Prevalence of #mcr-type genes among #colistin-resistant #Enterobacteriaceae collected in 2014-2016 as part of the #INFORM global #surveillance program (PLoS One, abstract)

[Source: PLoS One, full page: (LINK). Abstract, edited.]

OPEN ACCESS /  PEER-REVIEWED / RESEARCH ARTICLE

Prevalence of mcr-type genes among colistin-resistant Enterobacteriaceae collected in 2014-2016 as part of the INFORM global surveillance program

Mark G. Wise , Mark A. Estabrook, Daniel F. Sahm, Gregory G. Stone, Krystyna M. Kazmierczak

Published: April 2, 2018 / DOI: https://doi.org/10.1371/journal.pone.0195281

 

Abstract

A set of 908 clinically derived colistin-resistant Enterobacteriaeae isolates collected worldwide in 2014–2016 were screened for the presence of the plasmid-borne mcr-1, mcr-2, mcr-3, mcr-4 and mcr-5 genes. In total 3.2% (29/908) of the collection were positive for mcr, including 27 Escherichia coli, 1 Klebsiella pneumoniae and 1 Enterobacter cloacae. Twenty-four isolates possessed genes from the mcr-1 family, including the original mcr-1 (n = 22), as well as mcr-1.2 (n = 1) and mcr-1.5 (n = 1), which each differ from mcr-1 by encoding single amino acid variations. Genes from the mcr-3 family were found in isolates from Thailand, including mcr-3.1 (n = 3) and mcr-3.2 (n = 1). An E. coli isolated from a patient with a urinary tract infection in Colombia contained the recently discovered mcr-5. The full colistin-resistant collection was tested against a panel of antimicrobial agents with ceftazidime-avibactam and tigecycline exhibiting the highest activity.

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Citation: Wise MG, Estabrook MA, Sahm DF, Stone GG, Kazmierczak KM (2018) Prevalence of mcr-type genes among colistin-resistant Enterobacteriaceae collected in 2014-2016 as part of the INFORM global surveillance program. PLoS ONE 13(4): e0195281. https://doi.org/10.1371/journal.pone.0195281

Editor: Yung-Fu Chang, Cornell University, UNITED STATES

Received: December 13, 2017; Accepted: March 19, 2018; Published: April 2, 2018

Copyright: © 2018 Wise et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are contained within the manuscript.

Funding: All work was performed at IHMA and sponsored by AstraZeneca Pharmaceuticals, LP, which also included compensation fees for manuscript preparation. AstraZeneca’s rights to ceftazidime-avibactam were acquired by Pfizer in December 2016.

Competing interests: All work was performed at IHMA and sponsored by AstraZeneca Pharmaceuticals, LP, which also included compensation fees for manuscript preparation. AstraZeneca’s rights to ceftazidime-avibactam were acquired by Pfizer in December 2016. G.S. was an employee of and shareholder in AstraZeneca Pharmaceuticals at the time of the study, and is currently an employee of Pfizer. M.W., M.E., D.S. and K.K. are employees of IHMA which received funding from AstraZeneca for the conduct of the study and development of this manuscript. None of the IHMA authors have any personal financial interest in the study sponsor (AstraZeneca Pharmaceuticals, LP) to disclose. This does not alter our adherence to all PLOS ONE policies on sharing data and materials.

Keywords: Antibiotics; Drugs Resistance; Colistin; Enterobacteriaceae; Ceftazidime-Avibactam; Tigecycline.

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Clinical #outcomes after combination #treatment with #ceftazidime / #avibactam and #aztreonam for NDM-1/OXA-48/CTX-M-15-producing #Klebsiella pneumoniae infection (J Antimicrob Chemother., summary)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Summary, edited.]

