Pilar Retamar

β-Lactam/β-Lactam Inhibitor Combinations for the Treatment of Bacteremia Due to Extended-Spectrum β-Lactamase–Producing Escherichia coli: A Post Hoc Analysis of Prospective Cohorts

BACKGROUND Extended-spectrum ß-lactamase-producing Escherichia coli (ESBL-EC) is an important cause of invasive infections. Alternatives to carbapenems--considered the drugs of choice--are needed because of the emergence of carbapenemase-producing enterobacteria. The efficacy of ß-lactam/ß-lactam inhibitors (BLBLI) in such infections is controversial. METHODS The authors performed a post hoc analysis of patients with bloodstream infections due to ESBL-EC from 6 published prospective cohorts. Mortality and length of hospital stay in patients treated with an active BLBLI (amoxicillin-clavulanic acid [AMC] and piperacillin-tazobactam [PTZ]) or carbapenem were compared in 2 cohorts: the empirical therapy cohort (ETC) and the definitive therapy cohort (DTC). Confounding was controlled by multivariate analysis; for patients in the ETC, a propensity score for receiving carbapenem was also used. RESULTS The ETC included 103 patients (BLBLI, 72; carbapenem, 31), and the DTC included 174 (BLBLI, 54; carbapenem, 120). Mortality rates at day 30 for those treated with BLBLI versus carbapenems were 9.7% versus 19.4% for the ETC and 9.3% versus 16.7% for the DTC, respectively (P > .2, log-rank test). After adjustment for confounders, no association was found between either empirical therapy with BLBLI (adjusted hazard ratio [HR], 1.14; 95% confidence interval [CI], .29-4.40; P = .84) or definitive therapy (adjusted HR, 0.76; 95% CI, .28-2.07; P = .5) and increased mortality. Furthermore, BLBLI therapy, with respect to carbapenem, was not found to influence length of hospital stay. CONCLUSIONS These results suggest that AMC and PTZ are suitable alternatives to carbapenems for treating patients with bloodstream infections due to ESBL-EC if active in vitro and would be particularly useful as definitive therapy.

Impact of Inadequate Empirical Therapy on the Mortality of Patients with Bloodstream Infections: a Propensity Score-Based Analysis

ABSTRACT The impact of the adequacy of empirical therapy on outcome for patients with bloodstream infections (BSI) is key for determining whether adequate empirical coverage should be prioritized over other, more conservative approaches. Recent systematic reviews outlined the need for new studies in the field, using improved methodologies. We assessed the impact of inadequate empirical treatment on the mortality of patients with BSI in the present-day context, incorporating recent methodological recommendations. A prospective multicenter cohort including all BSI episodes in adult patients was performed in 15 hospitals in Andalucía, Spain, over a 2-month period in 2006 to 2007. The main outcome variables were 14- and 30-day mortality. Adjusted analyses were performed by multivariate analysis and propensity score-based matching. Eight hundred one episodes were included. Inadequate empirical therapy was administered in 199 (24.8%) episodes; mortality at days 14 and 30 was 18.55% and 22.6%, respectively. After controlling for age, Charlson index, Pitt score, neutropenia, source, etiology, and presentation with severe sepsis or shock, inadequate empirical treatment was associated with increased mortality at days 14 and 30 (odds ratios [ORs], 2.12 and 1.56; 95% confidence intervals [95% CI], 1.34 to 3.34 and 1.01 to 2.40, respectively). The adjusted ORs after a propensity score-based matched analysis were 3.03 and 1.70 (95% CI, 1.60 to 5.74 and 0.98 to 2.98, respectively). In conclusion, inadequate empirical therapy is independently associated with increased mortality in patients with BSI. Programs to improve the quality of empirical therapy in patients with suspicion of BSI and optimization of definitive therapy should be implemented.

Impact of the MIC of Piperacillin-Tazobactam on the Outcome of Patients with Bacteremia Due to Extended-Spectrum-β-Lactamase-Producing Escherichia coli

ABSTRACT We investigated the impact of the piperacillin-tazobactam MIC in the outcome of 39 bloodstream infections due to extended-spectrum-β-lactamase-producing Escherichia coli. All 11 patients with urinary tract infections survived, irrespective of the MIC. For other sources, 30-day mortality was lower for isolates with a MIC of ≤2 mg/liter than for isolates with a higher MIC (0% versus 41.1%; P = 0.02).

