From #farm to #fork: identical #clones and Tn6674-like elements in #linezolid-resistant #Enterococcus faecalis from #food-producing #animals and #retail meat (J Antimicrob Chemother., abstract)

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

From farm to fork: identical clones and Tn6674-like elements in linezolid-resistant Enterococcus faecalis from food-producing animals and retail meat

Houyem Elghaieb, Ana P Tedim, Mohamed S Abbassi, Carla Novais, Bárbara Duarte, Abdennaceur Hassen, Luísa Peixe, Ana R Freitas

Journal of Antimicrobial Chemotherapy, dkz419, https://doi.org/10.1093/jac/dkz419

Published: 11 October 2019

 

Abstract

Objectives

Increasing numbers of linezolid-resistant Enterococcus carrying optrA are being reported across different niches worldwide. We aimed to characterize the first optrA-carrying Enterococcus faecalis obtained from food-producing animals and retail meat samples in Tunisia.

Methods

Seven optrA-carrying E. faecalis obtained from chicken faeces (n = 3, August 2017) and retail chicken meat (n = 4, August 2017) in Tunisia were analysed. Antimicrobial susceptibility was determined by disc diffusion, broth microdilution and Etest against 13 antibiotics, linezolid and tedizolid, respectively (EUCAST/CLSI). optrA stability (∼600 bacterial generations), transfer (filter mating) and location (S1-PFGE/hybridization) were characterized. WGS (Illumina-HiSeq) was done for four representatives that were analysed through in silico and genomic mapping tools.

Results

Four MDR clones carrying different virulence genes were identified in chicken faeces (ST476) and retail meat (the same ST476 clone plus ST21 and ST859) samples. MICs of linezolid and tedizolid were stably maintained at 8 and 1–2 mg/L, respectively. optrA was located in the same transferable chromosomal Tn6674-like element in ST476 and ST21 clones, similar to isolates from pigs in Malaysia and humans in China. ST859 carried a non-conjugative plasmid of ∼40 kb with an impB-fexA-optrA segment, similar to plasmids from pigs and humans in China.

Conclusions

The same chromosomal and transferable Tn6674-like element was identified in different E. faecalis clones from humans and animals. The finding of retail meat contaminated with the same linezolid-resistant E. faecalis strain obtained from a food-producing animal highlights the potential role of the food chain in the worrisome dissemination of optrA that can be stably maintained without selective pressure over generations.

Topic: antibiotics – enterococcus – plasmids – diffusion – chickens – china – chromosomes – clone cells – electrophoresis, gel, pulsed-field – enterococcus faecalis – feces – food – food chain – genes – genome – malaysia – meat – suidae – tunisia – virulence – linezolid – antimicrobial susceptibility – transfer technique – filters – mating – tedizolid – malnutrition-inflammation-cachexia syndrome – whole genome sequencing

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. 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.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Linezolid; Enterococci; Pigs; Poultry; Food Safety; Plasmids.

——

Once-daily oral #omadacycline versus twice-daily oral #linezolid for acute bacterial #skin and skin structure #infections (OASIS-2):… (Lancet Infect Dis., abstract)

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

Once-daily oral omadacycline versus twice-daily oral linezolid for acute bacterial skin and skin structure infections (OASIS-2): a phase 3, double-blind, multicentre, randomised, controlled, non-inferiority trial

William O’Riordan, MD, Carrie Cardenas, MD, Elliot Shin, MD, Alissa Sirbu, BS, Lynne Garrity-Ryan, PhD, Anita F Das, PhD, Paul B Eckburg, MD, Amy Manley, BS, Judith N Steenbergen, PhD, Evan Tzanis, BS, Paul C McGovern, MD, Evan Loh, MD, on behalf of theOASIS-2 Investigators†

Published: August 29, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30275-0

 

Summary

Background

Pathogen resistance and safety concerns limit oral antibiotic options for the treatment of acute bacterial skin and skin structure infections (ABSSSI). We aimed to compare the efficacy and safety of once-daily oral omadacycline, an aminomethylcycline antibiotic, versus twice-daily oral linezolid for treatment of ABSSSI.

