Inappropriate empirical antibiotic therapy for bloodstream infections based on discordant in-vitro susceptibilities: a retrospective cohort analysis of prevalence, predictors, and mortality risk in US hospitals

Abstract

Background: The prevalence and effects of inappropriate empirical antibiotic therapy for bloodstream infections are unclear. We aimed to establish the population-level burden, predictors, and mortality risk of in-vitro susceptibility-discordant empirical antibiotic therapy among patients with bloodstream infections.

Methods: Our retrospective cohort analysis of electronic health record data from 131 hospitals in the USA included patients with suspected-and subsequently confirmed-bloodstream infections who were treated empirically with systemic antibiotics between Jan 1, 2005, and Dec 31, 2014. We included all patients with monomicrobial bacteraemia caused by common bloodstream pathogens who received at least one systemic antibiotic either on the day blood cultures were drawn or the day after, and for whom susceptibility data were available. We calculated the prevalence of discordant empirical antibiotic therapy-which was defined as receiving antibiotics on the day blood culture samples were drawn to which the cultured isolate was not susceptible in vitro-overall and by hospital type by using regression tree analysis. We used generalised estimating equations to identify predictors of receiving discordant empirical antibiotic therapy, and used logistic regression to calculate adjusted odds ratios for the relationship between in-hospital mortality and discordant empirical antibiotic therapy.

Findings: 21 608 patients with bloodstream infections received empirical antibiotic therapy on the day of first blood culture collection. Of these patients, 4165 (19%) received discordant empirical antibiotic therapy. Discordant empirical antibiotic therapy was independently associated with increased risk of mortality (adjusted odds ratio 1·46 [95% CI, 1·28-1·66]; p<0·0001), a relationship that was unaffected by the presence or absence of resistance or sepsis or septic shock. Infection with antibiotic-resistant species strongly predicted receiving discordant empirical therapy (adjusted odds ratio 9·09 [95% CI 7·68-10·76]; p<0·0001). Most incidences of discordant empirical antibiotic therapy and associated deaths occurred among patients with bloodstream infections caused by Staphylococcus aureus or Enterobacterales.

Interpretation: Approximately one in five patients with bloodstream infections in US hospitals received discordant empirical antibiotic therapy, receipt of which was closely associated with infection with antibiotic-resistant pathogens. Receiving discordant empirical antibiotic therapy was associated with increased odds of mortality overall, even in patients without sepsis. Early identification of bloodstream pathogens and resistance will probably improve population-level outcomes.

Funding: US National Institutes of Health, US Centers for Disease Control and Prevention, and US Agency for Healthcare Research and Quality.

Figure 1:. Case-selection flowchart.

The figure describes the process of selecting patients with monomicrobial bloodstream infection due to common pathogens that were eligible for assessment of concordance of empiric antibiotic therapy. Empiric antibiotic therapy was considered discordant (DEAT) if the bloodstream isolate did not display in vitro susceptibility to any systemic antibiotic administered on the day of blood culture sampling.

Figure 2:. Regression Tree Analysis: Association between Hospital Type and Reliability-adjusted Hospital Prevalence of Discordant Empiric Antibiotic Therapy in BSI.

Given that hospital-level factors do not occur in isolation, recursive partitioning was performed by means of a regression tree analysis using combinations of the following characteristics: bed capacity, teaching status, geographic region, urban status and quartile of baseline resistance prevalence encountered at each hospital. Reliability adjustment of mean (95% CI) prevalence of DEAT in BSI for each of the 129 hospitals (with >1 BSI patient receiving DEAT) included was performed using a random effects model. Pruning was used to select the optimal nested subtree with the smallest misclassification cost. All calculations were performed in SAS version 9·4. The GLIMMIX procedure was used to fit the generalized linear mixed model and PROC HPSPLIT was used to conduct the regression tree analysis. The first split occurred at between baseline resistance quartiles 1 vs. 2,3,4, followed by teaching status and then region at which point the regression tree was pruned, yielding 7 distinct hospital types. The reliability-adjusted prevalence of DEAT in BSI ranged from 16·6% (95% CI,15·0–18·5) at 8 teaching hospitals in the first quartile of baseline resistance in the Midwest, Northeast and West, to 21·1% (95% CI, 20·1–22·1) at 28 teaching hospitals in the South and Midwest in the top 3 quartiles of baseline resistance.

Figure 3 A-C:. Discordant empiric antibiotic therapy and antibiotic-resistant phenotypes by taxon of bloodstream isolate.

Horizontal bars in sub-figures A and B depict proportions of discordant empiric antibiotic therapy and antibiotic-resistant pathogens respectively. Counts to the right of the bar represents the denominator for each bar. Sub-figure C provides the ratio of count of discordant empiric antibiotic therapy vs. antibiotic-resistant phenotypes by taxon. Footnote: Antibiotic resistance phenotypes are defined for each pathogen as follows: Staphylococcus aureus – Methicillin (MRSA); Enterococcus spp. – Vancomycin (VRE); Enterobacteriaceae spp., non-glucose fermenters other than Stenotrophomonas maltophilia – Extended-spectrum cephalosporin (ESBL) or carbapenem (CR); Stenotrophomonas maltophilia – TMP/SMX, quinolone, or ceftazidime; β-hemolytic Streptococcus – Clindamycin; Pneumococcus spp. – Penicillin. Please refer to eTable 1 for additional details on resistance definitions.

Figure 4 A-D:. Adjusted Odds Ratio of Mortality associated with Discordant and Delayed Empiric Antibiotic Therapy:

Primary, subset and sensitivity analyses. Estimates are represented by squares and 95% confidence intervals are represented by vertical bars. Sub-figure A displays results from overall and taxon-specific logistic regression models evaluating the odds ratio of mortality associated with discordant empiric antibiotic therapy adjusted for patient, pathogen and center-level characteristics. Sub-figure B examines the relationship between aOR for mortality associated with discordant empiric antibiotic therapy across sepsis strata and antibiotic resistant phenotypes. Sub-figure C examines sensitivity analyses without incorporating imputed susceptibilities and where concordant or discordant empiric antibiotic therapy were adjudicated based on empiric therapy in a window that included culture day or the next. Sub-figure D examines sensitivity analysis of the aOR of mortality associated with delayed therapy (i.e., where empiric therapy was initiated on the day after culture sampling day) while controlling for concordance of therapy.