Diagnosis and antimicrobial treatment of invasive infections due to multidrug-resistant Enterobacteriaceae. Guidelines of the Spanish Society of Infectious Diseases and Clinical Microbiology

The spread of multidrug-resistant Enterobacteriaceae related to the production of extended-spectrum β-lactamases and carbapenemases is a serious public health problem worldwide. Microbiological diagnosis and therapy of these infections are challenging and controversial. Clinically relevant questions were selected and the literature was reviewed for each of them. The information from the selected articles was extracted and recommendations were provided and graded according to the strength of the recommendations and quality of the evidence. The document was opened to comments from the members from the Spanish Society of Infectious Diseases and Clinical Microbiology, which were considered for inclusion in the final version. Evidence-based recommendations are provided for the use of microbiological techniques for the detection of extended-spectrum β-lactamases and carbapenemases in Enterobacteriaceae, and for antibiotic therapy for invasive/severe infections caused by these organisms. The absence of randomised controlled trials is noteworthy; thus, recommendations are mainly based on observational studies (that have important methodological limitations), pharmacokinetic and pharmacodynamics models, and data from animal studies. Additionally, areas for future research were identified.

Current management of bloodstream infections.

Bloodstream infection (BSI) is a frequent complication of invasive infections. The presence of bacteremia has therapeutic and prognostic implications. Here we review recent changes in the epidemiology, diagnosis and treatment of BSI (excluding candidemia). The evidence of the impact of healthcare-association in many community-onset episodes and the increase in drug-resistant pathogens causing BSI in the community and hospitals is reviewed. The emergence of molecular methods as an alternative tool for the diagnosis of BSI and novel aspects of clinical management, particularly of some multidrug-resistant organisms. Several quality indicators related to the diagnosis and management of bacteremia in hospitals are proposed.

Predictors of early mortality in very elderly patients with bacteremia: a prospective multicenter cohort

OBJECTIVES The proportion of very elderly people in the population is increasing, and infectious diseases in this patient group may present with specific characteristics. The objective of this study was to investigate the outcome predictors of bacteremia among the very elderly. METHODS This was a multicenter prospective cohort study of bloodstream infections (BSI) in patients ≥ 80 years old in 15 hospitals in Spain. The outcome variables were 14-day and 30-day mortality. Multivariate analysis was performed. RESULTS One hundred and twenty episodes were included. Mortality was 22% (n = 26) on day 14 and 28% (n = 34) on day 30. In the univariate analysis, the variables associated with mortality were neutropenia, recent surgery, Pitt score ≥ 2, intensive care unit (ICU) admission, severe sepsis or shock, and abdominal, unknown, and respiratory tract sources. In the multivariate analysis, variables associated with mortality on day 14 were high-risk source (abdominal, unknown, and respiratory tract sources; odds ratio (OR) 7.9, 95% confidence interval (CI) 1.8-33.9), Pitt score ≥ 2 (OR 5.6, 95% CI 1.3-23.3), inadequate empirical treatment (OR 11.24, 95% CI 1.6-80.2), and severe sepsis or shock at presentation (OR 5.3, 95% CI 1.4-20.7); the interaction between empiric treatment and high-risk source was significant. On day 30, mortality was independently related to a high-risk source (OR 2.92, 95% CI 1.1-7.5) and presentation with severe sepsis or shock (OR 3.81, 95% CI 1.2-12.4). CONCLUSIONS Presentation with severe sepsis or shock and a high-risk source of BSI were independent predictors of 14-day and 30-day mortality. Inadequate empirical treatment was also a predictor of early mortality in patients with a high-risk source.

Is reduced vancomycin susceptibility a factor associated with poor prognosis in MSSA bacteraemia

OBJECTIVES The known data about the influence of vancomycin MIC on Staphylococcus aureus bacteraemia are contradictory. Our objective was to study the possible impact of vancomycin MIC ≥1.5 mg/L on short- and medium-term mortality. METHODS A prospective cohort study was carried out from March 2008 to January 2011 on adult patients with MSSA bacteraemia admitted to a tertiary hospital located in Seville (Spain). We studied the relationship between vancomycin MIC, accessory gene regulator (agr) type and absence of δ-haemolysin and poor prognosis. All isolates were genotyped by PFGE. Multivariate analysis, including a propensity score for having a vancomycin MIC of ≥1.5 mg/L, was performed by Cox regression. RESULTS One hundred and thirty-five episodes of bacteraemia due to MSSA were included in the analysis. Twenty-nine (21.5%) isolates had a vancomycin MIC of ≥1.5 mg/L by Etest. There were no differences in agr distribution or absence of δ-haemolysin between isolates with reduced vancomycin susceptibility (RVS) and those without. RVS was not more frequent in specific clones; RVS was not associated with higher 14 or 30 day crude mortality (relative risk = 0.44, 95% CI = 0.14-1.35; and relative risk = 1.01, 95% CI = 0.52-1.96) rates, and it did not show higher rates of complicated bacteraemia (14.2% versus 13.8%, P = 0.61). Cox regression analysis did not significantly modify the results for 14 day mortality (HR = 0.39, 95% CI = 0.11-1.34) or 30 day mortality (HR = 0.89, 95% CI = 0.39-2.04). CONCLUSIONS Contrary to previously published data, we did not find a relationship between RVS and higher mortality in patients with MSSA bacteraemia and we did not find a link with higher complicated bacteraemia rates.

