Elsevier

Journal of Infection

Volume 73, Issue 4, October 2016, Pages 336-345
Journal of Infection

Bacteremia due to carbapenem-resistant Enterobacteriaceae in neutropenic patients with hematologic malignancies

https://doi.org/10.1016/j.jinf.2016.07.002Get rights and content

Highlights

  • CRE caused 2.2% of all BSIs and 4.7% of Gram-negative BSIs in neutropenic patients.

  • Multiple antibiotics, steroids and a prior CRE culture were CRE BSI risk factors.

  • Patients with CRE BSI had a 2–3-day delay until receipt of CRE-active therapy.

  • The CRE BSI-related mortality rate was 51%, with a median of 4 days until death.

  • New strategies are needed to mitigate this threat in this vulnerable population.

Summary

Objectives

To determine the prevalence, risk factors, treatments, and outcomes of bloodstream infections (BSIs) due to carbapenem-resistant Enterobacteriaceae (CRE) in adult neutropenic patients with hematologic malignancies.

Methods

We reviewed all BSIs between 2008 and 2012 in this population at two New York City oncology centers. A case-control study was conducted to identify CRE BSI risk factors, using three controls of non-CRE BSIs per case.

Results

CRE caused 43 (2.2%) of 1992 BSIs overall and 4.7% of Gram-negative bacteremias. Independent risk factors for CRE BSI were prior β-lactam/β-lactamase inhibitor (adjusted odds ratio [aOR] 3.2; P = 0.03) or carbapenem (aOR 3.0; P = 0.05) use, current trimethoprim-sulfamethoxazole (aOR 24; P = 0.001) or glucocorticoid (aOR 5.4, P = 0.004) use, and having a prior CRE culture (aOR 12; P = 0.03). Patients with CRE bacteremia had a median of 52 h from culture collection until receipt of active therapy. They had a 51% BSI-related mortality rate, with a median of 4 days from bacteremia onset until death. CRE-active empirical therapy was associated with a lower 30-day mortality rate (17% vs. 59%; P = 0.08).

Conclusions

CRE are lethal emerging causes of bacteremia in neutropenic patients. New strategies are needed to shorten the delay in administration of CRE-active agents and improve outcomes in this vulnerable population.

Introduction

Neutropenic patients with hematologic malignancies are uniquely threatened by multidrug-resistant Gram-negative bacteria because they rely on immediate bactericidal therapy to combat Gram-negative infections. Enterobacteriaceae are the most common causes of Gram-negative bacteremia in this population and have historically been susceptible to recommended β-lactam agents for the treatment of fever and neutropenia.1, 2 However, over the last decade, carbapenem-resistant Enterobacteriaceae (CRE) have emerged worldwide as lethal pathogens that are typically resistant to all β-lactam agents due to production of β-lactam-hydrolyzing enzymes such as Klebsiella pneumoniae carbapenemase (KPC).3 Given that currently recommended empirical therapies are inactive against CRE, and identification of CRE by culture typically takes 2–3 days, the spread of CRE into neutropenic patients with hematologic malignancies could have devastating consequences because effective therapy would be delayed.4

We recently reported 18 patients with hematologic malignancies who developed bacteremia due to CRE.5 Nine of 13 neutropenic patients in this study died, there were long delays until receipt of active therapy, and all deaths were related to CRE bacteremia. Given these preliminary findings, we sought to better understand the epidemiology of CRE in this patient population in an area where CRE are endemic nosocomial pathogens. Thus, we conducted a study at two large oncology centers in New York City, USA, a global epicenter for CRE, to determine the prevalence, risk factors, and outcomes of CRE bacteremia in neutropenic patients with hematologic malignancies.

Section snippets

Study design

The study was approved by the Institutional Review Boards of Weill Cornell Medicine and Memorial Sloan Kettering Cancer Center (MSKCC). We first identified all episodes of bloodstream infection (BSI) in adult (age ≥18 years) neutropenic patients (absolute neutrophil count ≤500 cells/mm3) with hematologic malignancies at New York-Presbyterian Hospital/Weill Cornell Medical Center and MSKCC from 2008 to 2012. BSIs where the patient had a prior positive blood culture for the same organism(s)

Prevalence and characteristics of CRE

We identified 1992 BSI episodes in neutropenic patients with hematologic malignancies during the study period, of which 43 (2.2%; 95% confidence interval [CI]: 1.6–2.9%) were caused by CRE (Fig. 1). The proportion of BSIs due to CRE at each hospital was 2.4% and 1.9%, respectively, and varied from 0.8% to 3.0% by study year, with no clear trend over time. CRE caused 4.7% of bacteremias that included a Gram-negative bacterium and 6.5% of bacteremias that included an Enterobacteriaceae. Eighteen

Discussion

To our knowledge, this is the first reported study to assess the prevalence, risk factors, and outcomes of CRE bacteremia in neutropenic patients with hematologic malignancies. We conducted this study at two large oncology centers in New York City, where CRE have been endemic for over a decade,15 and found that CRE represent 2.2% of all BSIs and 4.7% of Gram-negative bacteremias in this population. The number of CRE bacteremia cases was similar to that of candidemia and greater than that of

Conflict of interest

M.J.S. has received research grants/contracts from Allergan and Achaogen. T.J.W. has received research grants/contracts from Allergan and Merck. All other authors report no potential conflicts of interest.

Funding

This work was partially supported by the National Institute of Allergy and Infectious Diseases [K23 AI114994 to M.J.S., R01 AI090155 to B.N.K., and R21 AI117338 to L.C.] and the National Center for Advancing Translational Science [UL1 TR000457] at the National Institutes of Health (NIH), the National Institutes of Health/National Cancer Institute Cancer Center Support Grant [P30 CA008748 to N.C., Z.G., S.K.S], and Save Our Sick Kids Foundation and Sharp Family Foundation [to T.J.W].

Author contributions

M.J.S., N.C., T.J.W., and S.K.S. contributed to the conception and design of the study. M.J.S., N.C., K.M., Z.G., S.K.S. contributed to acquisition of data. M.S., N.C., R.S., G.A., L.C., B.N.K., T.J.W., and S.K.S. contributed to the analysis and interpretation of the data.

Acknowledgments

This study was presented, in part, at IDWeek 2014, Philadelphia, PA, USA (abstract #434). Nine of the 43 CRE bacteremia episodes in this study were included in a previously published manuscript.5

References (27)

  • M.J. Satlin et al.

    Emergence of carbapenem-resistant Enterobacteriaceae as causes of bloodstream infections in patients with hematologic malignancies

    Leuk Lymphoma

    (2013)
  • Centers for Disease Control and Prevention. Device-associated module: bloodstream infection event. Available at:...
  • M.M. Levy et al.

    2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference

    Crit Care Med

    (2003)
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