agar-based antimicrobial susceptibility testing were initially performed to determine the in vitro efficacy of a unique combination of CAZ-AVI and ATM against 21 representative Enterobacteriaceae isolates with a complex molecular background that included blaIMP, blaNDM, blaOXA-48, blaCTX-M, blaAmpC, and combinations thereof. Time-kill assays were conducted, and the in vivo efficacy of this combination was assessed in a murine neutropenic thigh infection model. By disk diffusion assay, all 21 isolates were resistant to CAZ-AVI alone, and 19/21 were resistant to ATM. The in vitro activity of CAZ-AVI in combination with ATM against diverse Enterobacteriaceae possessing MBLs was demonstrated in 17/21 isolates, where the zone of inhibition was ≥21 mm. All isolates demonstrated a reduction in CAZ-AVI agar dilution MICs with the addition of ATM. At 2 h, time-kill assays demonstrated a ≥4-log10-CFU decrease for all groups that had CAZ-AVI with ATM (8 μg/ml) added, compared to the group treated with CAZ-AVI alone. In the murine neutropenic thigh infection model, an almost 4-log10-CFU reduction was noted at 24 h for CAZ-AVI (32 mg/kg every 8 h [q8h]) plus ATM (32 mg/kg q8h) versus CAZ-AVI (32 mg/kg q8h) alone. The data presented herein require us to carefully consider this new therapeutic combination to treat infections caused by MBL-producing Enterobacteriaceae.

Published
2017

6. Informing Antibiotic Treatment Decisions: Evaluating Rapid Molecular Diagnostics To Identify Susceptibility and Resistance to Carbapenems against Acinetobacter spp. in PRIMERS III

Author

Evans, Scott R, Hujer, Andrea M, Jiang, Hongyu, Hill, Carol B, Hujer, Kristine M, Mediavilla, Jose R, Manca, Claudia, Tran, Thuy Tien T, Domitrovic, T Nicholas, Higgins, Paul G, Seifert, Harald, Kreiswirth, Barry N, Patel, Robin, Jacobs, Michael R, Chen, Liang, Sampath, Rangarajan, Hall, Thomas, Marzan, Christine, Fowler, Vance G, Chambers, Henry F, and Bonomo, Robert A

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Clinical Sciences, Infectious Diseases, Biodefense, Antimicrobial Resistance, Prevention, Emerging Infectious Diseases, Vaccine Related, Infection, Acinetobacter, Anti-Bacterial Agents, Bacterial Proteins, Carbapenems, DNA Primers, Humans, Microbial Sensitivity Tests, Pathology, Molecular, Predictive Value of Tests, Sensitivity and Specificity, Time Factors, beta-Lactam Resistance, beta-Lactamases, beta-lactams, carbapenemases, Biological Sciences, Agricultural and Veterinary Sciences, Medical and Health Sciences, Microbiology, Clinical sciences, Medical microbiology
Abstract

The widespread dissemination of carbapenem-resistant Acinetobacter spp. has created significant therapeutic challenges. At present, rapid molecular diagnostics (RMDs) that can identify this phenotype are not commercially available. Two RMD platforms, PCR combined with electrospray ionization mass spectrometry (PCR/ESI-MS) and molecular beacons (MB), for detecting genes conferring resistance/susceptibility to carbapenems in Acinetobacter spp. were evaluated. An archived collection of 200 clinical Acinetobacter sp. isolates was tested. Predictive values for susceptibility and resistance were estimated as a function of susceptibility prevalence and were based on the absence or presence of beta-lactamase (bla) NDM, VIM, IMP, KPC, and OXA carbapenemase genes (e.g., blaOXA-23, blaOXA-24/40, and blaOXA-58 found in this study) against the reference standard of MIC determinations. According to the interpretation of MICs, 49% (n = 98) of the isolates were carbapenem resistant (as defined by either resistance or intermediate resistance to imipenem). The susceptibility sensitivities (95% confidence interval [CI]) for imipenem were 82% (74%, 89%) and 92% (85%, 97%) for PCR/ESI-MS and MB, respectively. Resistance sensitivities (95% CI) for imipenem were 95% (88%, 98%) and 88% (80%, 94%) for PCR/ESI-MS and MB, respectively. PRIMERS III establishes that RMDs can discriminate between carbapenem resistance and susceptibility in Acinetobacter spp. In the context of a known prevalence of resistance, SPVs and RPVs can inform clinicians regarding the best choice for empiric antimicrobial therapy against this multidrug-resistant pathogen.

Published
2017

7. The Real Crisis in Antimicrobial Resistance: Failure to Anticipate and Respond.

Author

Bonomo, Robert A, Perez, Federico, Hujer, Andrea M, Hujer, Kristine M, and Vila, Alejandro J

Subjects
ANTIBIOTICS, DRUG resistance in microorganisms, BLOODBORNE infections, CATHETER-related infections, BACTEREMIA, CRISIS intervention (Mental health services), ESCHERICHIA coli diseases, TREATMENT failure, AZTREONAM, CEFTAZIDIME, CEPHALOSPORINS, BETA lactamases, GENETIC mutation
Abstract

The article discusses the growing threat of multidrug-resistant Gram-negative infections. Topics discussed include the rapid evolution of bacterial resistance mechanisms, the pharmaceutical industry's challenges in developing effective antibiotics, and a poignant case study of fatal antibiotic-resistant E. coli in a child.