Executive summary of the diagnosis and antimicrobial treatment of invasive infections due to multidrug-resistant Enterobacteriaceae. Guidelines of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC)

The spread of multidrug-resistant Enterobacteriaceae related to the production of extended-spectrum β-lactamases (ESBL) and carbapenemases is a serious public health problem worldwide. Microbiological diagnosis and therapy of these infections are challenging and controversial. After the selection of clinically relevant questions, this document provides evidence-based recommendations for the use of microbiological techniques for the detection of ESBL- and carbapenemase-producing Enterobacteriaceae, and for antibiotic therapy for invasive infections caused by these organisms. The absence of randomized-controlled trials is noteworthy, thus recommendations are mainly based on observational studies, that have important methodological limitations, pharmacokinetic and pharmacodynamics models, and data from animal studies. Additionally, areas for future research were identified.

Evaluating the quality of antimicrobial prescribing: is standardisation possible?

The quality of antimicrobial prescribing refers to the optimal way to use antibiotics in regard to their benefits, safety (e.g., resistance generation and toxicity) and cost. Evaluating the quality of antimicrobial prescribing in a way that focuses not only on reducing antimicrobial consumption but also on using them in a more optimal way allows us to understand patterns of use and to identify targets for intervention. The lack of standardisation is the primary problem to be addressed when planning an evaluation of antimicrobial prescribing. There is little information specifically describing an evaluation methodology. Information related to prescription evaluation can be obtained from the guidelines of Antimicrobial Stewardship Programs (ASPs) and from local and international experience. The criteria used to evaluate the quality of prescription should include the indication for antimicrobial therapy, the timeliness of initiation, the correct antibiotic choice (according to local guidelines), the dosing, the duration, the route of administration and the time at which to switch to oral administration. A locally developed guideline on antimicrobial therapy should preferably be the gold standard by which to evaluate the appropriatenes of prescriptions. Various approaches used to carry out the evaluations have been described in the literature. Repeated point-prevalence surveys (PPS) have been proven to be effective in identifying targets for quality improvement. Continuous prospective monitoring allows the identification of more precise intervention points at different times during prescription. The design of the study chosen to perform the evaluation should be adapted according to the resources available in each centre. Evaluating the quality of antimicrobial prescribing should be the first step to designing ASPs, as well as to evaluating their impact and the changes in prescribing trends over time.

Reappraisal of the outcome of healthcare-associated and community-acquired bacteramia: a prospective cohort study

BackgroundHealthcare-associated (HCA) bloodstream infections (BSI) have been associated with worse outcomes, in terms of higher frequencies of antibiotic-resistant microorganisms and inappropriate therapy than strict community-acquired (CA) BSI. Recent changes in the epidemiology of community (CO)-BSI and treatment protocols may have modified this association. The objective of this study was to analyse the etiology, therapy and outcomes for CA and HCA BSI in our area.MethodsA prospective multicentre cohort including all CO-BSI episodes in adult patients was performed over a 3-month period in 2006–2007. Outcome variables were mortality and inappropriate empirical therapy. Adjusted analyses were performed by logistic regression.Results341 episodes of CO-BSI were included in the study. Acquisition was HCA in 56% (192 episodes) of them. Inappropriate empirical therapy was administered in 16.7% (57 episodes). All-cause mortality was 16.4% (56 patients) at day 14 and 20% (71 patients) at day 30. After controlling for age, Charlson index, source, etiology, presentation with severe sepsis or shock and inappropriate empirical treatment, acquisition type was not associated with an increase in 14-day or 30-day mortality. Only an stratified analysis of 14th-day mortality for Gram negatives BSI showed a statically significant difference (7% in CA vs 17% in HCA, p = 0,05). Factors independently related to inadequate empirical treatment in the community were: catheter source, cancer, and previous antimicrobial use; no association with HCA acquisition was found.ConclusionHCA acquisition in our cohort was not a predictor for either inappropriate empirical treatment or increased mortality. These results might reflect recent changes in therapeutic protocols and epidemiological changes in community pathogens. Further studies should focus on recognising CA BSI due to resistant organisms facilitating an early and adequate treatment in patients with CA resistant BSI.