Lessons learned from excess mortality associated with Klebsiella pneumoniae carbapenemase 2–producing k. pneumoniae in liver transplant recipients

Authors

  • Christoph Lübbert M.D., D.T.M.H.,

    Corresponding author
    1. Division of Infectious Diseases and Tropical Medicine Department of Gastroenterology and Rheumatology, Leipzig University Hospital, Leipzig, Germany
    • Address reprint requests to Christoph Lübbert, M.D., D.T.M.H., Division of Infectious Diseases and Tropical Medicine, Department of Gastroenterology and Rheumatology, Leipzig University Hospital, Liebigstrasse 20, D-04103 Leipzig, Germany. Telephone: +49-341-97-12200; FAX: +49-341-97-24979; E-mail: christoph.luebbert@medizin.uni-leipzig.de

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  • Arne C. Rodloff M.D., Ph.D.,

    1. Institute for Medical Microbiology and Epidemiology of Infectious Diseases, Leipzig University Hospital, Leipzig, Germany
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  • Sven Laudi M.D.,

    1. Department of Anesthesiology and Intensive Care Medicine, Leipzig University Hospital, Leipzig, Germany
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  • Philipp Simon M.D.,

    1. Department of Anesthesiology and Intensive Care Medicine, Leipzig University Hospital, Leipzig, Germany
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  • Thilo Busch Ph.D.,

    1. Department of Anesthesiology and Intensive Care Medicine, Leipzig University Hospital, Leipzig, Germany
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  • Joachim Mössner M.D., Ph.D.,

    1. Department of Gastroenterology and Rheumatology, Leipzig University Hospital, Leipzig, Germany
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  • Michael Bartels M.D., Ph.D.,

    1. Department of Visceral Transplant Thoracic and Vascular Surgery, Leipzig University Hospital, Leipzig, Germany
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  • Udo X. Kaisers M.D., Ph.D.

    1. Department of Anesthesiology and Intensive Care Medicine, Leipzig University Hospital, Leipzig, Germany
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  • There was no funding for this letter, and the authors have no potential conflicts of interest to disclose. The study protocol received a priori approval by the University of Leipzig Ethics Committee (Leipzig, Germany).

Abbreviations
APACHE II

Acute Physiology and Chronic Health Evaluation II

CRKP

carbapenem-resistant Klebsiella pneumoniae

ESBL

extended-spectrum-lactamase

KPC-2-KP

K. pneumoniae carbapenemase 2-producing K. pneumoniae

LT

liver transplantation

LTR

liver transplant recipient

MELD

Model for End-Stage Liver Disease

SAPS II

Simplified Acute Physiology Score II

SOFA

Sequential Organ Failure Assessment

TO THE EDITORS:

Klebsiella pneumoniae is a major cause of nosocomial infections, primarily among immunocompromised patients. The emergence of carbapenem-resistant K. pneumoniae (CRKP) strains has limited treatment options and has resulted in a high infection-related mortality rate.[1] However, only small case series are available on the effects of CRKP in organ transplant recipients.[2-5]

From July 2010 to April 2013, the Leipzig University Hospital experienced a large outbreak due to a K. pneumoniae carbapenemase 2–producing K. pneumoniae (KPC-2-KP) strain (sequence type ST258). The outbreak occurred after the transfer of a patient from Greece, where K. pneumoniae carbapenemase 2–producing organisms are endemic.[1] One hundred three patients became either colonized (58%) or infected (42%), and they included 9 liver transplant recipients (LTRs). Successful containment of the outbreak was achieved through the implementation of efficient infection control measures (strict barrier precautions, improved hand hygiene, antibiotic stewardship, systematic CRKP screening, and cohorting of CRKP-positive patients).[6, 7]

Eighty-nine percent (8/9) of the KPC-2-KP–positive LTRs progressed to infection (50% had radiologically and microbiologically confirmed pneumonia, 25% had surgical site infections, and 25% had recurrent secondary peritonitis). In 56% (5/9), a KPC-2-KP bloodstream infection was confirmed. With European Committee on Antimicrobial Susceptibility Testing breakpoints, broth microdilution tests revealed susceptible or intermediate results for tigecycline (minimum inhibitory concentration = 0.5-2 mg/L), gentamicin (minimum inhibitory concentration = 2 mg/L), and colistin (minimum inhibitory concentration = 0.25-1 mg/L). For treatment, these antimicrobials were used in combination [intravenous tigecycline (50-100 mg every 12 hours), intravenous gentamicin (5-7 mg/kg every 24 hours), and intravenous colistin methanesulfonate (2,000,000-3,000,000 IU every 8 hours)]. Four of the 9 patients received tigecycline, gentamicin, and colistin; 2 received tigecycline and colistin; and 2 received tigecycline and gentamicin. Combination therapy with carbapenems was not considered because the corresponding minimum inhibitory concentrations were ≥16 mg/L for all KPC-2-KP isolates.

