Risk Factors and Outcomes Associated With Acquisition of Daptomycin and Linezolid–Nonsusceptible Vancomycin-Resistant Enterococcus

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Abstract

Background

Vancomycin-resistant enterococcus (VRE) causes substantial health care–associated infection with increasing reports of resistance to daptomycin or linezolid. We conducted a case–control study reporting 81 cases of daptomycin and linezolid–nonsusceptible VRE (DLVRE), a resistance pattern not previously reported.

Methods

We reviewed VRE isolates from June 2010 through June 2015 for nonsusceptibility to both daptomycin (minimum inhibitory concentration [MIC] > 4) and linezolid (MIC ≥ 4). We matched cases by year to control patients with VRE susceptible to both daptomycin and linezolid and performed retrospective chart review to gather risk factor and outcome data.

Results

We identified 81 DLVRE cases. Resistance to both daptomycin and linezolid was more common than resistance to either agent individually. Compared with susceptible VRE, DLVRE was more likely to present as bacteremia without focus ( P < 0.01), with DLVRE patients more likely to be immune suppressed ( P = .04), to be neutropenic ( P = .03), or to have had an invasive procedure in the prior 30 days ( P = .04). Any antibiotic exposure over the prior 30 days conferred a 4-fold increased risk for DLVRE (odds ratio [OR], 4.25; 95% confidence interval [CI], 1.43−12.63; P = .01); multivariate analysis implicated daptomycin days of therapy (DOT) over the past year as a specific risk factor (OR, 1.10; 95% CI, 1.01−1.19; P = .03). DLVRE cases had longer hospitalizations ( P = .04) but no increased risk for in-hospital death.

Conclusions

DLVRE is an emerging multidrug-resistant pathogen associated with immune suppression, neutropenia, and recent invasive procedure. Prior antibiotic exposure, specifically daptomycin exposure, confers risk for acquisition of DLVRE.

Related collections

Most cited references 35

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Comparison of mortality associated with vancomycin-resistant and vancomycin-susceptible enterococcal bloodstream infections: a meta-analysis.

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Whether vancomycin resistance is independently associated with mortality among patients with enterococcal bloodstream infection (BSI) is controversial. To address this issue, we performed a systematic literature review with meta-analysis. Data sources were studies identified using the MEDLINE database (for articles from 1988 through March 2003), the Cochrane Library (for articles published up to March 2003), and bibliographies of identified articles. Inclusion criteria were that the study assessed mortality after enterococcal BSI, compared mortality after vancomycin-resistant enterococci (VRE) BSI with that after vancomycin-susceptible enterococci (VSE) BSI, and adjusted for severity of illness. Study exclusion criteria were as follows: no report of the adjusted measure of effect (adjusted odds ratio [OR], adjusted hazard ratio, or adjusted relative risk) of vancomycin resistance on mortality available and/or its adjusted 95% confidence interval (95% CI). Data in the tables, figures, or text were independently extracted by 2 of the authors. Individual weights were calculated using the 95% CI of the adjusted measures of effect performing both fixed-effect and random-effects models. Nine studies were eligible (11 studies met the inclusion criteria, and 2 were excluded), with a total of 1614 enterococcal BSI episodes (683 VRE episodes and 931 VSE episodes). Patients with bacteremia caused by VRE were more likely to die than were those with VSE bacteremia (summary OR, 2.52; 95% CI, 1.9-3.4). Vancomycin resistance is independently associated with increased mortality among patients with enterococcal bloodstream infection.

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On the basis of noninferiority trials, tigecycline received Food and Drug Administration (FDA) approval in 2005. In 2010, the FDA warned in a safety communication that tigecycline was associated with an increased risk of death. PubMed, EMBASE, Scopus, and ClinicalTrials.gov were searched using the terms "tigecycline" and "randomized controlled trial (RCT)" through April 2011. Excess deaths and noncure rates for both approved and nonapproved indications were examined using meta-analysis. Ten published and 3 unpublished studies met inclusion criteria (N = 7434). No significant heterogeneity was seen for mortality (I(2 )= 0%; P = .99) or noncure rates (I(2 )= 25%; P = .19). Across randomized controlled trials, tigecycline was associated with increased mortality (risk difference [RD], 0.7%; 95% confidence interval [CI], 0.1%-1.2%; P = .01) and noncure rates (RD, 2.9%; 95% CI, 0.6%-5.2%; P = .01). Effects were not isolated to type of infection or comparator antibiotic regimen, and the impact on survival remained significant when limited to trials of approved indications (I(2 )= 0%; RD, 0.6%; P = .04). A pooled analysis of the 5 trials completed by early 2005 before tigecycline was approved would have demonstrated a similar harmful effect of tigecycline on survival (I(2 )= 0%; RD, 0.7%; P = .06). Pooling noninferiority studies to examine survival may help ensure the safety and efficacy of new antibiotics. The association of tigecycline with excess deaths and noncure includes indications for which it is approved and marketed. Tigecycline cannot be relied on in serious infections.

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A current perspective on daptomycin for the clinical microbiologist.

Romney M Humphries, Simon Pollett, George Sakoulas (2013)

Daptomycin is a lipopeptide antimicrobial with in vitro bactericidal activity against Gram-positive bacteria that was first approved for clinical use in 2004 in the United States. Since this time, significant data have emerged regarding the use of daptomycin for the treatment of serious infections, such as bacteremia and endocarditis, caused by Gram-positive pathogens. However, there are also increasing reports of daptomycin nonsusceptibility, in Staphylococcus aureus and, in particular, Enterococcus faecium and Enterococcus faecalis. Such nonsusceptibility is largely in the context of prolonged treatment courses and infections with high bacterial burdens, but it may occur in the absence of prior daptomycin exposure. Nonsusceptibility in both S. aureus and Enterococcus is mediated by adaptations to cell wall homeostasis and membrane phospholipid metabolism. This review summarizes the data on daptomycin, including daptomycin's unique mode of action and spectrum of activity and mechanisms for nonsusceptibility in key pathogens, including S. aureus, E. faecium, and E. faecalis. The challenges faced by the clinical laboratory in obtaining accurate susceptibility results and reporting daptomycin MICs are also discussed.

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Author and article information

Journal

Journal ID (nlm-ta): Open Forum Infect Dis

Journal ID (iso-abbrev): Open Forum Infect Dis

Journal ID (publisher-id): ofid

Title: Open Forum Infectious Diseases

Publisher: Oxford University Press (US )

ISSN (Electronic): 2328-8957

Publication date Collection: October 2018

Publication date (Electronic): 09 October 2018

Publication date PMC-release: 09 October 2018

Volume: 5

Issue: 10

Electronic Location Identifier: ofy185

Affiliations

[1 ]Vanderbilt University Medical Center, Nashville, Tennessee

[2 ]Emory Healthcare, Atlanta, Georgia

Author notes

Correspondence: M. H. Greene, MD, 1161 21st Avenue South, A2200 Medical Center North, Nashville, TN 37232 ( matthew.h.greene@ 123456vanderbilt.edu ).

Article

Publisher ID: ofy185

DOI: 10.1093/ofid/ofy185

PMC ID: 6176497

PubMed ID: 30320147

SO-VID: a6f9cc44-abeb-475b-afeb-f6eb95de1766

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence ( http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

History

Date received : 10 May 2018

Date accepted : 31 July 2018

Page count

Pages: 5

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