Examining the clinical impact of rapid multiplex polymerase chain reaction-based diagnostic testing for bloodstream infections in a national cohort of the Veterans Health Administration.

STUDY OBJECTIVE: Bloodstream infections (BSIs) are a significant cause of mortality. Use of a rapid multiplex polymerase chain reaction-based blood culture identification panel (BCID) may improve antimicrobial utilization and clinical outcomes by shortening the time to appropriate therapy and de-escalating antibiotics among patients on overly broad-spectrum empiric therapy. The effect of BCID on clinical outcomes across varying institutional antimicrobial stewardship program (ASP) practices is unclear. This study evaluated clinical outcomes associated with the "real-world" implementation of BCID in a national health system with varying ASP practices. DESIGN: National, multicenter, retrospective, pre-post quasi-experimental study of hospitalized patients admitted from 2015 to 2020 to VHA facilities, which introduced the BCID for ≥1 year. SETTING: United States Veterans Health Administration (VHA) hospitals with BCID. PATIENTS: Hospitalized VHA patients with ≥1 blood culture positive for bacteria featured on the BCID panel. INTERVENTION: Comparison of outcomes between the pre- and post-BCID implementation groups. MEASUREMENTS: Outcomes evaluated included early antimicrobial de-escalation within 48 h, defined as reduction in antimicrobial spectrum scores, time to appropriate therapy, and 30-day mortality. MAIN RESULTS: A total of 4138 patients (pre-BCID, n = 2100; post-BCID, n = 2038) met the study criteria. Implementation of BCID was associated with significant improvements in early antimicrobial de-escalation (34.6%: pre-BCID vs. 38.1%: post-BCID; p = 0.022), which persisted after adjusting for other covariates (adjusted risk ratio [aRR], 1.11; 95% confidence interval [CI], 1.02-1.20; p = 0.011). Median time to appropriate therapy was shorter in the post-BCID implementation group relative to the pre-BCID group (9 h: pre-BCID vs. 8 h: post-BCID, respectively, p = 0.005), and a greater percentage of patients received early appropriate antimicrobial therapy within 48 h in the post-BCID implementation group (91.7%: pre-BCID vs. 93.8%: post-BCID; p = 0.008). In the multivariable regression analysis, BCID implementation was significantly associated with a higher likelihood of appropriate therapy within 48 h (aRR, 1.02; 95% CI, 1.01-1.08; p = 0.020). There was no difference in 30-day mortality between groups overall (12.6% pre-BCID vs. 11.2% post-BCID; p = 0.211). CONCLUSIONS: In a "real-world" clinical setting, the implementation of BCID was associated with clinical improvements in antimicrobial utilization. The BCID platform may serve as a useful adjunct for BSI management in facilities with ASP.

Impact of Implementation of the Core Elements of Outpatient Antibiotic Stewardship Within Veterans Health Administration Emergency Departments and Primary Care Clinics on Antibiotic Prescribing and Patient Outcomes.

BACKGROUND: The Core Elements of Outpatient Antibiotic Stewardship provide a framework to improve antibiotic use. We report the impact of core elements implementation within Veterans Health Administration sites. METHODS: In this quasiexperimental controlled study, effects of an intervention targeting antibiotic prescription for uncomplicated acute respiratory tract infections (ARIs) were assessed. Outcomes included per-visit antibiotic prescribing, treatment appropriateness, ARI revisits, hospitalization, and ARI diagnostic changes over a 3-year pre-implementation period and 1-year post-implementation period. Logistic regression adjusted for covariates (odds ratio [OR], 95% confidence interval [CI]) and a difference-in-differences analysis compared outcomes between intervention and control sites. RESULTS: From 2014-2019, there were 16 712 and 51 275 patient visits within 10 intervention and 40 control sites, respectively. Antibiotic prescribing rates pre- and post-implementation within intervention sites were 59.7% and 41.5%, compared to 73.5% and 67.2% within control sites, respectively (difference-in-differences, P < .001). Intervention site pre- and post-implementation OR to receive appropriate therapy increased (OR, 1.67; 95% CI, 1.31-2.14), which remained unchanged within control sites (OR,1.04; 95% CI, .91-1.19). ARI-related return visits post-implementation (-1.3% vs -2.0%; difference-in-differences P = .76) were not different, but all-cause hospitalization was lower within intervention sites (-0.5% vs -0.2%; difference-in-differences P = .02). The OR to diagnose non-specific ARI compared with non-ARI diagnoses increased post-implementation forintervention (OR, 1.27; 95% CI, 1.21 -1.34) but not control (OR, 0.97; 95% CI, .94-1.01) sites. CONCLUSIONS: Implementation of the core elements was associated with reduced antibiotic prescribing for RIs and a reduction in hospitalizations. Diagnostic coding changes were observed.

