Attributable mortality of vancomycin resistance in ampicillin-resistant Enterococcus faecium bacteremia in Denmark and the Netherlands: A matched cohort study.

OBJECTIVE: To study whether replacement of nosocomial ampicillin-resistant Enterococcus faecium (ARE) clones by vancomycin-resistant E. faecium (VRE), belonging to the same genetic lineages, increases mortality in patients with E. faecium bacteremia, and to evaluate whether any such increase is mediated by a delay in appropriate antibiotic therapy. DESIGN: Retrospective, matched-cohort study. SETTING: The study included 20 Dutch and Danish hospitals from 2009 to 2014. PATIENTS: Within the study period, 63 patients with VRE bacteremia (36 Dutch and 27 Danish) were identified and subsequently matched to 234 patients with ARE bacteremia (130 Dutch and 104 Danish) for hospital, ward, length of hospital stay prior to bacteremia, and age. For all patients, 30-day mortality after bacteremia onset was assessed. METHODS: The risk ratio (RR) reflecting the impact of vancomycin resistance on 30-day mortality was estimated using Cox regression with further analytic control for confounding factors. RESULTS: The 30-day mortality rates were 27% and 38% for ARE in the Netherlands and Denmark, respectively, and the 30-day mortality rates were 33% and 48% for VRE in these respective countries. The adjusted RR for 30-day mortality for VRE was 1.54 (95% confidence interval, 1.06-2.25). Although appropriate antibiotic therapy was initiated later for VRE than for ARE bacteremia, further analysis did not reveal mediation of the increased mortality risk. CONCLUSIONS: Compared to ARE bacteremia, VRE bacteremia was associated with higher 30-day mortality. One explanation for this association would be increased virulence of VRE, although both phenotypes belong to the same well-characterized core genomic lineage. Alternatively, it may be the result of unmeasured confounding.

An International Prospective Cohort Study To Validate 2 Prediction Rules for Infections Caused by Third-generation Cephalosporin-resistant Enterobacterales.

BACKGROUND: The possibility of bloodstream infections caused by third-generation cephalosporin-resistant Enterobacterales (3GC-R-BSI) leads to a trade-off between empiric inappropriate treatment (IAT) and unnecessary carbapenem use (UCU). Accurately predicting 3GC-R-BSI could reduce IAT and UCU. We externally validate 2 previously derived prediction rules for community-onset (CO) and hospital-onset (HO) suspected bloodstream infections. METHODS: In 33 hospitals in 13 countries we prospectively enrolled 200 patients per hospital in whom blood cultures were obtained and intravenous antibiotics with coverage for Enterobacterales were empirically started. Cases were defined as 3GC-R-BSI or 3GC-R gram-negative infection (3GC-R-GNI) (analysis 2); all other outcomes served as a comparator. Model discrimination and calibration were assessed. Impact on carbapenem use was assessed at several cutoff points. RESULTS: 4650 CO infection episodes were included and the prevalence of 3GC-R-BSI was 2.1% (n = 97). IAT occurred in 69 of 97 (71.1%) 3GC-R-BSI and UCU in 398 of 4553 non-3GC-R-BSI patients (8.7%). Model calibration was good, and the AUC was .79 (95% CI, .75-.83) for 3GC-R-BSI. The prediction rule potentially reduced IAT to 62% (60/97) while keeping UCU comparable at 8.4% or could reduce UCU to 6.3% (287/4553) while keeping IAT equal. IAT and UCU in all 3GC-R-GNIs (analysis 2) improved at similar percentages. 1683 HO infection episodes were included and the prevalence of 3GC-R-BSI was 4.9% (n = 83). Here model calibration was insufficient. CONCLUSIONS: A prediction rule for CO 3GC-R infection was validated in an international cohort and could improve empirical antibiotic use. Validation of the HO rule yielded suboptimal performance.

The burden of bacteremic and non-bacteremic Gram-negative infections: A prospective multicenter cohort study in a low-resistance country.

Objectives There is a global increase in infections caused by Gram-negative bacteria. The majority of research is on bacteremic Gram-negative infections (GNI), leaving a knowledge gap on the burden of non-bacteremic GNI. Our aim is to describe characteristics and determine the burden of bacteremic and non-bacteremic GNI in hospitalized patients in the Netherlands. Methods We conducted a prospective cohort study of patients in eight hospitals with microbiologically confirmed GNI, between June 2013 and November 2015. In each hospital the first five adults meeting the eligibility criteria per week were enrolled. We estimated the national incidence and mortality of GNI by combining the cohort data with a national surveillance database for antimicrobial resistance. Results 1,954 patients with GNI were included of which 758 (39%) were bloodstream infections (BSI). 243 GNI (12%) involved multi-drug resistant pathogens. 30-day mortality rate was 11.1% (n = 217) Estimated national incidences of non-bacteremic GNI and bacteremic GNI in hospitalized adults were 74 (95% CI 58 - 89) and 86 (95% CI 72-100) per 100,000 person years, yielding estimated annual numbers of 30-day all-cause mortality deaths of 1,528 (95% CI 1,102-1,954) for bacteremic and 982 (95% CI 688 - 1,276) for non-bacteremic GNI. Conclusion GNI form a large mortality burden in a low-resistance country. A third of the associated mortality occurs after non-bacteremic GNI.