Published
2024
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9. Rapid Molecular Diagnostics, Antibiotic Treatment Decisions, and Developing Approaches to Inform Empiric Therapy: PRIMERS I and II

Author

Evans, Scott R, Hujer, Andrea M, Jiang, Hongyu, Hujer, Kristine M, Hall, Thomas, Marzan, Christine, Jacobs, Michael R, Sampath, Rangarajan, Ecker, David J, Manca, Claudia, Chavda, Kalyan, Zhang, Pan, Fernandez, Helen, Chen, Liang, Mediavilla, Jose R, Hill, Carol B, Perez, Federico, Caliendo, Angela M, Fowler, Vance G, Chambers, Henry F, Kreiswirth, Barry N, and Bonomo, Robert A

Subjects
Prevention, Vaccine Related, Infectious Diseases, Emerging Infectious Diseases, Antimicrobial Resistance, Biodefense, Infection, Anti-Bacterial Agents, Enterobacteriaceae Infections, Escherichia coli, Genotyping Techniques, Humans, Klebsiella pneumoniae, Microbial Sensitivity Tests, Molecular Diagnostic Techniques, Time Factors, beta-Lactam Resistance, beta-lactams, molecular diagnostics, empiric therapy, Antibacterial Resistance Leadership Group, β-lactams, Biological Sciences, Medical and Health Sciences, Microbiology
Abstract

BackgroundRapid molecular diagnostic (RMD) platforms may lead to better antibiotic use. Our objective was to develop analytical strategies to enhance the interpretation of RMDs for clinicians.MethodsWe compared the performance characteristics of 4 RMD platforms for detecting resistance against β-lactams in 72 highly resistant isolates of Escherichia coli and Klebsiella pneumoniae (PRIMERS I). Subsequently, 2 platforms were used in a blinded study in which a heterogeneous collection of 196 isolates of E. coli and K. pneumoniae (PRIMERS II) were examined. We evaluated the genotypic results as predictors of resistance or susceptibility against β-lactam antibiotics. We designed analytical strategies and graphical representations of platform performance, including discrimination summary plots and susceptibility and resistance predictive values, that are readily interpretable by practitioners to inform decision-making.ResultsIn PRIMERS I, the 4 RMD platforms detected β-lactamase (bla) genes and identified susceptibility or resistance in >95% of cases. In PRIMERS II, the 2 platforms identified susceptibility against extended-spectrum cephalosporins and carbapenems in >90% of cases; however, against piperacillin/tazobactam, susceptibility was identified in 95% of cases, while prediction of resistance was 69%-73% for ceftazidime and 41%-50% for imipenem.ConclusionsRMD platforms can help inform empiric β-lactam therapy in cases where bla genes are not detected and the prevalence of resistance is known. Our analysis is a first step in bridging the gap between RMDs and empiric treatment decisions.

Published
2016

10. Transcending the challenge of evolving resistance mechanisms in Pseudomonas aeruginosa through β-lactam-enhancer-mechanism-based cefepime/zidebactam

Author

Hujer, Andrea M., primary, Marshall, Steven H., additional, Mack, Andrew R., additional, Hujer, Kristine M., additional, Bakthavatchalam, Yamuna Devi, additional, Umarkar, Kushal, additional, Palwe, Snehal R., additional, Takalkar, Swapna, additional, Joshi, Prashant R., additional, Shrivastava, Rahul, additional, Periasamy, Hariharan, additional, Bhagwat, Sachin S., additional, Patel, Mahesh V., additional, Veeraraghavan, Balaji, additional, and Bonomo, Robert A., additional

Published
2023
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11. An Analysis of the Epidemic of Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae : Convergence of Two Evolutionary Mechanisms Creates the “Perfect Storm”

Author

Rojas, Laura J., Weinstock, George M., De La Cadena, Elsa, Diaz, Lorena, Rios, Rafael, Hanson, Blake M., Brown, Joseph S., Vats, Purva, Phillips, Daniel S., Nguyen, Hoan, Hujer, Kristine M., Correa, Adriana, Adams, Mark D., Perez, Federico, Sodergren, Erica, Narechania, Apurva, Planet, Paul J., Villegas, Maria V., Bonomo, Robert. A., and Arias, Cesar A.

Published
2018

12. Evaluation of Sensititre Broth Microdilution Plate for determining the susceptibility of carbapenem-resistant Klebsiella pneumoniae to polymyxins

Author

Richter, Sandra S., Karichu, James, Otiso, Joshua, Van Heule, Hillary, Keller, George, Cober, Eric, Rojas, Laura J., Hujer, Andrea M., Hujer, Kristine M., Marshall, Steve, Perez, Frederico, Rudin, Susan D., Domitrovic, T. Nicholas, Kaye, Keith S., Salata, Robert, van Duin, David, and Bonomo, Robert A.