Methods

In this phase 3, double-blind, randomised, non-inferiority study, eligible adults with ABSSSI at 33 sites in the USA were randomly assigned (1:1) to receive omadacycline (450 mg orally every 24 h over the first 48 h then 300 mg orally every 24 h) or linezolid (600 mg orally every 12 h) for 7–14 days. Randomisation was done via an interactive response system using a computer-generated schedule, and stratified by type of infection (wound infection, cellulitis or erysipelas, or major abscess) and receipt (yes or no) of allowed previous antibacterial treatment. Investigators, funders, and patients were masked to treatment assignments. Primary endpoints were early clinical response, 48–72 h after first dose, in the modified intention-to-treat (mITT) population (randomised patients without solely Gram-negative ABSSSI pathogens at baseline), and investigator-assessed clinical response at post-treatment evaluation, 7–14 days after the last dose, in the mITT population and clinically evaluable population (ie, mITT patients who had a qualifying infection as per study-entry criteria, received study drug, did not receive a confounding antibiotic, and had an assessment of outcome during the protocol-defined window). The safety population included randomised patients who received any amount of study drug. We set a non-inferiority margin of 10%. This study is registered with ClinicalTrials.gov, NCT02877927, and is complete.

Findings

Between Aug 11, 2016, and June 6, 2017, 861 participants were assessed for eligibility. 735 participants were randomly assigned, of whom 368 received omadacycline and 367 received linezolid. Omadacycline (315 [88%] of 360) was non-inferior to linezolid (297 [83%] of 360) for early clinical response (percentage-point difference 5·0, 95% CI −0·2 to 10·3) in the mITT population. For investigator-assessed clinical response at post-treatment evaluation, omadacycline was non-inferior to linezolid in the mITT (303 [84%] of 360 vs 291 [81%] of 360; percentage-point difference 3·3, 95% CI −2·2 to 9·0) and clinically evaluable (278 [98%] of 284 vs 279 [96%] of 292; 2·3, −0·5 to 5·8) populations. Mild to moderate nausea and vomiting were the most frequent treatment-emergent adverse events in omadacycline (111 [30%] of 368 and 62 [17%] of 368, respectively) and linezolid (28 [8%] of 367 and 11 [3%] of 367, respectively) groups.

Interpretation

Once-daily oral omadacycline was non-inferior to twice-daily oral linezolid in adults with ABSSSI, and was safe and well tolerated. Oral-only omadacycline represents a new treatment option for ABSSSI, with potential for reduction in hospital admissions and cost savings.

Funding

Paratek Pharmaceuticals.

Keywords: Antibiotics; Drugs Resistance; Omadacycline; Linezolid.

—–

#Dispersal of #linezolid-resistant #enterococci carrying poxtA or optrA in retail #meat and #food-producing #animals from #Tunisia (J Antimicrob Chemother., abstract)

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

Dispersal of linezolid-resistant enterococci carrying poxtA or optrA in retail meat and food-producing animals from Tunisia

Houyem Elghaieb, Ana R Freitas, Mohamed Salah Abbassi, Carla Novais, Mohamed Zouari, Abdennaceur Hassen, Luísa Peixe

Journal of Antimicrobial Chemotherapy, dkz263, https://doi.org/10.1093/jac/dkz263

Published: 26 June 2019

 

Abstract

Objectives

The epidemiology of Enterococcus resistant to priority antibiotics including linezolid has mainly been investigated in developed countries and especially in hospitals. We aimed to evaluate the contribution of different non-human reservoirs for the burden of MDR enterococci in Tunisia, where scarce data are available.

