Marlieke de Kraker

Mortality and Hospital Stay Associated with Resistant Staphylococcus aureus and Escherichia coli Bacteremia: Estimating the Burden of Antibiotic Resistance in Europe

The authors calculate excess mortality, excess hospital stay, and related hospital expenditure associated with antibiotic-resistant bacterial bloodstream infections (Staphylococcus aureus and Escherichia coli) in Europe.

Clinical Impact of Antimicrobial Resistance in European Hospitals: Excess Mortality and Length of Hospital Stay Related to Methicillin-Resistant Staphylococcus aureus Bloodstream Infections

ABSTRACT Antimicrobial resistance is threatening the successful management of nosocomial infections worldwide. Despite the therapeutic limitations imposed by methicillin-resistant Staphylococcus aureus (MRSA), its clinical impact is still debated. The objective of this study was to estimate the excess mortality and length of hospital stay (LOS) associated with MRSA bloodstream infections (BSI) in European hospitals. Between July 2007 and June 2008, a multicenter, prospective, parallel matched-cohort study was carried out in 13 tertiary care hospitals in as many European countries. Cohort I consisted of patients with MRSA BSI and cohort II of patients with methicillin-susceptible S. aureus (MSSA) BSI. The patients in both cohorts were matched for LOS prior to the onset of BSI with patients free of the respective BSI. Cohort I consisted of 248 MRSA patients and 453 controls and cohort II of 618 MSSA patients and 1,170 controls. Compared to the controls, MRSA patients had higher 30-day mortality (adjusted odds ratio [aOR] = 4.4) and higher hospital mortality (adjusted hazard ratio [aHR] = 3.5). Their excess LOS was 9.2 days. MSSA patients also had higher 30-day (aOR = 2.4) and hospital (aHR = 3.1) mortality and an excess LOS of 8.6 days. When the outcomes from the two cohorts were compared, an effect attributable to methicillin resistance was found for 30-day mortality (OR = 1.8; P = 0.04), but not for hospital mortality (HR = 1.1; P = 0.63) or LOS (difference = 0.6 days; P = 0.96). Irrespective of methicillin susceptibility, S. aureus BSI has a significant impact on morbidity and mortality. In addition, MRSA BSI leads to a fatal outcome more frequently than MSSA BSI. Infection control efforts in hospitals should aim to contain infections caused by both resistant and susceptible S. aureus.

Will 10 Million People Die a Year due to Antimicrobial Resistance by 2050

Marlieke de Kraker and colleagues reflect on the need for better global estimates for the burden of antimicrobial resistance.

Mortality associated with in-hospital bacteraemia caused by Staphylococcus aureus: a multistate analysis with follow-up beyond hospital discharge

OBJECTIVES The main objective was to study the impact of in-hospital bacteraemia caused by Staphylococcus aureus on mortality within 90 days after admission. We compared methicillin-resistant S. aureus (MRSA) with methicillin-susceptible S. aureus (MSSA). PATIENTS AND METHODS The study population consisted of adult residents of Tayside, Scotland, UK, from 1 January 2005 to 30 September 2006 who had a new admission to Ninewells Hospital between 1 July 2005 and 30 June 2006. All patients (n = 3132) in the same wards as the patients infected with S. aureus were included. We addressed key weaknesses in previous studies by using a cohort design and applying a multistate model, which addressed the temporal dynamics. Critically, the model recognized that death and discharge from the hospital are competing events and that delay in discharge independently increases the risk of death. RESULTS The cohort included 3132 patients, of whom 494 died within 90 days after admission, 34 developed MRSA bacteraemia and 26 MSSA bacteraemia in the hospital. In comparison with patients without S. aureus bacteraemia, the death hazard was 5.6 times greater with MRSA [95% confidence interval (CI) 3.36-9.41] and 2.7 times greater with MSSA bacteraemia (95% CI 1.33-5.39). After adjustment for co-morbidity, hospitalization, age and sex, the death hazard was 2.9 times greater with MRSA (95% CI 1.70-4.88) and 1.7 times greater with MSSA bacteraemia (95% CI 0.84-3.47). CONCLUSIONS Time-dependent models such as the proposed multistate model are necessary to address the temporal dynamics of admission, infection, discharge and death. The impact of S. aureus bacteraemia on mortality should be considered on two levels: the burden of disease, i.e. nosocomial infection with S. aureus bacteraemia, and the burden of resistance to methicillin.