Published
2018
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14. Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae: Laboratory Detection and Impact on Mortality

Author

Antibacterial Resistance Leadership Group, Rojas, Laura J., Salim, Madiha, Cober, Eric, Richter, Sandra S., Perez, Federico, Salata, Robert A., Kalayjian, Robert C., Watkins, Richard R., Marshall, Steve, Rudin, Susan D., Domitrovic, T. Nicholas, Hujer, Andrea M., Hujer, Kristine M., Doi, Yohei, Kaye, Keith S., Evans, Scott, Fowler, Vance G., Bonomo, Robert A., and van Duin, David

Published
2017

15. Synthesis of a Novel Boronic Acid Transition State Inhibitor, MB076: A Heterocyclic Triazole Effectively Inhibits Acinetobacter-Derived Cephalosporinase Variants with an Expanded-Substrate Spectrum

Author

Powers, Rachel A., primary, June, Cynthia M., additional, Fernando, Micah C., additional, Fish, Erin R., additional, Maurer, Olivia L., additional, Baumann, Rachelle M., additional, Beardsley, Trevor J., additional, Taracila, Magdalena A., additional, Rudin, Susan D., additional, Hujer, Kristine M., additional, Hujer, Andrea M., additional, Santi, Nicolò, additional, Villamil, Valentina, additional, Introvigne, Maria Luisa, additional, Prati, Fabio, additional, Caselli, Emilia, additional, Bonomo, Robert A., additional, and Wallar, Bradley J., additional

Published
2023
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16. Sulfonamidoboronic Acids as “Cross-Class” Inhibitors of an Expanded-Spectrum Class C Cephalosporinase, ADC-33, and a Class D Carbapenemase, OXA-24/40: Strategic Compound Design to Combat Resistance in Acinetobacter baumannii

Author

Introvigne, Maria Luisa, primary, Beardsley, Trevor J., additional, Fernando, Micah C., additional, Leonard, David A., additional, Wallar, Bradley J., additional, Rudin, Susan D., additional, Taracila, Magdalena A., additional, Rather, Philip N., additional, Colquhoun, Jennifer M., additional, Song, Shaina, additional, Fini, Francesco, additional, Hujer, Kristine M., additional, Hujer, Andrea M., additional, Prati, Fabio, additional, Powers, Rachel A., additional, Bonomo, Robert A., additional, and Caselli, Emilia, additional

Published
2023
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17. Benefit-risk Evaluation for Diagnostics: A Framework (BED-FRAME)

Author

Antibacterial Resistance Leadership Group, Evans, Scott R., Pennello, Gene, Pantoja-Galicia, Norberto, Jiang, Hongyu, Hujer, Andrea M., Hujer, Kristine M., Manca, Claudia, Hill, Carol, Jacobs, Michael R., Chen, Liang, Patel, Robin, Kreiswirth, Barry N., and Bonomo, Robert A.

Published
2016

18. Rapid Molecular Diagnostics, Antibiotic Treatment Decisions, and Developing Approaches to Inform Empiric Therapy: PRIMERS I and II

Author

Antibacterial Resistance Leadership Group, Evans, Scott R., Hujer, Andrea M., Jiang, Hongyu, Hujer, Kristine M., Hall, Thomas, Marzan, Christine, Jacobs, Michael R., Sampath, Rangarajan, Ecker, David J., Manca, Claudia, Chavda, Kalyan, Zhang, Pan, Fernandez, Helen, Chen, Liang, Mediavilla, Jose R., Hill, Carol B., Perez, Federico, Caliendo, Angela M., Fowler, Vance G., Chambers, Henry F., Kreiswirth, Barry N., and Bonomo, Robert A.

Published
2016
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20. A Prospective Observational Study of the Epidemiology, Management, and Outcomes of Skin and Soft Tissue Infections Due to Carbapenem-Resistant Enterobacteriaceae

Author

Henig, Oryan, Cober, Eric, Richter, Sandra S, Perez, Federico, Salata, Robert A, Kalayjian, Robert C, Watkins, Richard R, Marshall, Steve, Rudin, Susan D, Domitrovic, T Nicholas, Hujer, Andrea M, Hujer, Kristine M, Doi, Yohei, Evans, Scott, Fowler, Vance G, Jr., Bonomo, Robert A, van Duin, David, and Kaye, Keith S

Published
2017
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22. A standard numbering scheme for class c β-lactamases

Author

Mack, Andrew R., Barnes, Melissa D., Taracila, Magdalena A., Hujer, Andrea M., Hujer, Kristine M., Cabot, Gabriel, Feldgarden, Michael, Haft, Daniel H., Klimke, William, Akker, Focco van den, Vila, Alejandro J., Smania, Andrea, Haider, Shozeb, Papp-Wallace, Krisztina M., Bradford, Patricia A., Rossolini, Gian Maria, Docquier, Jean-Denis, Frère, Jean-Marie, Galleni, Moreno, Hanson, Nancy D., Oliver, Antonio, Plésiatyz, Patrick, Poirel, Laurent, Nordmann, Patrice, Palzkill, Timothy G., Jacoby, George A., Bush, Karen, and Bonomo, Robert A.

Abstract

Unlike for classes A and B, a standardized amino acid numbering scheme has not been proposed for the class C (AmpC) β-lactamases, which complicates communication in the field. Here, we propose a scheme developed through a collaborative approach that considers both sequence and structure, preserves traditional numbering of catalytically important residues (Ser64, Lys67, Tyr150, and Lys315), is adaptable to new variants or enzymes yet to be discovered and includes a variation for genetic and epidemiological applications.