Methods

Samples (n = 287) were collected from urban wastewater (n = 57), retail meat (n = 29; poultry/bovine/ovine), milk (n = 89; bovine/ovine), farm animal faeces (n = 80; poultry/bovine/ovine) and pets (n = 32; rabbit/dogs/cats/birds) in different Tunisian regions (2014–17). They were plated onto Slanetz–Bartley agar after pre-enrichment without antibiotics. Standard methods were used for bacterial identification and characterization of antibiotic resistance and virulence genes (PCR), antibiotic susceptibility testing (disc diffusion/broth microdilution; EUCAST/CLSI) and clonality (SmaI-PFGE/MLST).

Results

All samples carried Enterococcus (n = 377 isolates) resistant to antibiotics considered to be critical or highly important by WHO. Even without antibiotic selection, 38% of Enterococcus faecalis (Efs) and 22% of Enterococcus faecium(Efm) were identified as MDR. Linezolid-resistant isolates (5%; MIC = 8 mg/L) comprised six poxtA-carrying Efm (cow milk), seven optrA-carrying Efs (chicken faeces/meat) and five Efm lacking cfr/optrA/poxtA(poultry/bovine/ovine/wastewater). Clinically relevant Efm clones (clade A1) were identified in animal/meat sources. Ampicillin resistance (1%) was confined to ST18/ST78-like MDR Efm clones from bovine meat/milk samples carrying relevant virulence markers (e.g. ptsD/IS16).

Conclusions

This study provides evidence of the contribution of livestock and foodstuffs to the dispersal of acquired linezolid resistance genes including poxtA and optrA. We report the first poxtA-carrying Efm in Tunisia, and for the first time in bovine samples, stressing the urgent need for alternative measures to counteract the spread of linezolid-resistant enterococci globally.

Topic: antibiotics – enterococcus – antibiotic resistance, bacterial – diffusion – cattle – chickens – clone cells – dog, domestic – electrophoresis, gel, pulsed-field – feces – food – genes – meat – milk – sheep – tunisia – poultry meat – virulence – linezolid –  antimicrobial  susceptibility – farm animals – pet animal

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. 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.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Linezolid; Enterococcus spp.; Livestock; Food Safety; Tunisia.

——

Detection of the phenicol–oxazolidinone– #tetracycline #resistance gene poxtA in #Enterococcus faecium and Enterococcus faecalis of #food-producing #animal origin in #China (J Antimicrob Chemother., abstract)

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

Detection of the phenicol–oxazolidinone–tetracycline resistance gene poxtA in Enterococcus faecium and Enterococcus faecalis of food-producing animal origin in China

Chang-Wei Lei, Zhuang-Zhuang Kang, Shun-Kang Wu, Yan-Peng Chen, Ling-Han Kong, Hong-Ning Wang

Journal of Antimicrobial Chemotherapy, dkz198, https://doi.org/10.1093/jac/dkz198

Published: 18 May 2019

Issue Section: Research letter

___

Sir,

Oxazolidinones, including linezolid and tedizolid, are effective antimicrobial agents for treating infections caused by MDR Gram-positive bacteria, including VRE.1,2Linezolid is the first commercially available oxazolidinone that can inhibit protein synthesis by binding to the peptidyltransferase centre of the bacterial 23S rRNA. After introduction of linezolid, the resistance mechanism that emerged rapidly was related to mutations in genes coding for the 23S rRNA. The transferable oxazolidinone resistance determinants, cfr and optrA, have been reported in enterococci in several regions worldwide.3–6 Very recently, another transferable oxazolidinone resistance gene, poxtA, was reported in an MRSA of clinical origin…

(…)

___

© The Author(s) 2019. 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.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Linezolid; Enterococcus spp.; Food Safety; China.

——

#Linezolid #resistance in patients with drug-resistant #TB and treatment failure in South Africa (J Antimicrob Chemother., abstract)

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

Linezolid resistance in patients with drug-resistant TB and treatment failure in South Africa

Sean Wasserman, Gail Louw, Limpho Ramangoaela, Garrick Barber, Cindy Hayes, Shaheed Vally Omar, Gary Maartens, Clifton Barry, III, Taeksun Song, Graeme Meintjes

Journal of Antimicrobial Chemotherapy, dkz206, https://doi.org/10.1093/jac/dkz206

Published: 12 May 2019

 

Abstract

Objectives

Limited data exist on clinical associations and genotypic correlates of linezolid resistance in Mycobacterium tuberculosis. We aimed to describe mutations and clinical factors associated with phenotypic linezolid resistance from patients with drug-resistant TB at two public sector facilities in South Africa.