Clinical outcomes after combination treatment with ceftazidime/avibactam and aztreonam for NDM-1/OXA-48/CTX-M-15-producing Klebsiella pneumoniae infection

Evelyn Shaw, Alexander Rombauts, Fe Tubau, Ariadna Padullés, Jordi Càmara, Toni Lozano, Sara Cobo-Sacristán, Núria Sabe, Imma Grau, Raül Rigo-Bonnin, M Angeles Dominguez, Jordi Carratalà

Journal of Antimicrobial Chemotherapy, dkx496, https://doi.org/10.1093/jac/dkx496

Published:  19 December 2017

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Sir,

The growing spread of bacteria producing carbapenemases, such as the New Delhi MBL (NDM),1 has created an urgent need to identify effective therapeutic options that can treat serious infections caused by these XDR bacteria. Ceftazidime/avibactam has been successfully used to treat infection caused by carbapenem-resistant Enterobacteriaceae;2,3 however, the combination lacks activity against strains producing NDM. These carbapenemases remain susceptible to aztreonam, although most MBL-producing isolates also harbour ESBLs or other β-lactamases that confer resistance to aztreonam.4 The combination of aztreonam and avibactam has demonstrated potent in vitroactivity against MBL-producing Enterobacteriaceae including those isolates that also carry other β-lactamases.5 However, this combination is currently in clinical development and unavailable for clinical use.

(…)

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Issue Section:  Research letter

© The Author(s) 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Keywords: Antibiotics; Drugs Resistance; Klebsiella Pneumoniae; NDM1; Ceftazidime; Avibactam; Aztreonam.

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#Ceftazidime – #avibactam versus #meropenem in #nosocomial #pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Ceftazidime-avibactam versus meropenem in nosocomial pneumonia, including ventilator-associated pneumonia (REPROVE): a randomised, double-blind, phase 3 non-inferiority trial

Prof Antoni Torres, Prof Nanshan Zhong, MD, Prof Jan Pachl, MD, Prof Jean-François Timsit, MD, Prof Marin Kollef, MD, Zhangjing Chen, MD, Jie Song, MD, Dianna Taylor, BSc, Peter J Laud, MSc, Gregory G Stone, PhD, Joseph W Chow, MD

Published: 15 December 2017 / DOI: http://dx.doi.org/10.1016/S1473-3099(17)30747-8

© 2017 Elsevier Ltd. All rights reserved.

 

Summary

Background

Nosocomial pneumonia is commonly associated with antimicrobial-resistant Gram-negative pathogens. We aimed to assess the efficacy and safety of ceftazidime-avibactam in patients with nosocomial pneumonia, including ventilator-associated pneumonia, compared with meropenem in a multinational, phase 3, double-blind, non-inferiority trial (REPROVE).

Methods

Adults with nosocomial pneumonia (including ventilator-associated pneumonia), enrolled at 136 centres in 23 countries, were randomly assigned (1:1) to 2000 mg ceftazidime and 500 mg avibactam (by 2 h intravenous infusion every 8 h) or 1000 mg meropenem (by 30-min intravenous infusion every 8 h) for 7–14 days; regimens were adjusted for renal function. Computer-generated randomisation codes were stratified by infection type and geographical region with a block size of four. Participants and investigators were masked to treatment assignment. The primary endpoint was clinical cure at the test-of-cure visit (21–25 days after randomisation). Non-inferiority was concluded if the lower limit of the two-sided 95% CI for the treatment difference was greater than −12·5% in the coprimary clinically modified intention-to-treat and clinically evaluable populations. This trial is registered with ClinicalTrials.gov (NCT01808092) and EudraCT (2012-004006-96).

Findings

Between April 13, 2013, and Dec 11, 2015, 879 patients were randomly assigned. 808 patients were included in the safety population, 726 were included in the clinically modified intention-to-treat population, and 527 were included in the clinically evaluable population. Predominant Gram-negative baseline pathogens in the microbiologically modified intention-to-treat population (n=355) were Klebsiella pneumoniae (37%) and Pseudomonas aeruginosa (30%); 28% were ceftazidime-non-susceptible. In the clinically modified intention-to-treat population, 245 (68·8%) of 356 patients in the ceftazidime-avibactam group were clinically cured, compared with 270 (73·0%) of 370 patients in the meropenem group (difference −4·2% [95% CI −10·8 to 2·5]). In the clinically evaluable population, 199 (77·4%) of 257 participants were clinically cured in the ceftazidime-avibactam group, compared with 211 (78·1%) of 270 in the meropenem group (difference −0·7% [95% CI −7·9 to 6·4]). Adverse events occurred in 302 (75%) of 405 patients in the ceftazidime-avibactam group versus 299 (74%) of 403 in the meropenem group (safety population), and were mostly mild or moderate in intensity and unrelated to study treatment. Serious adverse events occurred in 75 (19%) patients in the ceftazidime-avibactam group and 54 (13%) patients in the meropenem group. Four serious adverse events (all in the ceftazidime-avibactam group) were judged to be treatment related.