Published
2021

23. A comprehensive and contemporary snapshot of beta-lactamases in carbapenem resistant Acinetobacter baumannii

Author

Hujer, Andrea M., Hujer, Kristine M., Leonard, David A., Powers, Rachel A., Wallar, Bradley J., Mack, Andrew R., Taracila, Magdalena A., Rather, Philip N., Higgins, Paul G., Prati, Fabio, Caselli, Emilia, Marshall, Steven H., Clarke, Thomas, Greco, Christopher, Venepally, Pratap, Brinkac, Lauren, Kreiswirth, Barry N., Fouts, Derrick E., Bonomo, Robert A., Hujer, Andrea M., Hujer, Kristine M., Leonard, David A., Powers, Rachel A., Wallar, Bradley J., Mack, Andrew R., Taracila, Magdalena A., Rather, Philip N., Higgins, Paul G., Prati, Fabio, Caselli, Emilia, Marshall, Steven H., Clarke, Thomas, Greco, Christopher, Venepally, Pratap, Brinkac, Lauren, Kreiswirth, Barry N., Fouts, Derrick E., and Bonomo, Robert A.

Abstract

Successful treatment of Acinetobacter baumannii infections require early and appropriate antimicrobial therapy. One of the first steps in this process is understanding which beta-lactamase (bla) alleles are present and in what combinations. Thus, we performed WGS on 98 carbapenem-resistant A. baumannii (CR Ab). In most isolates, an acquired bla(OXA) carbapenemase was found in addition to the intrinsic bla(OXA) allele. The most commonly found allele was bla(OXA-23) (n = 78/98). In some isolates, bla(OXA-23) was found in addition to other carbapenemase alleles: bla(OXA-82) (n = 12/78), bla(OXA-72) (n = 2/78) and bla(OXA-24/40) (n = 1/78). Surprisingly, 20% of isolates carried carbapenemases not routinely assayed for by rapid molecular diagnostic platforms, i.e., bla(OXA-82) and bla(OXA-172); all had ISAba1 elements. In 8 CR Ab, bla(OXA-82) or bla(OXA-172) was the only carbapenemase. Both bla(OXA-24/40) and its variant bla(OXA-72) were each found in 6/98 isolates. The most prevalent ADC variants were bla(ADC-30) (21%), bla(ADC-162) (21%), and bla(ADC-212) (26%). Complete combinations are reported. Published by Elsevier Inc.

Published
2021

24. A γ-Lactam Siderophore Antibiotic Effective against Multidrug-Resistant Gram-Negative Bacilli

Author

Goldberg, Joel A., primary, Nguyen, Ha, additional, Kumar, Vijay, additional, Spencer, Elizabeth J., additional, Hoyer, Denton, additional, Marshall, Emma K., additional, Cmolik, Anna, additional, O’Shea, Margaret, additional, Marshall, Steven H., additional, Hujer, Andrea M., additional, Hujer, Kristine M., additional, Rudin, Susan D., additional, Domitrovic, T. Nicholas, additional, Bethel, Christopher R., additional, Papp-Wallace, Krisztina M., additional, Logan, Latania K., additional, Perez, Federico, additional, Jacobs, Michael R., additional, van Duin, David, additional, Kreiswirth, Barry M., additional, Bonomo, Robert A., additional, Plummer, Mark S., additional, and van den Akker, Focco, additional

Published
2020
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25. A Standard Numbering Scheme for Class C β-Lactamases

Author

Mack, Andrew R., primary, Barnes, Melissa D., additional, Taracila, Magdalena A., additional, Hujer, Andrea M., additional, Hujer, Kristine M., additional, Cabot, Gabriel, additional, Feldgarden, Michael, additional, Haft, Daniel H., additional, Klimke, William, additional, van den Akker, Focco, additional, Vila, Alejandro J., additional, Smania, Andrea, additional, Haider, Shozeb, additional, Papp-Wallace, Krisztina M., additional, Bradford, Patricia A., additional, Rossolini, Gian Maria, additional, Docquier, Jean-Denis, additional, Frère, Jean-Marie, additional, Galleni, Moreno, additional, Hanson, Nancy D., additional, Oliver, Antonio, additional, Plésiat, Patrick, additional, Poirel, Laurent, additional, Nordmann, Patrice, additional, Palzkill, Timothy G., additional, Jacoby, George A., additional, Bush, Karen, additional, and Bonomo, Robert A., additional

Published
2020
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26. Targeting Multidrug-Resistant Acinetobacter spp.: Sulbactam and the Diazabicyclooctenone β-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent

Author

Barnes, Melissa D., primary, Kumar, Vijay, additional, Bethel, Christopher R., additional, Moussa, Samir H., additional, O’Donnell, John, additional, Rutter, Joseph D., additional, Good, Caryn E., additional, Hujer, Kristine M., additional, Hujer, Andrea M., additional, Marshall, Steve H., additional, Kreiswirth, Barry N., additional, Richter, Sandra S., additional, Rather, Philip N., additional, Jacobs, Michael R., additional, Papp-Wallace, Krisztina M., additional, van den Akker, Focco, additional, and Bonomo, Robert A., additional

Published
2019
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27. ARGONAUT-I: Activity of Cefiderocol (S-649266), a Siderophore Cephalosporin, against Gram-Negative Bacteria, Including Carbapenem-Resistant Nonfermenters and Enterobacteriaceae with Defined Extended-Spectrum β-Lactamases and Carbapenemases

Author

Jacobs, Michael R., primary, Abdelhamed, Ayman M., additional, Good, Caryn E., additional, Rhoads, Daniel D., additional, Hujer, Kristine M., additional, Hujer, Andrea M., additional, Domitrovic, T. Nicholas, additional, Rudin, Susan D., additional, Richter, Sandra S., additional, van Duin, David, additional, Kreiswirth, Barry N., additional, Greco, Chris, additional, Fouts, Derrick E., additional, and Bonomo, Robert A., additional

