Difficult-to-Treat Resistance in Gram-negative Bacteremia at 173 US Hospitals: Retrospective Cohort Analysis of Prevalence, Predictors, and Outcome of Resistance to All First-line Agents

Abstract

Background: Resistance to all first-line antibiotics necessitates the use of less effective or more toxic "reserve" agents. Gram-negative bloodstream infections (GNBSIs) harboring such difficult-to-treat resistance (DTR) may have higher mortality than phenotypes that allow for ≥1 active first-line antibiotic.

Methods: The Premier Database was analyzed for inpatients with select GNBSIs. DTR was defined as intermediate/resistant in vitro to all ß-lactam categories, including carbapenems and fluoroquinolones. Prevalence and aminoglycoside resistance of DTR episodes were compared with carbapenem-resistant, extended-spectrum cephalosporin-resistant, and fluoroquinolone-resistant episodes using CDC definitions. Predictors of DTR were identified. The adjusted relative risk (aRR) of mortality was examined for DTR, CDC-defined phenotypes susceptible to ≥1 first-line agent, and graded loss of active categories.

Results: Between 2009-2013, 471 (1%) of 45011 GNBSI episodes at 92 (53.2%) of 173 hospitals exhibited DTR, ranging from 0.04% for Escherichia coli to 18.4% for Acinetobacter baumannii. Among patients with DTR, 79% received parenteral aminoglycosides, tigecycline, or colistin/polymyxin-B; resistance to all aminoglycosides occurred in 33%. Predictors of DTR included urban healthcare and higher baseline illness. Crude mortality for GNBSIs with DTR was 43%; aRR was higher for DTR than for carbapenem-resistant (1.2; 95% confidence interval, 1.0-1.4; P = .02), extended-spectrum cephalosporin-resistant (1.2; 1.1-1.4; P = .001), or fluoroquinolone-resistant (1.2; 1.0-1.4; P = .008) infections. The mortality aRR increased 20% per graded loss of active first-line categories, from 3-5 to 1-2 to 0.

Conclusion: Nonsusceptibility to first-line antibiotics is associated with decreased survival in GNBSIs. DTR is a simple bedside prognostic measure of treatment-limiting coresistance.

Figure 1.

Schematic relationship between difficult-to-treat resistance (DTR) and Centers for Disease Control and Prevention (CDC)–defined coresistance phenotypes. As represented in this figure, DTR isolates fall completely within the CDC-defined multidrug-resistant (MDR) phenotype and overlap with the extensively drug-resistant (XDR) phenotype. Although pandrug-resistant (PDR) organisms all fall within the DTR phenotype, the DTR definition introduced here offers more clinical utility, in that it requires resistance only to all first-line agents, instead of all antimicrobial agents available. (Note that proportions of overlap among coresistance phenotypes are not displayed to scale. Refer to Magiorakos et al [6] for CDC definitions.)

Figure 2.

Flowchart showing selection process for inpatient encounters with gram-negative bloodstream infections (GNBSIs) exhibiting difficult-to-treat resistance (DTR) in the Premier Healthcare Database. To estimate DTR prevalence, all inpatient encounters reporting microbiology and in vitro antimicrobial susceptibility results were included if patients had ≥1 blood culture isolate belonging to 1 of 5 gram-negative bacterial taxa (see Methods). A GNBSI episode comprised all isolates of the same bacterial taxon within 30 days, and prevalence was calculated among episodes that met minimum testing requirements for DTR. For risk factor and outcome analysis, the most resistant phenotype from the last inpatient encounter was selected, given its proximity to the last known outcome for a given patient. Abbreviations: CR, carbapenem resistant; ECR, extended-spectrum cephalosporin resistant; FQR, fluoroquinolone resistant.

Figure 3.

Prevalence of difficult-to-treat resistance (DTR) compared with Centers for Disease Control and Prevention (CDC)–defined resistance phenotypes among gram-negative bloodstream isolates. The prevalences of DTR organisms and of CDC-defined phenotypes were compared across gram-negative bloodstream isolates for the 5 taxa of interest. Prevalence was calculated using all gram-negative bloodstream infection episodes, overall and for each respective organism. A, Overall prevalence of DTR compared with the CDC-defined phenotypes. B–F, Prevalence among Escherichia coli (B), Klebsiella spp. (C), Enterobacter spp. (D), Pseudomonas aeruginosa (E), and Acinetobacter baumannii (F) isolates. Abbreviations: CR, carbapenem resistant; ECR, extended-spectrum cephalosporin resistant; FQR, fluoroquinolone resistant; I, intermediate.