Recommendations for the Empirical Treatment of Complicated Urinary Tract Infections Using Surveillance Data on Antimicrobial Resistance in the Netherlands

Background Complicated urinary tract infections (c-UTIs) are among the most common nosocomial infections and a substantial part of the antimicrobial agents used in hospitals is for the treatment of c-UTIs. Data from surveillance can be used to guide the empirical treatment choices of clinicians when treating c-UTIs. We therefore used nation-wide surveillance data to evaluate antimicrobial coverage of agents for the treatment of c-UTI in the Netherlands. Methods We included the first isolate per patient of urine samples of hospitalised patients collected by the Infectious Disease Surveillance Information System for Antibiotic Resistance (ISIS-AR) in 2012, and determined the probability of inadequate coverage for antimicrobial agents based on species distribution and susceptibility. Analyses were repeated for various patient groups and hospital settings. Results The most prevalent bacteria in 27,922 isolates of 23,357 patients were Escherichia coli (47%), Enterococcus spp. (14%), Proteus mirabilis (8%), and Klebsiella pneumoniae (7%). For all species combined, the probability of inadequate coverage was <5% for amoxicillin or amoxicillin-clavulanic acid combined with gentamicin and the carbapenems. When including gram-negative bacteria only, the probability of inadequate coverage was 4.0%, 2.7%, 2.3% and 1.7%, respectively, for amoxicillin, amoxicillin-clavulanic acid, a second or a third generation cephalosporin in combination with gentamicin, and the carbapenems (0.4%). There were only small variations in results among different patient groups and hospital settings. Conclusions When excluding Enterococcus spp., considered as less virulent, and the carbapenems, considered as last-resort drugs, empirical treatment for c-UTI with the best chance of adequate coverage are one of the studied beta-lactam-gentamicin combinations. This study demonstrates the applicability of routine surveillance data for up-to-date clinical practice guidelines on empirical antimicrobial therapy, essential in patient care given the evolving bacterial susceptibility.

Appropriate endpoints for evaluation of new antibiotic therapies for severe infections: a perspective from COMBACTE’s STAT-Net

PurposeIn this era of rising antimicrobial resistance, slowly refilling antibiotic development pipelines, and an aging population, we need to ensure that randomized clinical trials (RCTs) determine the added benefit of new antibiotic agents effectively and in a valid way, especially for severely ill patients. Unfortunately, universally accepted endpoints for the evaluation of new drugs in severe infections are lacking.MethodsWe review and discuss the current practices and challenges regarding endpoints in RCTs in this field and propose novel approaches.ResultsUsual endpoints actually recommended for drug development suffer from important flaws. Mortality requires large sample size and only partly related to the infectious process. Clinical cure rate is highly subjective in critically ill patients where symptoms may be related to other intercurrent events. Currently, composite endpoints, hierarchical nested designs, and competing risks analysis seem to be the most promising new tools for designing and analyzing clinical trials in this area, although they require further validation.ConclusionRegulatory authorities, pharmaceutical companies, and clinicians need to agree on the most appropriate clinical endpoints for severe infections to ensure efficient approval of new, effective antibiotic agents.

Clinical impact of antimicrobial resistance: design matters.

1did a large retrospective study in intensive care units (ICU) from ten European countries. They concluded that ICU-acquired pneumonia and bloodstream infections substantially increased mortality and ICU stay, while the additional eff ect of antibiotic resistance in this group of patients was relatively modest. We believe that this study design is unlikely to fully capture the public health eff ect of antibiotic resistance for two reasons: fi rst, patients with bacterial infection in ICUs often receive early empirical treatment that typically covers the resistance phenotypes that the authors chose as exposures; and second, the median follow-up was limited to 5 days, and this short follow-up might have concealed the long-term eff ects of treatment failure. The authors included a summary estimate for the eff ect of resistance in their discussion, thereby neglecting the pathogenspecifi c eff ect of antibiotic resistance on mortality. We have reported data for more than 2000 patients with Staphylococcus aureus or Escherichia coli bloodstream infections with follow-up beyond hospital discharge, and pathogen-specifi c estimates showed that resistance increased mortality 30-days after infection by 80–150%. 2,3