Published
2019
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28. The Role of Trimethoprim/Sulfamethoxazole in the Treatment of Infections Caused by Carbapenem-Resistant Enterobacteriaceae

Author

Luterbach, Courtney L, primary, Boshe, Ashley, additional, Henderson, Heather I, additional, Cober, Eric, additional, Richter, Sandra S, additional, Salata, Robert A, additional, Kalayjian, Robert C, additional, Watkins, Richard R, additional, Hujer, Andrea M, additional, Hujer, Kristine M, additional, Rudin, Susan D, additional, Domitrovic, T Nicholas, additional, Doi, Yohei, additional, Kaye, Keith S, additional, Evans, Scott, additional, Fowler, Vance G, additional, Bonomo, Robert A, additional, and van Duin, David, additional

Published
2018
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29. Rapid Molecular Diagnostics to Inform Empiric Use of Ceftazidime/Avibactam and Ceftolozane/Tazobactam Against Pseudomonas aeruginosa: PRIMERS IV

Author

Evans, Scott R, primary, Tran, Thuy Tien T, additional, Hujer, Andrea M, additional, Hill, Carol B, additional, Hujer, Kristine M, additional, Mediavilla, Jose R, additional, Manca, Claudia, additional, Domitrovic, T Nicholas, additional, Perez, Federico, additional, Farmer, Michael, additional, Pitzer, Kelsey M, additional, Wilson, Brigid M, additional, Kreiswirth, Barry N, additional, Patel, Robin, additional, Jacobs, Michael R, additional, Chen, Liang, additional, Fowler, Vance G, additional, Chambers, Henry F, additional, and Bonomo, Robert A, additional

Published
2018
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30. Informing Antibiotic Treatment Decisions: Evaluating Rapid Molecular Diagnostics To Identify Susceptibility and Resistance to Carbapenems against Acinetobacter spp. in PRIMERS III

Author

Evans, Scott R., Hujer, Andrea M., Jiang, Hongyu, Hill, Carol B., Hujer, Kristine M., Mediavilla, Jose R., Manca, Claudia, Tran, Thuy Tien T., Domitrovic, T. Nicholas, Higgins, Paul G., Seifert, Harald, Kreiswirth, Barry N., Patel, Robin, Jacobs, Michael R., Chen, Liang, Sampath, Rangarajan, Hall, Thomas, Marzan, Christine, Fowler, Vance G., Jr., Chambers, Henry F., Bonomo, Robert A., Evans, Scott R., Hujer, Andrea M., Jiang, Hongyu, Hill, Carol B., Hujer, Kristine M., Mediavilla, Jose R., Manca, Claudia, Tran, Thuy Tien T., Domitrovic, T. Nicholas, Higgins, Paul G., Seifert, Harald, Kreiswirth, Barry N., Patel, Robin, Jacobs, Michael R., Chen, Liang, Sampath, Rangarajan, Hall, Thomas, Marzan, Christine, Fowler, Vance G., Jr., Chambers, Henry F., and Bonomo, Robert A.

Abstract

The widespread dissemination of carbapenem-resistant Acinetobacter spp. has created significant therapeutic challenges. At present, rapid molecular diagnostics (RMDs) that can identify this phenotype are not commercially available. Two RMD platforms, PCR combined with electrospray ionization mass spectrometry (PCR/ESI-MS) and molecular beacons (MB), for detecting genes conferring resistance/susceptibility to carbapenems in Acinetobacter spp. were evaluated. An archived collection of 200 clinical Acinetobacter sp. isolates was tested. Predictive values for susceptibility and resistance were estimated as a function of susceptibility prevalence and were based on the absence or presence of beta-lactamase (bla) NDM, VIM, IMP, KPC, and OXA carbapenemase genes (e.g., bla(OXA-23), bla(OXA-24/40), and bla(OXA-58) found in this study) against the reference standard of MIC determinations. According to the interpretation of MICs, 49% (n = 98) of the isolates were carbapenem resistant (as defined by either resistance or intermediate resistance to imipenem). The susceptibility sensitivities (95% confidence interval [CI]) for imipenem were 82% (74%, 89%) and 92% (85%, 97%) for PCR/ESI-MS and MB, respectively. Resistance sensitivities (95% CI) for imipenem were 95% (88%, 98%) and 88% (80%, 94%) for PCR/ESI-MS and MB, respectively. PRIMERS III establishes that RMDs can discriminate between carbapenem resistance and susceptibility in Acinetobacter spp. In the context of a known prevalence of resistance, SPVs and RPVs can inform clinicians regarding the best choice for empiric antimicrobial therapy against this multidrug-resistant pathogen.

Published
2017

31. Informing Antibiotic Treatment Decisions: Evaluating Rapid Molecular Diagnostics To Identify Susceptibility and Resistance to Carbapenems against Acinetobacter spp. in PRIMERS III (vol 55, pg 1970, 2017)

Author

Evans, Scott R., Hujer, Andrea M., Jiang, Hongyu, Hill, Carol B., Hujer, Kristine M., Mediavilla, Jose R., Manca, Claudia, Tran, Thuy Tien T., Domitrovic, T. Nicholas, Higgins, Paul G., Seifert, Harald, Kreiswirth, Barry N., Patel, Robin, Jacobs, Michael R., Chen, Liang, Sampath, Rangarajan, Hall, Thomas, Marzan, Christine, Fowler, Vance G., Jr., Chambers, Henry F., Bonomo, Robert A., Evans, Scott R., Hujer, Andrea M., Jiang, Hongyu, Hill, Carol B., Hujer, Kristine M., Mediavilla, Jose R., Manca, Claudia, Tran, Thuy Tien T., Domitrovic, T. Nicholas, Higgins, Paul G., Seifert, Harald, Kreiswirth, Barry N., Patel, Robin, Jacobs, Michael R., Chen, Liang, Sampath, Rangarajan, Hall, Thomas, Marzan, Christine, Fowler, Vance G., Jr., Chambers, Henry F., and Bonomo, Robert A.