Methods

Adults and adolescents with treatment failure (culture positivity ≥4 months) on a linezolid-containing regimen were retrospectively identified. Phenotypic resistance, as defined by a linezolid MIC >1 mg/L, was assessed for retrieved isolates using broth microdilution. Targeted sequencing of rrl and rplC was performed, irrespective of growth on subculture.

Results

Thirty-nine patients with linezolid-based treatment failure were identified, 13 (33%) of whom had phenotypic or genotypic linezolid resistance after a median duration of 22 months (range = 7–32) of linezolid therapy. Paired MIC testing and genotyping was performed on 55 unique isolates. All isolates with phenotypic resistance (n = 16) were associated with known resistance mutations, most frequently due to the T460C substitution in rplC (n = 10); rrlmutations included G2814T, G2270C/T and A2810C. No mutations were detected in isolates with MICs at or below the critical concentration.

Conclusions

Linezolid resistance occurred in a third of patients with drug-resistant TB and treatment failure. Resistance occurred late and was predicted by a limited number of mutations in rrl and rplC. Screening for genotypic resistance should be considered for patients with a positive culture after 4 months of linezolid therapy in order to optimize treatment and avoid the toxicity of ineffective linezolid therapy.

Topic: phenotype – mutation – south africa – treatment failure – linezolid
– drug-resistant tuberculosis

Issue Section:  ORIGINAL RESEARCH

Keywords: Antibiotics; Drugs Resistance; Linezolid; Tuberculosis; S. Africa.

——-

#Detection in #Greece of a #clinical #Enterococcus faecium isolate carrying the novel #oxazolidinone #resistance gene poxtA (J Antimicrob Chemother., abstract)

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

Detection in Greece of a clinical Enterococcus faeciumisolate carrying the novel oxazolidinone resistance gene poxtA

Costas C Papagiannitsis, Katerina Tsilipounidaki, Ergina Malli, Efi Petinaki

Journal of Antimicrobial Chemotherapy, dkz155, https://doi.org/10.1093/jac/dkz155

Published: 22 April 2019

___

Sir,

Oxazolidinones possess potent activity against Gram-positive pathogens such as VRE. Soon after their introduction into clinical practice, linezolid-resistant enterococcal isolates were reported.1 Resistance of enterococci to oxazolidines is mainly associated with mutations in 23S rRNA genes and L3 and L4 ribosomal proteins.2 Additionally, transferable resistance determinants including the cfr, optrAand poxtA genes have also emerged.3–5 Here we report, to the best of our knowledge, the first detection of a poxtA-positive Enterococcus faecium strain isolated in Greece.

…E. faecium isolate (Efa-955) was recovered, in 2018, from a urine sample of a patient treated in the University Hospital…

(…)

____

© The Author(s) 2019. 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.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Linezolid; Enterococcus faecium; Greece.

——

Emergence of optrA-mediated #linezolid #resistance in #enterococci from #France, 2006–16 (J Antimicrob Chemother., abstract)

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

Emergence of optrA-mediated linezolid resistance in enterococci from France, 2006–16

Mohamed Sassi, François Guérin, Asma Zouari, Racha Beyrouthy, Michel Auzou, Marguerite Fines-Guyon, Sophie Potrel, Loren Dejoies, Anaïs Collet, Sarrah Boukthir, Gabriel Auger, Richard Bonnet, Vincent Cattoir

Journal of Antimicrobial Chemotherapy, dkz097, https://doi.org/10.1093/jac/dkz097

Published: 20 March 2019

 

Abstract

Objectives

To describe the epidemiological trend of linezolid-resistant enterococci (LRE) collected in France from 2006 to 2016 and to extensively characterize LRE isolates.