Interpretation

Ceftazidime-avibactam was non-inferior to meropenem in the treatment of nosocomial pneumonia. These results support a role for ceftazidime-avibactam as a potential alternative to carbapenems in patients with nosocomial pneumonia (including ventilator-associated pneumonia) caused by Gram-negative pathogens.

Funding

AstraZeneca.

Keywords: Antibiotics; Avibactam; Meropenem; Ceftazidime; Pneumonia; Nosocomial Outbreraks.

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Activity of #ceftazidime/avibactam against problem #Enterobacteriaceae and #Pseudomonas aeruginosa in the #UK, 2015–16 (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Activity of ceftazidime/avibactam against problem Enterobacteriaceae and Pseudomonas aeruginosa in the UK, 2015–16

David M Livermore, Danièle Meunier, Katie L Hopkins, Michel Doumith, Robert Hill, Rachel Pike, Peter Staves, Neil Woodford

Journal of Antimicrobial Chemotherapy, dkx438, https://doi.org/10.1093/jac/dkx438

Published: 08 December 2017 – Received: 04 August 2017 – Revision Requested: 10 October 2017 – Revision Received: 23 October 2017 – Accepted: 30 October 2017

Citation: David M Livermore, Danièle Meunier, Katie L Hopkins, Michel Doumith, Robert Hill, Rachel Pike, Peter Staves, Neil Woodford; Activity of ceftazidime/avibactam against problem Enterobacteriaceae and Pseudomonas aeruginosa in the UK, 2015–16, Journal of Antimicrobial Chemotherapy, , dkx438, https://doi.org/10.1093/jac/dkx438

© 2017 Oxford University Press

 

Abstract

Background

Ceftazidime/avibactam combines an established oxyimino-cephalosporin with the first diazabicyclooctane β-lactamase inhibitor to enter clinical use. We reviewed its activity against Gram-negative isolates, predominantly from the UK, referred for resistance investigation in the first year of routine testing, beginning in July 2015.

Methods

Isolates were as received from referring laboratories; there is a bias to submit those with suspected carbapenem resistance. Identification was by MALDI-TOF mass spectroscopy, and susceptibility testing by BSAC agar dilution. Carbapenemase genes were sought by PCR; other resistance mechanisms were inferred using genetic data and interpretive reading.

Results

Susceptibility rates to ceftazidime/avibactam exceeded 95% for: (i) Enterobacteriaceae with KPC, GES or other Class A carbapenemases; (ii) Enterobacteriaceae with OXA-48-like enzymes; and (iii) for ESBL or AmpC producers, even when these had impermeability-mediated ertapenem resistance. Almost all isolates with metallo-carbapenemases were resistant. Potentiation of ceftazidime by avibactam was seen for 87% of ceftazidime-resistant Enterobacteriaceae with ‘unassigned’ ceftazidime resistance mechanisms, including two widely referred groups of Klebsiella pneumoniae where no synergy was seen between cephalosporins and established β-lactamase inhibitors. Potentiation here may be a diazabicyclooctane/cephalosporin enhancer effect. Activity was seen against Pseudomonas aeruginosa with derepressed AmpC, but not for those with efflux-mediated resistance.

Conclusions

Of the available β-lactams or inhibitor combinations, ceftazidime/avibactam has the widest activity spectrum against problem Enterobacteriaceae, covering all major types except metallo-carbapenemase producers; against P. aeruginosa it has a slightly narrower spectrum than ceftolozane/tazobactam, which also covers efflux-type resistance.

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; UK; Enterobacteriaceae; Ceftazidime; Avibactam; Pseudomonas aeruginosa.

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#Ceftazidime / #avibactam alone or in combination with #aztreonam against #colistin-resistant and carbapenemase-producing #Klebsiella pneumoniae (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Summary, edited.]