Effect of Continuous and Sequential Therapy among Veterans Receiving Daptomycin or Linezolid for Vancomycin-Resistant Enterococcus faecium Bacteremia.

Vancomycin-resistant Enterococcus faecium bloodstream infections (VREF-BSI) cause significant mortality, highlighting the need to optimize their treatment. We compared the effectiveness and safety of daptomycin (DAP) and linezolid (LZD) as continuous or sequential therapy for VREF-BSI in a national, retrospective, propensity score (PS)-matched cohort study of hospitalized Veterans Affairs patients (2004 to 2014). We compared clinical outcomes and adverse events among patients treated with continuous LZD, continuous DAP, or sequential LZD followed by DAP (LZD-to-DAP). Secondarily, we analyzed the impact of infectious diseases (ID) consultation and source of VREF-BSI. A total of 2,630 patients were included in the effectiveness analysis (LZD [n = 1,348], DAP [n = 1,055], LZD-to-DAP [n = 227]). LZD was associated with increased 30-day mortality versus DAP (risk ratio [RR], 1.11; 95% confidence interval [CI], 1.01 to 1.22; P = 0.042). After PS matching, this relationship persisted (RR, 1.13; 95% CI, 1.02 to 1.26; P = 0.015). LZD-to-DAP switchers had lower mortality than those remaining on LZD (RR, 1.29; 95% CI, 1.03 to 1.63; P = 0.021), suggesting a benefit may still be derived with sequential therapy. LZD-treated patients experienced more adverse events, including a ≥50% reduction in platelets (RR, 1.07; 95% CI, 1.03 to 1.11; P = 0.001). DAP was associated with lower mortality than was LZD in patients with endocarditis (RR, 1.20; 95% CI, 1.02 to 1.41; P = 0.024); however, there was no statistically significant association between treatment group and mortality with regard to other sources of infection. Therefore, source of infection appears to be important in selection of patients most likely to benefit from DAP over LZD.

Comparative Effectiveness and Safety of Standard-, Medium-, and High-Dose Daptomycin Strategies for the Treatment of Vancomycin-Resistant Enterococcal Bacteremia Among Veterans Affairs Patients.

Background: Vancomycin-resistant Enterococcus bloodstream infections (VRE-BSIs) are associated with significant mortality. Daptomycin exhibits concentration-dependent activity vs VRE in vitro, yet the clinical impact of higher-dose strategies remains unclear. Methods: We performed a national retrospective cohort study of hospitalized Veterans Affairs patients treated with standard-dose (6 mg/kg total body weight), medium-dose (8 mg/kg total body weight), or high-dose (≥10 mg/kg total body weight) daptomycin for VRE-BSI. Patient-related, microbiological, and outcomes data were abstracted from clinical databases. The primary outcome was overall survival, evaluated by Cox regression. Secondary outcomes included 30-day mortality, time to microbiological clearance, and creatine phosphokinase (CPK) elevation. Results: A total of 911 patients were included (standard dose, n = 709; medium dose, n = 142; high dose, n = 60). Compared to high-dose daptomycin, both standard-dose (hazard ratio [HR], 2.68; 95% confidence interval; [CI], 1.33-3.06; P = .002) and medium-dose (HR, 2.66; 95% CI, 1.33-3.92; P = .003) daptomycin were associated with poorer survival. After adjusting for confounders, the relationship between poorer survival and standard-dose (adjusted HR [aHR], 2.58; 95% CI, 1.27-4.88; P = .004) and medium-dose (aHR, 2.52; 95% CI, 1.27-5.00; P = .008) daptomycin persisted. Thirty-day mortality was significantly lower among high-dose daptomycin-treated patients compared with other dosing strategies (risk ratio, 0.83; 95% CI, .74-.94; P = .015). Compared with standard-dose daptomycin, both medium-dose (HR, 0.78; 95% CI, .55-.90; P = .012) and high-dose daptomycin (HR, 0.70; 95% CI, .41-.84; P = .006) were associated with significantly improved microbiological clearance. No difference in the risk of CPK elevation was observed between the treatment groups (P = .504). Conclusions: High-dose daptomycin was associated with improved survival and microbiological clearance in VRE-BSI.

Clinical epidemiology of vancomycin-resistant Enterococcus gallinarum and Enterococcus casseliflavus bloodstream infections.