Methods

The National Reference Center for Enterococci (NRC-Enc) received enterococcal isolates suspected to be VRE and/or LRE from all French hospitals between 2006 and 2016. LRE isolates were phenotypically characterized and their genomes were entirely sequenced by Miseq (Illumina). Transfer of linezolid resistance was attempted by filter mating experiments.

Results

Out of 3974 clinical isolates of enterococci received at the NRC-Enc over the period, 9 (0.2%) were LRE (MICs 8 to >32 mg/L), including 6 Enterococcus faecium and 3 Enterococcus faecalis. This overall prevalence significantly increased over the study period, reaching 0.8% in 2016. The five LRE isolated before 2016 were vanA-positive E. faecium whereas strains isolated in 2016 (one E. faecium and three E. faecalis) were susceptible to vancomycin. None of these isolates was part of an outbreak, while E. faecium strains were assigned to four different STs [17 (1), 80 (3), 412 (1) and 650 (1)] and all three E. faecalis belonged to ST480. Except for the strain isolated in 2010, all LRE were positive for optrA, which was located on plasmids (5/8) or in the chromosome (3/8). Plasmid transfer of optrA was successful in three cases.

Conclusions

There has been a significant increase in the prevalence of LRE in France over time; this is due to the spread of optrA among E. faecium and E. faecalis human clinical isolates (VRE or not).

Topic: vancomycin – enterococcus – plasmids – chromosomes – disease outbreaks – enterococcus faecalis – enterococcus faecium – genome – ichthyosis, x-linked – sequence tagged sites – linezolid – sodium thiosulfate – transfer technique – filters – low rectal endometriosis – mating – malnutrition-inflammation-cachexia syndrome

Issue Section: ORIGINAL RESEARCH

© The Author(s) 2019. 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.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Keywords: Antibiotics; Drugs Resistance; Linesolid; Enterococcus spp.

——

Novel #linezolid #resistance #plasmids in #Enterococcus from #food #animals in the #USA (J Antimicrob Chemother., abstract)

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

Novel linezolid resistance plasmids in Enterococcusfrom food animals in the USA

Gregory H Tyson, Jonathan L Sabo, Maria Hoffmann, Chih-Hao Hsu, Sampa Mukherjee, Jacqueline Hernandez, Glenn Tillman, Jamie L Wasilenko, Jovita Haro, Mustafa Simmons, Wanda Wilson Egbe, Patricia L White, Uday Dessai, Patrick F Mcdermott

Journal of Antimicrobial Chemotherapy, dky369, https://doi.org/10.1093/jac/dky369

Published: 01 October 2018

 

Abstract

Objectives

To sequence the genomes and determine the genetic mechanisms for linezolid resistance identified in three strains of Enterococcus isolated from cattle and swine caecal contents as part of the US National Antimicrobial Resistance Monitoring System (NARMS) surveillance programme.

Methods

Broth microdilution was used for in vitro antimicrobial susceptibility testing to assess linezolid resistance. Resistance mechanisms and plasmid types were identified from data generated by WGS on Illumina® and PacBio® platforms. Conjugation experiments were performed to determine whether identified mechanisms were transmissible.

Results

Linezolid resistance plasmids containing optrA were identified in two Enterococcus faecalis isolates and one Enterococcus faecium. The E. faecium isolate also carried the linezolid resistance gene cfr on the same plasmid as optrA. The linezolid resistance plasmids had various combinations of additional resistance genes conferring resistance to phenicols (fexA), aminoglycosides [spc and aph(3′)-III] and macrolides [erm(A) and erm(B)]. One of the plasmids was confirmed to be transmissible by conjugation, resulting in linezolid resistance in the transconjugant.

Conclusions

To the best of our knowledge, this is the first identification of linezolid resistance in the USA in bacteria isolated from food animals. The oxazolidinone class of antibiotics is not used in food animals in the USA, but the genes responsible for resistance were identified on plasmids with other resistance markers, indicating that there may be co-selection for these plasmids due to the use of different antimicrobials. The transmissibility of one of the plasmids demonstrated the potential for linezolid resistance to spread horizontally. Additional surveillance is necessary to determine whether similar plasmids are present in human strains of Enterococcus.