Attributable mortality of antibiotic resistance in gram-negative infections in the Netherlands: a parallel matched cohort study.

OBJECTIVES: Antibiotic resistance in Gram-negative bacteria has been associated with increased mortality. This was demonstrated mostly for third-generation cephalosporin-resistant (3GC-R) Enterobacterales bacteraemia in international studies. Yet, the burden of resistance specifically in the Netherlands and created by all types of Gram-negative infection has not been quantified. We therefore investigated the attributable mortality of antibiotic resistance in Gram-negative infections in the Netherlands. METHODS: In eight hospitals, a sample of Gram-negative infections was identified between 2013 and 2016, and separated into resistant and susceptible infection cohorts. Both cohorts were matched 1:1 to non-infected control patients on hospital, length of stay at infection onset, and age. In this parallel matched cohort set-up, 30-day mortality was compared between infected and non-infected patients. The impact of resistance was then assessed by dividing the two separate risk ratios (RRs) for mortality attributable to Gram-negative infection. RESULTS: We identified 1954 Gram-negative infections, of which 1190 (61%) involved Escherichia coli, 210 (11%) Pseudomonas aeruginosa, and 758 (39%) bacteraemia. Resistant Gram-negatives caused 243 infections (12%; 189 (78%) 3GC-R Enterobacterales, nine (4%) multidrug-resistant P. aeruginosa, no carbapenemase-producing Enterobacterales). Subsequently, we matched 1941 non-infected controls. After adjustment, point estimates for RRs comparing mortality between infections and controls were similarly higher than 1 in case of resistant infections and susceptible infections (1.42 (95% confidence interval 0.66-3.09) and 1.32 (1.06-1.65), respectively). By dividing these, the RR reflecting attributable mortality of resistance was calculated as 1.08 (0.48-2.41). CONCLUSIONS: In the Netherlands, antibiotic resistance did not increase 30-day mortality in Gram-negative infections.

Predictive value of prior colonization and antibiotic use for third-generation cephalosporin-resistant enterobacteriaceae bacteremia in patients with sepsis.

BACKGROUND: To prevent inappropriate empiric antibiotic treatment in patients with bacteremia caused by third-generation cephalosporin (3GC)-resistant Enterobacteriaceae (3GC-R EB), Dutch guidelines recommend ß-lactam and aminoglycoside combination therapy or carbapenem monotherapy in patients with prior 3GC-R EB colonization and/or recent cephalosporin or fluoroquinolone usage. Positive predictive values (PPVs) of these determinants are unknown. METHODS: We retrospectively studied patients with a clinical infection in whom blood cultures were obtained and empiric therapy with broad-spectrum ß-lactams and/or aminoglycosides and/or fluoroquinolones was started. We determined the PPVs of prior colonization and antibiotic use for 3GC-R EB bacteremia, and the consequences of guideline adherence on appropriateness of empiric treatment. RESULTS: Of 9422 episodes, 773 (8.2%) were EB bacteremias and 64 (0.7%) were caused by 3GC-R EB. For bacteremia caused by 3GC-R EB, PPVs of prior colonization with 3GC-R EB (90-day window) and prior usage of cephalosporins or fluoroquinolones (30-day window) were 7.4% and 1.3%, respectively, and PPV was 1.8% for the presence of any of these predictors. Adherence to Dutch sepsis guideline recommendations was 27%. Of bacteremia episodes caused by 3GC-R and 3GC-sensitive EB, 56% and 94%, respectively, were initially treated with appropriate antibiotics. Full adherence to guideline recommendations would hardly augment proportions of appropriate therapy, but could considerably increase carbapenem use. CONCLUSIONS: In patients receiving empiric treatment for sepsis, prior colonization with 3GC-R EB and prior antibiotic use have low PPV for infections caused by 3GC-R EB. Strict guideline adherence would unnecessarily stimulate broad-spectrum antibiotic use.

Improved treatment of multidrug-resistant bacterial infections: utility of clinical studies.