This study aimed to evaluate the clinical outcomes of vancomycin-resistant enterococcal bloodstream infections (VRE BSI) caused by Enterococcus gallinarum or Enterococcus casseliflavus. Variables associated with treatment failure were determined and treatment options were compared. This was a national retrospective study of hospitalised Veterans Affairs patients with non-faecium, non-faecalis VRE BSI. The primary outcome was treatment failure, defined as a composite of: (i) 30-day all-cause mortality; (ii) microbiological failure; and (iii) 30-day VRE BSI recurrence. Stepwise Poisson regression was conducted to determine variables associated with treatment failure. In total, 48 patients were included, with 29 cases (60.4%) caused by E. gallinarum and 19 cases (39.6%) caused by E. casseliflavus. Among these cases, 20 (41.7%) were treated with an anti-VRE agent (linezolid or daptomycin) and 28 (58.3%) were treated with an anti-enterococcal ß-lactam. Overall, 30-day mortality was 10.4% (5/48) and composite treatment failure was 39.6% (19/48). In multivariate analysis, treatment with an anti-enterococcal ß-lactam was associated with increased treatment failure in comparison with anti-VRE therapy (adjusted risk ratio = 1.73, 95% confidence interval 1.06-4.97; P = 0.031). Overall, treatment with linezolid or daptomycin for vancomycin-resistant E. gallinarum or E. casseliflavus BSI resulted in improved clinical outcomes in comparison with anti-enterococcal ß-lactam treatment.

Comparison of the Effectiveness and Safety of Linezolid and Daptomycin in Vancomycin-Resistant Enterococcal Bloodstream Infection: A National Cohort Study of Veterans Affairs Patients.

BACKGROUND: Vancomycin-resistant Enterococcus bloodstream infections (VRE-BSIs) are becoming increasingly common. Linezolid and daptomycin are the primary treatment options for VRE-BSI, but optimal treatment is unclear. METHODS: This was a national retrospective cohort study comparing linezolid and daptomycin for the treatment of VRE-BSI among Veterans Affairs Medical Center patients admitted during 2004-2013. The primary outcome was treatment failure, defined as a composite of (1) 30-day all-cause mortality; (2) microbiologic failure; and (3) 60-day VRE-BSI recurrence. Poisson regression was conducted to determine if antimicrobial treatment was independently associated with clinical outcomes. RESULTS: A total of 644 patients were included (linezolid, n = 319; daptomycin, n = 325). Overall, treatment failure was 60.9% (n = 392/644), and 30-day all-cause mortality was 38.2% (n = 246/644). Linezolid was associated with a significantly higher risk of treatment failure compared with daptomycin (risk ratio [RR], 1.37; 95% confidence interval [CI], 1.13-1.67; P = .001). After adjusting for confounding factors in Poisson regression, the relationship between linezolid use and treatment failure persisted (adjusted RR, 1.15; 95% CI, 1.02-1.30; P = .026). Linezolid was also associated with higher 30-day mortality (42.9% vs 33.5%; RR, 1.17; 95% CI, 1.04-1.32; P = .014) and microbiologic failure rates (RR, 1.10; 95% CI, 1.02-1.18; P = .011). No difference in 60-day VRE-BSI recurrence was observed between treatment groups. CONCLUSIONS: Treatment with linezolid for VRE-BSI resulted in significantly higher treatment failure in comparison to daptomycin. Linezolid treatment was also associated with greater 30-day all-cause mortality and microbiologic failure in this cohort.

Tigecycline for the Treatment of Severe and Severe Complicated Clostridium difficile Infection.

INTRODUCTION: Clostridium difficile infection (CDI) is a common cause of nosocomial diarrhea. Metronidazole and vancomycin are the primary treatment options for CDI, but increasing rates of antimicrobial resistance and severe, refractory disease have prompted the need for alternative agents. Tigecycline has previously demonstrated favorable in vitro activity against C. difficile isolates, but clinical data on its use in the treatment of CDI are severely lacking. The objective of this study was to describe our experience using tigecycline in the treatment of severe and severe complicated CDI. METHODS: This was a retrospective case series of hospitalized patients with severe and severe complicated CDI who were treated with tigecycline. Disease severity assessments were determined according to current practice guidelines. Diagnosis of toxigenic CDI was confirmed by polymerase chain reaction and patients were excluded if they received tigecycline for <48 h. Data were collected by review of the electronic medical record. The primary outcome was clinical cure. Secondary outcomes were sustained response, hospital mortality, and 28-day all-cause mortality. RESULTS: A total of 7 cases of severe and complicated CDI were reviewed. Intravenous tigecycline administered as a 100-mg loading dose followed by 50 mg twice daily resulted in clinical cure in 85.7% (n = 6/7) of cases. The majority of patients (n = 4/5) were treated with the novel triple therapy combination of tigecycline, vancomycin, and metronidazole and resulted in clinical cure in 80% (n = 4/5) cases. Sustained response at 28 days was 100% among evaluable cases (n = 5/5). Hospital mortality did not occur in any patients, and 28-day all-cause mortality was 28.6% (n = 2/7). CONCLUSION: Tigecycline appears to be a reasonable addition to the therapeutic regimen in the treatment of severe or complicated CDI, including cases that are refractory to standard therapy. A prospective clinical trial confirming these observational findings is warranted.