Infections due to gram-negative rods (GNRs) have become increasingly difficult to manage due to emerging antibiotic resistance. Previous studies have shown GNR bacteremia caused by strains resistant to extended-spectrum cephalosporinsReference Rottier, Ammerlaan and Bonten1 and fluoroquinolonesReference Lautenbach, Metlay, Bilker, Edelstein and Fishman2 have higher mortality than bacteremia caused by drug-susceptible strains. Resistance to multiple classes of antibiotics limits treatment options and contributes to increased mortality.Reference Rottier, Ammerlaan and Bonten1 However, the contribution of individual phenotypic-resistance profiles on mortality as well as the combined effects remains unclear.
The Veterans’ Health Administration (VHA), the largest integrated healthcare system in the United States, has recently aggregated microbiology results nationally. We examined national VHA microbiology data, as well as other clinical and administrative data, to explore the relationship between fluoroquinolone resistance (FR), extended-spectrum cephalosporin resistance (ESCR), and mortality among patients with hospital-onset GNR bacteremia. We aimed to quantify the attributable fraction of mortality (AF) due to fluoroquinolone resistance and ESCR in Escherichia coli and Klebsiella spp hospital-onset (HO) bacteremia.
Methods
We used a patient-level matched cohort design with uninfected patients as the control group.Reference Kaye, Engemann, Mozaffari and Carmeli3 Case patients were all veterans admitted to acute-care units at VHA hospitals in 48 continental states and the District of Columbia in the United States during January 2003–December 2013 and who had first positive blood cultures for E. coli or Klebsiella spp at least 48 hours after admission. If a patient had multiple positive blood cultures for the same species during the same hospital admission, we included only the first isolate in the analysis. We selected uninfected controls who were matched at the patient-level based on sex, month of admission, and facility. Also, length of stay of uninfected controls was matched to the length of stay before onset of bacteremia of case patients.Reference Harris, Karchmer, Carmeli and Samore4 For each case, up to 3 uninfected controls were selected.
We obtained data from the Corporate Data Warehouse (CDW) through the Veterans’ Affairs Informatics and Computing Infrastructure (VINCI), which includes data extracted from VHA’s integrated electronic medical record system. Patient characteristics were compared between cases and controls using the Fisher exact test for categorical variables and the Mann-Whitney U test for continuous variables. Susceptibility results in microbiology reports were recorded in a standardized manner, and isolates were classified as nonsusceptible if they were reported as intermediately resistant or resistant. Minimal inhibitory concentrations (MICs) and sizes of inhibition zones were not typically available.
Our primary outcome measure was all-cause 30-day mortality after the first positive blood culture. Dates of death were obtained from the VHA Vital Status File, which combines mortality information from multiple VHA and non-VHA sources and tracks patients even if they leave the VHA system.
Comorbidities were assessed using diagnosis codes based on the Charlson method with administrative data.Reference Deyo, Cherkin and Ciol5 Hospital-onset bacteremia was defined as the first positive blood culture taken after the patient had been in the hospital for 48 hours or longer. Fluoroquinolone resistance was defined as a nonsusceptible result to at least 1 of the fluoroquinolones: ciprofloxacin, levofloxacin, or moxifloxacin. ESCR was defined as a nonsusceptible result to at least 1 the following: ceftriaxone, ceftazidime, or cefepime. The attributable fraction of mortality was defined as the proportional reduction in mortality that would occur if risk factors were removed, and could be interpreted as relative impact on mortality.
To examine the association between each antibiotic resistance pattern and 30-day mortality, and to estimate their relative risks directly from the models, we used the modified Poisson regression analysis for binary outcomes proposed by Zou.Reference Zou6 Crude and adjusted attributable fractions of mortality were calculated with Levin’s formulaReference Levin7 for each antibiotic resistance group by comparing the group to uninfected controls, considering age, body mass index (BMI), and comorbidity index as patient-level confounders, based on separate models for each matched comparison group. Variables for risk-adjustment models were selected manually based on the logistic regression model to predict 30-day mortality for all groups combined, with comparisons of models for each group, and all models were adjusted for the same confounders. All statistical analyses were conducted using SAS version 9.4 software (SAS Institute, Cary, NC). The institutional review board of the University of Iowa and Research & Development Committee of Iowa City Veterans Affairs Health Care System approved this study. A waiver for informed consent was granted by the institutional review board for this retrospective cohort.