In a time of increasing antibacterial resistance and limited availability of new antibiotics, clinical studies are much needed to assess treatment options against multidrug-resistant organisms (MDROs). In this review, we describe the clinical challenge caused by MDROs and present recent evidence on how clinical studies may generate quality data to improve antibiotic treatment of MDRO infections. To this aim, we critically assess the current status, gaps and challenges associated with observational and interventional studies performed to assess MDRO treatment options. We address why observational studies are useful, which treatment options for MDRO have been explored by observational studies and how to improve quality and usefulness of observational studies. Furthermore, the utility of clinical pharmacokinetic/pharmacodynamic studies for improving MDRO treatment is described. Finally, we discuss interventional study designs, end points and margins, as well as ethical, logistic and statistical challenges, and current regulatory changes proposed to foster the development of new antibiotics.

Appropriateness of empirical treatment and outcome in bacteremia caused by extended-spectrum-ß-lactamase-producing bacteria.

We studied clinical characteristics, appropriateness of initial antibiotic treatment, and other factors associated with day 30 mortality in patients with bacteremia caused by extended-spectrum-ß-lactamase (ESBL)-producing bacteria in eight Dutch hospitals. Retrospectively, information was collected from 232 consecutive patients with ESBL bacteremia (due to Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae) between 2008 and 2010. In this cohort (median age of 65 years; 24 patients were <18 years of age), many had comorbidities, such as malignancy (34%) or recurrent urinary tract infection (UTI) (15%). One hundred forty episodes (60%) were nosocomial, 54 (23%) were otherwise health care associated, and 38 (16%) were community acquired. The most frequent sources of infection were UTI (42%) and intra-abdominal infection (28%). Appropriate therapy within 24 h after bacteremia onset was prescribed to 37% of all patients and to 54% of known ESBL carriers. The day 30 mortality rate was 20%. In a multivariable analysis, a Charlson comorbidity index of ≥ 3, an age of ≥ 75 years, intensive care unit (ICU) stay at bacteremia onset, a non-UTI bacteremia source, and presentation with severe sepsis, but not inappropriate therapy within <24 h (adjusted odds ratio [OR], 1.53; 95% confidence interval [CI], 0.68 to 3.45), were associated with day 30 mortality. Further assessment of confounding and a stratified analysis for patients with UTI and non-UTI origins of infection did not reveal a statistically significant effect of inappropriate therapy on day 30 mortality, and these results were insensitive to the possible misclassification of patients who had received ß-lactam-ß-lactamase inhibitor combinations or ceftazidime as initial treatment. In conclusion, ESBL bacteremia occurs mostly in patients with comorbidities requiring frequent hospitalization, and 84% of episodes were health care associated. Factors other than inappropriate therapy within <24 h determined day 30 mortality.

Effects of confounders and intermediates on the association of bacteraemia caused by extended-spectrum ß-lactamase-producing Enterobacteriaceae and patient outcome: a meta-analysis.

BACKGROUND AND OBJECTIVES: Bacteraemia caused by Enterobacteriaceae (EB) producing extended-spectrum ß-lactamase (ESBL+) has been associated with higher mortality compared with non-ESBL-producing (ESBL-) EB bacteraemia in observational studies. We conducted a systematic review and meta-analysis of these studies to assess how adjusting for confounding in multivariate analyses affects the pooled estimate, and whether multivariate analyses that include intermediates in the causal pathway of outcome (sepsis severity and inadequate empirical therapy) have lower estimates of attributable mortality. DATA SOURCES: PubMed search on 23 November 2010 followed by manually searching reference lists of included studies. STUDY ELIGIBILITY CRITERIA: Cohort studies published in English with separate mortality rates for ESBL+ and ESBL- EB bacteraemia. SYNTHESIS METHODS: Random-effects pooling of unadjusted and adjusted ORs followed by subgroup analyses to explore effects of adjustment procedures on adjusted ORs. RESULTS: The pooled OR for the unadjusted mortality associated with ESBL production was 2.35 (95% CI 1.90-2.91, I(2) = 42%, 32 studies). The pooled adjusted OR was 1.52 (95% CI 1.15-2.01, I(2) = 32%, 15 studies). Adjustment for more intermediates was associated with decreasing ORs. The pooled OR for the analyses adjusting for inadequate empirical therapy was 1.37 (95% CI 1.04-1.82). CONCLUSIONS: ESBL production in EB bacteraemia is associated with a higher mortality compared with bacteraemia with ESBL- EB, although the estimate of this association is affected by adjustment procedures. Adjustment for inadequate empirical therapy leads to a reduction in ORs, indicating that higher mortality is likely to be mediated through this phenomenon.