Ceftazidime/avibactam alone or in combination with aztreonam against colistin-resistant and carbapenemase-producing Klebsiella pneumoniae

Aurélie Jayol, Patrice Nordmann, Laurent Poirel, Véronique Dubois

Journal of Antimicrobial Chemotherapy, dkx393, https://doi.org/10.1093/jac/dkx393

Published: 18 November 2017

 

Summary

Sir,

The spread of carbapenemase-producing Klebsiella pneumoniae is a major public health concern since such isolates are basically resistant to most available antibiotics, including β-lactams, fluoroquinolones and aminoglycosides.1 Infections due to carbapenemase-producing K. pneumoniae are therefore commonly treated with a regimen containing colistin.1 However, acquired resistance to colistin now occurs frequently and has few therapeutic options.2 Outbreaks with colistin-resistant and carbapenemase-producing K. pneumoniae isolates have been reported worldwide2 and mortality rates are high owing to limited treatment options.3

(…)

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Issue Section: Research letter

© The Author 2017. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Keywords: Antibiotics; Drugs Resistance; Klebsiella Pneumoniae; Colistin; Carbapenem; Aztreonam; Ceftazidime; Avibactam.

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#Antimicrobial #Activity of #Ceftazidime-Avibactam When Tested against Gram-negative Bacteria Isolated from Patients Hospitalized with #Pneumonia in #US Medical Centers (2011-2015) (AAC, abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Antimicrobial Activity of Ceftazidime-Avibactam When Tested against Gram-negative Bacteria Isolated from Patients Hospitalized with Pneumonia in United States Medical Centers (2011-2015)

Helio S. Sader⇑, Mariana Castanheira and Robert K. Flamm

Author Affiliations: JMI Laboratories, North Liberty, Iowa, USA

 

ABSTRACT

Bacterial isolates were collected from patients hospitalized with pneumonia (PHP), including ventilator-associated (VAP), from 76 USA medical centers in 2011-2015. The Gram-negative organisms (n=11,185; including 1,097 from VAP) were tested for susceptibility against ceftazidime-avibactam and comparators by broth microdilution method. β-lactamase-encoding genes were screened using a microarray based assay on selected isolates. Pseudomonas aeruginosa and Klebsiella spp. were the most common Gram-negatives isolated from PHP and VAP. Ceftazidime-avibactam was very active against P. aeruginosa (n=3,402; MIC50/90, 2/4 μg/mL; 96.6% susceptible), including isolates non-susceptible to meropenem (86.3% susceptible to ceftazidime-avibactam), piperacillin-tazobactam (85.6% susceptible) or ceftazidime (80.6% susceptible). Ceftazidime-avibactam was also highly active against Enterobacteriaceae (MIC50/90, 0.12/0.5 μg/mL; 99.9% susceptible), including carbapenem-resistant (CRE, n=189; MIC50/90, 0.5/2 μg/mL; 98.0% susceptible), multidrug-resistant (MDR; n=674; MIC50/90, 0.25/1 μg/mL; 98.8% susceptible) and extensively drug-resistant Enterobacteriaceae (XDR; n=156; MIC50/90, 0.5/2 μg/mL; 98.1% susceptible) isolates, as well as Klebsiella spp. isolates showing an ESBL screening-positive phenotype (n=433; MIC50/90, 0.25/1 μg/mL; 99.5% susceptible). Among Enterobacter spp. (24.8% ceftazidime-non-susceptible), 99.8% of isolates, including 99.4% of ceftazidime-non-susceptible isolates, were susceptible to ceftazidime-avibactam. The most common β-lactamases detected among K. pneumoniae and E. coli were KPC-like and CTX-M-15, respectively. Only eight of 6,209 Enterobacteriaceae isolates (0.1%) were ceftazidime-avibactam-non-susceptible, three NDM-1 producing strains with ceftazidime-avibactam MIC values of >32 μg/mL and five isolates with ceftazidime-avibactam MIC values of 16 μg/mL and negative results for all β-lactamases tested. Susceptibility rates among isolates from VAP were generally similar or slightly higher compared to those from all PHP.

 

FOOTNOTES

Contact Information: Helio S. Sader, MD, PhD, JMI Laboratories, 345 Beaver Kreek Ctr, Ste A, North Liberty, Iowa, 52317, USA, Phone: 319-665-3370, Fax: 319-665-3371, helio-sader@jmilabs.com

Copyright © 2017 American Society for Microbiology.

Keywords: Pneumonia; Antibiotics; Drugs Resistance; Avibactam.