Results
During 2003–2013, a total of 6,860 patients (FR−/ESCR−, n = 4,813; FR−/ESCR+, n = 1,029; FR+/ESCR−, n = 202; FR+/ESCR+, n = 816) with E. coli or Klebsiella spp HO bacteremia were identified. Overall, 19,664 patient-level matched, uninfected controls were included in the analysis. The characteristics of the included patients are shown in Table 1. A comparison of patient characteristics within each stratum is shown in Supplementary Table 1 online. Crude and adjusted risk ratios (aRRs) and attributable fractions of mortality (AFs) for all-cause 30-day mortality are shown in Fig. 1. All 4 groups had higher 30-day mortality rates than uninfected controls. Among the 4 groups, the FR+/ESCR− group had the highest aRR and AF, followed by FR+/ESCR+, FR−/ESCR+, and FR−/ESCR−, in this order. The results of a subgroup analysis of patients with E. coli and Klebsiella spp bacteremia are shown in Supplementary Fig. 1 online. When E. coli and Klebsiella spp bacteremia were evaluated separately, the highest RRs and AFs were seen in the FR+/ESCR− group for each bacterial type, although it did not have a significant difference from other resistance patterns due to a wider confidence interval, especially in E. coli bacteremia.
Table 1. Characteristics of E. coli and Klebsiella spp Hospital-Onset Bacteremia Cases and Matched Uninfected Controls
Note. FR, fluoroquinolone resistance; ESCR, extended-spectrum cephalosporin resistance; BMI, body mass index; IQR, interquartile range; N/A, not applicable; HIV, human immunodeficiency virus; AIDS, acquired immune deficiency syndrome; CVD, cerebrovascular disease; COPD, chronic obstructive pulmonary disease; CHF, congestive heart failure; DM, diabetes mellitus; AMI, myocardial infarction; PUD, peptic ulcer disease; PVD, peripheral vascular disease.
Fig. 1. Association of bacteremia and all-cause 30-day mortality and attributable fraction of mortality.
Discussion
In this large cohort of E. coli and Klebsiella spp HO bacteremia from the VHA, isolated FR had a larger relative impact on mortality than other phenotypic antibiotic resistance profiles.
Currently, restriction of fluoroquinolones is one of the major targets of antimicrobial stewardship programs.Reference Nilholm, Holmstrand and Ahl8 This study may support increased antimicrobial stewardship efforts toward restricting fluoroquinolones.
Infection control programs have frequently targeted extended-spectrum β-lactamase (ESBL) and carbapenem-resistant Enterobacteriaceae (CRE)/carbapenemase-producing Enterobacteriaceae (CPE)–positive patients for enhanced infection control, including contact isolation and cohorts. However, given the poor outcomes we identified for FR E. coli and Klebsiella spp bacteremia, patients colonized or infected with these pathogens may deserve future investigation as potential focuses of infection control efforts.
This study has several limitations. First, the retrospective nature of this study makes it subject to unmeasured confounders. However, we used uninfected control patients matched at the patient level to represent a population with similar underlying risks. Second, we could not obtain detailed clinical information such as source of bacteremia, antimicrobial therapy, prior antimicrobial exposure, length of stay, infectious diseases consultation or intensive care unit admission. Obtaining this type of data would require extensive manual data extraction from medical records and would pose significant challenge in this type of large-scale study at 129 medical centers. Third, most included patients were male, which may limit generalizability to female population. Lastly, antibiotic resistances were assessed purely by phenotypic reports from clinical microbiology labs, and we did not have detailed microbiologic information, such as strain types or mechanisms of antibiotic resistance.
In conclusion, we found that isolated fluoroquinolone resistance had a larger impact on mortality than any other antibiotic phenotypic resistance pattern in a large cohort of hospital onset bacteremia caused by E. coli and Klebsiella spp. This finding may support increased antimicrobial stewardship efforts targeting fluoroquinolones and enhanced infection control protocols to prevent the transmission of these pathogens.
Supplementary Material
To view supplementary material for this article, please visit https://doi.org/10.1017/ice.2019.155
Author ORCIDs
Hiroyuki Suzuki 0000-0002-5953-3704
Acknowledgments
The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans’ Affairs or the United States Government.
Funding
This work was funded by Department of Veterans’ Affairs (VA) Health Services Research and Development (HSR&D) by the VA HSR&D Centers of Innovation: Center for Access & Delivery Research Evaluation (grant no: CIN 13-412; primary investigator, ENP), and supported with resources and the use of facilities of the Iowa City VA Health Care System.
Conflict of Interest
All authors have no conflict of interest to report.