Figure 4.

A, Distribution of active first-line agent categories by taxon among carbapenem-resistant (CR) with gram-negative bloodstream infection (GNBSI) encounters, comparing the availability of active noncarbapenem first-line agent categories among CR GNBSI episodes as a measure of the degree of coresistance across the various taxa of CR isolates. The population used for this analysis includes episodes of difficult-to-treat resistance (DTR) in addition to Centers for Disease Control and Prevention–defined CR episodes and excludes multiorganism bacteremia. B, Distribution of isolates by resistance category among 173 hospitals in the Premier Healthcare Database, showing the absolute number of isolates displaying each resistance phenotype across hospitals. More than half of all hospitals in this data set had ≥1 DTR isolate from 2009 to 2013. Abbreviations: ECR, extended-spectrum cephalosporin resistant; FQR, fluoroquinolone resistant.

Figure 5.

Adjusted relative mortality risk among inpatients with gram-negative bloodstream infections across resistance phenotypes (A) and diminished active first-line agent categories (B) at 173 US hospitals from 2009 to 2013. Variables adjusted for in both models included age, sex, Elixhauser index, 3M All Patient Refined Diagnosis Related Group risk of mortality assignment, infection site, intensive care unit stay, neutropenia, and ventilator use at the patient level; taxa/species, healthcare-associated status, culture day relative to hospital admission, and year at the organism level; and region, bed capacity, urban location, teaching status, and hospital indicator at the hospital level. A, The reference category was “all other isolates.” The significance of differences between difficult-to-treat resistance (DTR) and the other phenotypes was also tested: DTR versus carbapenem resistant (CR), P = .02; DTR versus extended-spectrum cephalosporin resistant (ECR), P = .001; and DTR versus fluoroquinolone resistant (FQR), P = .008. ^*Not significant (NS) for all pairwise comparisons among CR, ECR, and FQR categories. B, The reference category was 3–5 active categories of first-line agents (and 3–4 active categories for Acinetobacter baumannii isolates). Categories included carbapenems, extended-spectrum cephalosporins, quinolones, β-lactam/β-lactamase inhibitors (piperacillin-tazobactam), and monobactam (aztreonam); for A. baumannii cases, monobactams were not included, and the β-lactam/β-lactamase inhibitor category also included ampicillin-sulbactam. P values for comparison of categories are as follows: 0 versus 3–5 categories, P < .001; 1–2 versus 3–5 categories, P = .001. ^*P = .01 for the comparison of 0 versus 1–2 categories. Abbreviation: FQ, fluoroquinolone.

Figure 6.

Difficult-to-treat resistance (DTR)–associated mortality by taxon of bloodstream isolate. A, B, Taxon-specific distributions of DTR encounters (n = 440) (A) and deaths (n = 190) (B), respectively. C, Unadjusted mortality rates (in-hospital death or discharge to hospice). D, Estimates of adjusted relative risk of death from DTR obtained from taxon-specific models (reference category, encounters with susceptible gram-negative bloodstream isolates). The differences in adjusted relative risk of death among DTR Enterobacteriaceae, Pseudomonas aeruginosa, and Acinetobacter baumannii were not statistically significant (P ≥ .05 for all three 2-way comparisons). Note that there were only 10 encounters with DTR Escherichia coli, so the 3 taxa of Enterobacteriaceae are presented as 1 group to ensure better model fit.

Figure 7.

A, Proportion of episodes treated with intravenous aminoglycoside, tigecycline, or colistin/polymixin-B, shown as the proportion of episodes treated with ≥1 dose of intravenous reserve agents: aminoglycoside (gentamycin, tobramycin, and/or amikacin), tigecycline, or colistin/polymixin-B, by resistance phenotype. B, Proportion of isolates resistant to aminoglycosides among those from patients with gram-negative bloodstream infections exhibiting resistant phenotype(s) at 173 US hospitals from 2009 to 2013. The display shows the proportion of isolates in each resistance phenotype that are intermediate or resistant in vitro to ≥1 of the 3 aminoglycosides. The “Other” category represents isolates that could not be classified into one of the listed resistance categories. Abbreviations: CR, carbapenem resistant; ECR, extended-spectrum cephalosporin resistant; DTR, difficult-to-treat resistance; FQR, fluoroquinolone resistant.