Published
2017

32. An Analysis of the Epidemic of Klebsiella pneumoniae Carbapenemase-Producing K. pneumoniae: Convergence of Two Evolutionary Mechanisms Creates the “Perfect Storm”

Author

Rojas, Laura J, primary, Weinstock, George M, additional, De La Cadena, Elsa, additional, Diaz, Lorena, additional, Rios, Rafael, additional, Hanson, Blake M, additional, Brown, Joseph S, additional, Vats, Purva, additional, Phillips, Daniel S, additional, Nguyen, Hoan, additional, Hujer, Kristine M, additional, Correa, Adriana, additional, Adams, Mark D, additional, Perez, Federico, additional, Sodergren, Erica, additional, Narechania, Apurva, additional, Planet, Paul J, additional, Villegas, Maria V, additional, Bonomo, Robert A, additional, and Arias, Cesar A, additional

Published
2017
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33. NDM-5 and OXA-181 Beta-Lactamases, a Significant Threat Continues To Spread in the Americas

Author

Rojas, Laura J., primary, Hujer, Andrea M., additional, Rudin, Susan D., additional, Wright, Meredith S., additional, Domitrovic, T. Nicholas, additional, Marshall, Steven H., additional, Hujer, Kristine M., additional, Richter, Sandra S., additional, Cober, Eric, additional, Perez, Federico, additional, Adams, Mark D., additional, van Duin, David, additional, and Bonomo, Robert A., additional

Published
2017
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34. Correction for Evans et al., “Informing Antibiotic Treatment Decisions: Evaluating Rapid Molecular Diagnostics To Identify Susceptibility and Resistance to Carbapenems against Acinetobacter spp. in PRIMERS III”

Author

Evans, Scott R., primary, Hujer, Andrea M., additional, Jiang, Hongyu, additional, Hill, Carol B., additional, Hujer, Kristine M., additional, Mediavilla, Jose R., additional, Manca, Claudia, additional, Tran, Thuy Tien T., additional, Domitrovic, T. Nicholas, additional, Higgins, Paul G., additional, Seifert, Harald, additional, Kreiswirth, Barry N., additional, Patel, Robin, additional, Jacobs, Michael R., additional, Chen, Liang, additional, Sampath, Rangarajan, additional, Hall, Thomas, additional, Marzan, Christine, additional, Fowler, Vance G., additional, Chambers, Henry F., additional, and Bonomo, Robert A., additional

Published
2017
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36. Benefit-risk Evaluation for Diagnostics: A Framework (BED-FRAME)

Author

Evans, Scott R., additional, Pennello, Gene, additional, Pantoja-Galicia, Norberto, additional, Jiang, Hongyu, additional, Hujer, Andrea M., additional, Hujer, Kristine M., additional, Manca, Claudia, additional, Hill, Carol, additional, Jacobs, Michael R., additional, Chen, Liang, additional, Patel, Robin, additional, Kreiswirth, Barry N., additional, and Bonomo, Robert A., additional

Published
2016
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38. Choosing Ceftazidime/Avibactam and Ceftolozane/Tazobactam as Empiric Therapies against Pseudomonas aeruginosa (Pa) using Rapid Molecular Diagnostics (RMDs): PRIMERS IV

Author

Evans, Scott, primary, Tran, Thuy Tien T., additional, Hujer, Andrea, additional, Hill, Carol, additional, Hujer, Kristine M., additional, Mediavilla, Jose R., additional, Manca, Claudia, additional, Domitrovic, T. Nicholas, additional, Kreiswirth, Barry N., additional, Patel, Robin, additional, Jacobs, Michael R., additional, Perez, Federico, additional, Chen, Liang, additional, Sampath, Rangarajan, additional, Hall, Thomas, additional, Marzan, Christine, additional, Fowler, Vance, additional, Chambers, Henry, additional, and Bonomo, Robert A., additional

Published
2016
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39. Rapid Molecular Diagnostics, Antibiotic Treatment Decisions, and Developing Approaches to Inform Empiric Therapy: PRIMERS I and II

Author

Evans, Scott R., primary, Hujer, Andrea M., additional, Jiang, Hongyu, additional, Hujer, Kristine M., additional, Hall, Thomas, additional, Marzan, Christine, additional, Jacobs, Michael R., additional, Sampath, Rangarajan, additional, Ecker, David J., additional, Manca, Claudia, additional, Chavda, Kalyan, additional, Zhang, Pan, additional, Fernandez, Helen, additional, Chen, Liang, additional, Mediavilla, Jose R., additional, Hill, Carol B., additional, Perez, Federico, additional, Caliendo, Angela M., additional, Fowler, Vance G., additional, Chambers, Henry F., additional, Kreiswirth, Barry N., additional, and Bonomo, Robert A., additional