Topic: enterococcus – plasmids – cattle – food – genes  – suidae – bacteria – cecum – macrolides – linezolid – antimicrobials – antimicrobial susceptibility test – surveillance, medical – resistance genes – whole genome sequencing

Issue Section: ORIGINAL RESEARCH

Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy 2018. This work is written by US Government employees and is in the public domain in the US.

This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Keywords: Antibiotics; Drugs Resistance; Linezolid; Enterococcus; Macrolides.

——

The #resistance #potential of a quintessential #commensal (Sci Transl Med., abstract)

[Source: Science Translational Medicine, full page: (LINK). Abstract, edited.]

The resistance potential of a quintessential commensal

Chaz Langelier

Division of Infectious Diseases, University of California, San Francisco, San Francisco, CA 94049, USA. Email: chaz.langelier@ucsf.edu

Science Translational Medicine  15 Aug 2018: Vol. 10, Issue 454, eaau7387 / DOI: 10.1126/scitranslmed.aau7387

 

Abstract

Whole-genome sequencing and microbiome analysis illuminate the emergence of invasive, linezolid-resistant Staphylococcus epidermidis.

Keywords: Antibiotics; Drugs Resistance; Linezolid; Staphylococcus epidermidis.

——

Synergistic Activity of #Colistin-Containing #Combinations against Colistin-Resistant #Enterobacteriaceae (Antimicrob Agents Chemother., abstract)

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

Synergistic Activity of Colistin-Containing Combinations against Colistin-Resistant Enterobacteriaceae

Thea Brennan-Krohn a,b,d, Alejandro Pironti c and James E. Kirby a,d#

Author Affiliations: a Department of Pathology, Beth Israel Deaconess Medical Center, Boston, MA, USA; b Division of Infectious Diseases, Boston Children’s Hospital, Boston, MA, USA; c Broad Institute of MIT and Harvard, Cambridge, MA, USA; d Harvard Medical School, Boston, MA, USA

 

ABSTRACT

Resistance to colistin, a polypeptide drug used as an agent of last resort for treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Gram-negative bacteria including carbapenem-resistant Enterobacteriaceae (CRE), severely limits treatment options and may even transform an XDR organism into one that is pan-resistant. We investigated the synergistic activity of colistin in combination with 19 antibiotics against a collection of 20 colistin-resistant Enterobacteriaceae isolates, 15 of which are also CRE. All combinations were tested against all strains using an inkjet printer-assisted digital dispensing checkerboard array, and those that demonstrated synergy by this method were evaluated against a single isolate in a time-kill synergy study. Eighteen of 19 combinations demonstrated synergy against two or more isolates, and the four most highly synergistic combinations (colistin combined with linezolid, rifampin, azithromycin, and fusidic acid) were synergistic against ≥90% of strains. Sixteen of 18 combinations (88.9%) that were synergistic in checkerboard array were also synergistic in a time-kill study. Our findings demonstrate that colistin in combination with a range of antibiotics, particularly protein and RNA synthesis inhibitors, exhibits synergy against colistin-resistant strains, suggesting that colistin may exert a subinhibitory permeabilizing effect on the Gram-negative outer membrane even in isolates that are resistant to it. These findings suggest that colistin combination therapy may have promise as a treatment approach for patients infected with colistin-resistant XDR Gram-negative pathogens.

 

FOOTNOTES

#Corresponding Author: James E. Kirby, Beth Israel Deaconess Medical Center, 330 Brookline Avenue – YA309, Boston, MA 02215, jekirby@bidmc.harvard.edu, Phone: 617-667-3648, Fax: 617-667-4533

Copyright © 2018 American Society for Microbiology. All Rights Reserved.

Keywords: Antibiotics; Drugs Resistance; Colistin; Linezolid; Rifampin; Azithromycin; Fusidic Acid.

——