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#Ceftazidime, #avibactam as #salvage #therapy for #infections caused by #carbapenem-resistant organisms: a case series from the compassionate-use program (AAC, abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Ceftazidime-avibactam as salvage therapy for infections caused by carbapenem-resistant organisms: a case series from the compassionate-use program

Elizabeth Temkin a, Julian Torre-Cisneros b,c, Bojana Beovic d, Natividad Benito e,f, Maddalena Giannella g, Raúl Gilarranz h, Cameron Jeremiah i, Belén Loeches j, Isabel Machuca b,c, María José Jiménez-Martín k, José Antonio Martínez l, Marta Mora-Rillo j, Enrique Navas m, Michael Osthoff n, Juan Carlos Pozo o, Juan Carlos Ramos Ramos j, Marina Rodriguez o, Miguel Sánchez García k, Pierluigi Viale p, Michel Wolff q,r and Yehuda Carmeli a,s⇑

Author Affiliations: Department of Epidemiology and Preventive Medicine, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel{a}; Department of Infectious Diseases, Hospital Universitario Reina Sofía, Córdoba, Spain{b}; Instituto Maimónides de Investigación Biomédica, Universidad de Cordoba, Córdoba, Spain{c}; Department of Infectious Disease, University Medical Center Ljubljana, Ljubljana, Slovenia{d}; Infectious Diseases Unit, Department of Medicine, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain{e}; Institut d’Investigació Biomèdica Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain{f}; Infectious Diseases Unit, Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy{g}; Department of Clinical Microbiology, Hospital Universitario de Gran Canaria Doctor Negrín, Las Palmas de Gran Canaria, Spain{h}; Department of Infectious Diseases, St Vincent’s Hospital, Melbourne, Australia{i}; Infectious Diseases Unit, Hospital Universitario La Paz-IdiPAZ, Madrid, Spain{j}; Critical Care Department, Hospital Clínico San Carlos, Madrid, Spain{k}; Department of Infectious Diseases, Hospital Clínic, IDIBAPS, Barcelona University, Barcelona, Spain{l}; Infectious Diseases Department, Hospital Ramión y Cajal, Madrid, Spain{m}; Division of Infectious Diseases and Hospital Epidemiology, University Hospital Basel, Basel, Switzerland{n}; Department of Critical Care Medicine, Hospital Universitario Reina Sofía, Córdoba, Spain{o}; Department of Medical Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy{p}; Centre Hospitalier Universitaire Bichat-Claude, Paris, France{q}; Université Paris Diderot University, Paris, France{r}; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel{s}

 

ABSTRACT

Ceftazidime-avibactam (CAZ-AVI) is a recently approved β-lactam β-lactamase inhibitor combination with the potential to treat serious infections caused by carbapenem-resistant organisms. Few patients with such infections were included in the CAZ-AVI clinical trials, and clinical experience is lacking. We present a case series of patients with infections caused by carbapenem-resistant Enterobacteriaceae (CRE) or Pseudomonas aeruginosa (CRPa) who were treated with CAZ-AVI salvage therapy on a compassionate-use basis. Physicians who had prescribed CAZ-AVI completed a case report form. We used descriptive statistics to summarize patient characteristics and treatment outcomes. We used Wilcoxon rank-sum and Fisher’s exact tests to compare patients by treatment outcome. The sample included 36 patients with CRE and two with CRPa. The most common infections were intra-abdominal and respiratory. Physicians categorized 60.5% of patients as having life-threatening infections. All but two patients received other antibiotics before CAZ-AVI, for a median of 13 days. The median duration of CAZ-AVI treatment was 16 days. Twenty-five patients (65.8%) concurrently received other antibiotics to which their pathogen was non-resistant in vitro. Twenty-eight patients (73.7%, 95% CI; 56.9-86.6%) experienced clinical and/or microbiological cure. Five patients (20.8%) with documented microbiological cure died, whereas 10 patients (71.4%) with no documented microbiological cure died (p=0.01). In three-quarters of cases, CAZ-AVI (alone or combined with other antibiotics) cured infections caused by carbapenem-resistant organisms, 95% of which had failed previous therapy. Microbiological cure was associated with improved survival. CAZ-AVI shows promising clinical results for infections for which treatment options are limited.

 

FOOTNOTES

# Address correspondence to Yehuda Carmeli, yehudac@tlvmc.gov.il

Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Carbapenem.

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