Published
2015
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40. Erratum for “New Insights into Dissemination and Variation of the Health Care-Associated Pathogen Acinetobacter baumannii from Genomic Analysis”

Author

Wright, Meredith S., primary, Haft, Daniel H., additional, Harkins, Derek M., additional, Perez, Federico, additional, Hujer, Kristine M., additional, Bajaksouzian, Saralee, additional, Benard, Michael F., additional, Jacobs, Michael R., additional, Bonomo, Robert A., additional, and Adams, Mark D., additional

Published
2015
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41. Unexpected Challenges in Treating Multidrug-Resistant Gram-Negative Bacteria: Resistance to Ceftazidime-Avibactam in Archived Isolates of Pseudomonas aeruginosa

Author

Winkler, Marisa L., primary, Papp-Wallace, Krisztina M., additional, Hujer, Andrea M., additional, Domitrovic, T. Nicholas, additional, Hujer, Kristine M., additional, Hurless, Kelly N., additional, Tuohy, Marion, additional, Hall, Geraldine, additional, and Bonomo, Robert A., additional

Published
2015
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42. Benefit/Risk Evaluation in Diagnostics: An Example Comparing Two Rapid Molecular Diagnostics Testing Imipemem Susceptibility in Acinetobacter spp

Author

Evans, Scott, primary, Jiang, Hongyu, additional, Hujer, Andrea, additional, Hujer, Kristine M., additional, Manca, Claudia, additional, Hill, Carol, additional, Kreiswirth, Barry N., additional, Jacobs, Michael R., additional, Chen, Liang, additional, Sampath, Rangarajan, additional, Hall, Thomas, additional, Marzan, Christine, additional, and Bonomo, Robert A., additional

Published
2015
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43. Is It Time to Identify Acinetobacter spp. by Molecular Methods Only?

Author

Domitrovic, T. Nicholas, primary, Hujer, Andrea, additional, Higgins, Paul, additional, Seifert, Harald, additional, Hujer, Kristine M., additional, Jacobs, Michael R., additional, Hall, Thomas, additional, Marzan, Christine, additional, Kreiswirth, Barry N., additional, and Bonomo, Robert A., additional

Published
2015
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46. Informing Antibiotic Treatment Decisions: Evaluating Rapid Molecular Diagnostics (RMDs) to Identify Susceptibility and Resistance to Carbapenems Against Acinetobacter spp PRIMERS –III

Author

Evans, Scott, primary, Jiang, Hongyu, additional, Hujer, Andrea, additional, Hujer, Kristine M., additional, Mediavilla, Jose, additional, Manca, Claudia, additional, Hill, Carol, additional, Kreiswirth, Barry, additional, Patel, Robin, additional, Jacobs, Michael R., additional, Chen, Liang, additional, Sampath, Rangarajan, additional, Hall, Thomas, additional, Marzan, Christine, additional, Fowler, Vance G., additional, Chambers, Henry, additional, and Bonomo, Robert A., additional

Published
2015
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47. Colistin Resistance in Carbapenem-Resistant Klebsiella pneumoniae: Laboratory Detection and Impact on Mortality.

Author

Rojas, Laura J., Salim, Madiha, Cober, Eric, Richter, Sandra S., Perez, Federico, Salata, Robert A., Kalayjian, Robert C., Watkins, Richard R., Marshall, Steve, Rudin, Susan D., Domitrovic, T. Nicholas, Hujer, Andrea M., Hujer, Kristine M., Yohei Doi, Kaye, Keith S., Evans, Scott, Fowler Jr, Vance G., Bonomo, Robert A., and van Duin, David

Subjects
KLEBSIELLA pneumoniae, COLISTIN, DRUG resistance in bacteria, BACTERIAL disease treatment, DIAGNOSTIC microbiology, THERAPEUTICS
Abstract

Background. Polymyxins including colistin are an important "last-line" treatment for infections caused by carbapenem-resistant Klebsiella pneumoniae (CRKp). Increasing use of colistin has led to resistance to this cationic antimicrobial peptide. Methods. A cohort nested within the Consortium on Resistance against Carbapenems in Klebsiella pneumoniae (CRACKLE) was constructed of patients with infection, or colonization with CRKp isolates tested for colistin susceptibility during the study period of December, 2011 to October, 2014. Reference colistin resistance determination as performed by broth macrodilution was compared to results from clinical microbiology laboratories (Etest) and to polymyxin resistance testing. Each patient was included once, at the time of their first colistin-tested CRKp positive culture. Time to 30-day in-hospital all-cause mortality was evaluated by Kaplan-Meier curves and Cox proportional hazard modeling. Results. In 246 patients with CRKp, 13% possessed ColR CRKp. ColR was underestimated by Etest (very major error rate = 35%, major error rate = 0.4%). A variety of rep-PCR strain types were encountered in both the ColS and the ColR groups. Carbapenem resistance was mediated primarily by blaKPC-2 (46%) and blaKPC-3 (50%). ColR was associated with increased hazard for in-hospital mortality (aHR 3.48; 95% confidence interval, 1.73-6.57; P < .001). The plasmid-associated ColR genes, mcr-1 and mcr-2 were not detected in any of the ColR CRKp. Conclusions. In this cohort, 13% of patients with CRKp presented with ColR CRKp. The apparent polyclonal nature of the isolates suggests de novo emergence of ColR in this cohort as the primary factor driving ColR. Importantly, mortality was increased in patients with ColR isolates. [ABSTRACT FROM AUTHOR]