We retrospectively compared the clinical outcomes of these 9 LTRs with KPC-2-KP and 34 LTRs with proof of invasive infections due to carbapenem-susceptible Klebsiella spp. [71% had K. pneumoniae, and 29% had Klebsiella oxytoca; extended-spectrum β-lactamase (ESBL)–producing strains were included (71%); Table 1]. This analysis revealed hospital mortality rates of 78% for LTRs with KPC-2-KP and 32% for LTRs with carbapenem-susceptible Klebsiella strains (P = 0.02, Fisher's exact test). The 6-month survival rate for LTRs with KPC-2-KP (22%) was significantly reduced in comparison with the rates for LTRs with sensitive Klebsiella strains (70%) and LTRs with ESBL-producing Klebsiella strains (67%; P < 0.05; Fig. 1). The hospital mortality rate for all organ transplant recipients colonized or infected with KPC-2-KP (11 LTRs, including 2 patients who had already undergone transplantation more than 6 months before the outbreak; 3 kidney transplant recipients; 2 lung transplant recipients; and 3 stem cell transplant recipients) was 58% (11/19). Deaths attributable to KPC-2-KP were found only for LTRs, and this indicated a specific vulnerability in this patient population.

Table 1. Baseline Characteristics of LTRs With KPC-2-KP and LTRs With Invasive Infections Due to Carbapenem-Susceptible Klebsiella spp
Patient GroupLTRs With KPC-2-KP (n = 9)LTRs With Invasive Infections From Carbapenem-Susceptible Klebsiella Strains (n = 34)P Valuea
  1. a

    P values were determined with the Mann-Whitney U test (for numerical variables) or Fisher's exact test (for nominal variables); both tests were 2-tailed.

  2. b

    The data are presented as means and standard deviations.

Transplantation period2011-20122008-2011Not applicable
Age (years)b52.1 ± 12.255.6 ± 7.00.39
Sex: male/female (n/n)6/324/100.82
Laboratory MELD scoreb24.7 ± 11.322.2 ± 8.50.49
APACHE II scoreb22.1 ± 7.115.5 ± 5.60.01
SAPS II scoreb49.7 ± 11.347.5 ± 18.60.49
SOFA scoreb10.2 ± 3.211.2 ± 4.10.59
Length of hospital stay (days)b65.7 ± 46.465.1 ± 36.40.80
Mortality rate [n/N (%)]7/9 (78)11/34 (32)0.02
Figure 1.

Kaplan-Meier survival curves for LTRs with invasive Klebsiella spp. infections. The 6-month survival rate for LTRs with KPC-2-KP was significantly reduced in comparison with the rates for LTRs with sensitive Klebsiella strains (sensitive Klebsiella spp., P = 0.02) and LTRs with ESBL-producing Klebsiella strains (ESBL Klebsiella spp., P = 0.004). Cox-Mantel log-rank statistics, including multiple comparisons with the application of the Holm-Bonferroni method, were used.

Our findings are consistent with data from Kalpoe et al.,[2] who reported reduced 1-year survival for LTRs with CRKP infections (29% versus 86%, P < 0.001); this was independently associated with mortality (hazard ratio = 4.9, P = 0.007). Moreover, recent data provided by Ben-David et al.[8] suggest excess mortality due to carbapenem resistance in nontransplant patients with CRKP bloodstream infections (48% for CRKP, 22% for ESBL-producing K. pneumoniae, and 17% for sensitive K. pneumoniae strains; P < 0.001).

Delays in the high-dose administration of colistin, tigecycline, and gentamicin along with unsuccessful source control for 2 of the 4 LTRs with intra-abdominal KPC-2-KP infections and slight differences in disease severity [Acute Physiology and Chronic Health Evaluation II (APACHE II) score; see Table 1] probably influenced mortality in our study. Thus, it seems important to screen LTRs and liver transplantation (LT) candidates for multidrug-resistant organisms with active surveillance tests. Importantly, we could demonstrate that immunosuppression predisposes patients to long-term carriage of CRKP (up to 40 months).[9] Selective digestive decontamination with colistin and gentamicin, however, failed to demonstrate clinical effectiveness and constituted a substantial risk for secondary bacterial resistance.[7]

The limited amount of clinical data currently prevents definite conclusions on the eligibility of patients with end-stage liver disease and persistent CRKP carriage for transplantation.[10] Nevertheless, we propose that specifically in a CRKP outbreak situation (which implies a high risk of progression to fatal infection), these patients should not be considered for LT.

  • Christoph Lübbert, M.D., D.T.M.H.1

  • Arne C. Rodloff, M.D., Ph.D.2

  • Sven Laudi, M.D.3

  • Philipp Simon, M.D.3

  • Thilo Busch, Ph.D.3

  • Joachim Mössner, M.D., Ph.D.4

  • Michael Bartels, M.D., Ph.D.5

  • Udo X. Kaisers, M.D., Ph.D.3

  • 1Division of Infectious Diseases and Tropical Medicine, Department of Gastroenterology and Rheumatology, 2Institute for Medical Microbiology and Epidemiology of Infectious Diseases, 3Department of Anesthesiology and Intensive Care Medicine, 4Department of Gastroenterology and Rheumatology, and 5Department of Visceral, Transplant, Thoracic, and Vascular Surgery

  • Leipzig University Hospital

  • Leipzig, Germany

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