Published
2017
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48. Informing Antibiotic Treatment Decisions: Evaluating Rapid Molecular Diagnostics To Identify Susceptibility and Resistance to Carbapenems against Acinetobacterspp. in PRIMERS III

Author

Evans, Scott R., Hujer, Andrea M., Jiang, Hongyu, Hill, Carol B., Hujer, Kristine M., Mediavilla, Jose R., Manca, Claudia, Tran, Thuy Tien T., Domitrovic, T. Nicholas, Higgins, Paul G., Seifert, Harald, Kreiswirth, Barry N., Patel, Robin, Jacobs, Michael R., Chen, Liang, Sampath, Rangarajan, Hall, Thomas, Marzan, Christine, Fowler, Vance G., Chambers, Henry F., and Bonomo, Robert A.

Abstract

ABSTRACTThe widespread dissemination of carbapenem-resistant Acinetobacterspp. has created significant therapeutic challenges. At present, rapid molecular diagnostics (RMDs) that can identify this phenotype are not commercially available. Two RMD platforms, PCR combined with electrospray ionization mass spectrometry (PCR/ESI-MS) and molecular beacons (MB), for detecting genes conferring resistance/susceptibility to carbapenems in Acinetobacterspp. were evaluated. An archived collection of 200 clinical Acinetobactersp. isolates was tested. Predictive values for susceptibility and resistance were estimated as a function of susceptibility prevalence and were based on the absence or presence of beta-lactamase (bla) NDM, VIM, IMP, KPC, and OXA carbapenemase genes (e.g., blaOXA-23, blaOXA-24/40, and blaOXA-58found in this study) against the reference standard of MIC determinations. According to the interpretation of MICs, 49% (n= 98) of the isolates were carbapenem resistant (as defined by either resistance or intermediate resistance to imipenem). The susceptibility sensitivities (95% confidence interval [CI]) for imipenem were 82% (74%, 89%) and 92% (85%, 97%) for PCR/ESI-MS and MB, respectively. Resistance sensitivities (95% CI) for imipenem were 95% (88%, 98%) and 88% (80%, 94%) for PCR/ESI-MS and MB, respectively. PRIMERS III establishes that RMDs can discriminate between carbapenem resistance and susceptibility in Acinetobacterspp. In the context of a known prevalence of resistance, SPVs and RPVs can inform clinicians regarding the best choice for empiric antimicrobial therapy against this multidrug-resistant pathogen.

Published
2016
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49. Initial Assessment of the Molecular Epidemiology of blaNDM-1in Colombia

Author

Rojas, Laura J., Wright, Meredith S., De La Cadena, Elsa, Motoa, Gabriel, Hujer, Kristine M., Villegas, Maria V., Adams, Mark D., and Bonomo, Robert A.

Abstract

ABSTRACTWe report complete genome sequences of four blaNDM-1-harboring Gram-negative multidrug-resistant (MDR) isolates from Colombia. The blaNDM-1genes were located on 193-kb Inc FIA, 178-kb Inc A/C2, and 47-kb (unknown Inc type) plasmids. Multilocus sequence typing (MLST) revealed that these isolates belong to sequence type 10 (ST10) (Escherichia coli), ST392 (Klebsiella pneumoniae), and ST322 and ST464 (Acinetobacter baumanniiand Acinetobacter nosocomialis, respectively). Our analysis identified that the Inc A/C2 plasmid in E. colicontained a novel complex transposon (Tn125and Tn5393with three copies of blaNDM-1) and a recombination “hot spot” for the acquisition of new resistance determinants.

Published
2016
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50. Unexpected Challenges in Treating Multidrug-Resistant Gram-Negative Bacteria: Resistance to Ceftazidime-Avibactam in Archived Isolates of Pseudomonas aeruginosa

Author

Winkler, Marisa L., Papp-Wallace, Krisztina M., Hujer, Andrea M., Domitrovic, T. Nicholas, Hujer, Kristine M., Hurless, Kelly N., Tuohy, Marion, Hall, Geraldine, and Bonomo, Robert A.

Abstract

ABSTRACTPseudomonas aeruginosais a notoriously difficult-to-treat pathogen that is a common cause of severe nosocomial infections. Investigating a collection of β-lactam-resistant P. aeruginosaclinical isolates from a decade ago, we uncovered resistance to ceftazidime-avibactam, a novel β-lactam/β-lactamase inhibitor combination. The isolates were systematically analyzed through a variety of genetic, biochemical, genomic, and microbiological methods to understand how resistance manifests to a unique drug combination that is not yet clinically released. We discovered that avibactam was able to inactivate different AmpC β-lactamase enzymes and that blaPDCregulatory elements and penicillin-binding protein differences did not contribute in a major way to resistance. By using carefully selected combinations of antimicrobial agents, we deduced that the greatest barrier to ceftazidime-avibactam is membrane permeability and drug efflux. To overcome the constellation of resistance determinants, we show that a combination of antimicrobial agents (ceftazidime/avibactam/fosfomycin) targeting multiple cell wall synthetic pathways can restore susceptibility. In P. aeruginosa, efflux, as a general mechanism of resistance, may pose the greatest challenge to future antibiotic development. Our unexpected findings create concern that even the development of antimicrobial agents targeted for the treatment of multidrug-resistant bacteria may encounter clinically important resistance. Antibiotic therapy in the future must consider these factors.

Published
2014
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