Surveillance for control of antimicrobial resistance

Antimicrobial resistance poses a growing threat to public health and the provision of health care. Its surveillance should provide up-to-date and relevant information to monitor the appropriateness of therapy guidelines, antibiotic formulary, antibiotic stewardship programmes, public health interventions, infection control policies, and antimicrobial development. In Europe, although the European Antimicrobial Resistance Surveillance Network provides annual reports on monitored resistant bacteria, national surveillance efforts are still fragmented and heterogeneous, and have substantial structural problems and issues with laboratory data. Most incidence and prevalence data cannot be linked with relevant epidemiological, clinical, or outcome data. Genetic typing, to establish whether trends of antimicrobial resistance are caused by spread of resistant strains or by transfer of resistance determinants among different strains and species, is not routinely done. Furthermore, laboratory-based surveillance using only clinical samples is not likely to be useful as an early warning system for emerging pathogens and resistance mechanisms. Insufficient coordination of surveillance systems of human antimicrobial resistance with animal surveillance systems is even more concerning. Because results from food surveillance are considered commercially sensitive, they are rarely released publicly by regulators. Inaccurate or incomplete surveillance data delay a translational approach to the threat of antimicrobial resistance and inhibit the identification of relevant target microorganisms and populations for research and the revitalisation of dormant drug-discovery programmes. High-quality, comprehensive, and real-time surveillance data are essential to reduce the burden of antimicrobial resistance. Improvement of national antimicrobial resistance surveillance systems and better alignment between human and veterinary surveillance systems in Europe must become a scientific and political priority, coordinated with international stakeholders within a global approach to reduce the burden of antimicrobial resistance.

Methodological Challenges in Evaluating Antimicrobial Stewardship Programs: “Through Measuring to Knowledge”

Abstract The quantification of the impact of antimicrobial stewardship programs (ASPs) is a challenge. Disentangling the true effect from the impact of bias, confounding, and random time effects has proven difficult. In this chapter, we explain about the different sources of confounding and the most common types of biases in this field. This is followed by a discussion of advantages and disadvantages of various common study designs. Finally, the most suitable analytical methods for each study design are described. In general, cluster randomized controlled trials should be considered the golden standard for evaluation of ASPs. If only few clusters are available, controlled interrupted time series should be the design of choice. The statistical method of choice should acknowledge the structure of the data (multilevel analysis), and individual-level data should be preferred over aggregate data analyses. We are optimistic that the quality of future endeavors will benefit from these insights.

EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA): a protocol of a European multicentre observational study

Introduction The rapid worldwide spread of carbapenem-resistant Enterobacteriaceae (CRE) constitutes a major challenge. The aim of the EUropean prospective cohort study on Enterobacteriaceae showing REsistance to CArbapenems (EURECA), which is part of the Innovative Medicines Initiative Joint Undertaking (IMI JU) funded COMBACTE-CARE project, is to investigate risk factors for and outcome determinants of CRE infections to inform randomised clinical trial designs and to provide a historical cohort that could eventually be used for future comparisons with new drugs targeting CRE. Methods A multicentre (50 sites), multinational (11 European countries), analytical observational project was designed, comprising 3 studies. The aims of study 1 (a prospective cohort study) include characterising the features, clinical management and outcomes of hospitalised patients with intra-abdominal infection, pneumonia, complicated urinary tract infections and bloodstream infections caused by CRE (202 patients in each group). The main outcomes will be 30-day all-cause mortality and clinical response. Study 2 (a nested case–control study) will identify the risk factors for target infections caused by CRE; 248 selected patients from study 1 will be matched with patients with carbapenem-susceptible Enterobacteriaceae (1:1) and with hospitalised patients (1:3) and will provide a historical cohort of patients with CRE infections. Study 3 (a matched cohort study) will follow patients in study 2 in order to assess mortality, length of stay and hospital costs associated with CRE. All patients will be followed for 30 days. Different, up-to-date statistical methods will be applied to come to unbiased estimates for all 3 studies. Ethics and dissemination Before-study sites will be initiated, approval will be sought from appropriate regulatory agencies and local Ethics Committees of Research or Institutional Review Boards (IRBs) to conduct the study in accordance with regulatory requirements. This is an observational study and therefore no intervention in the diagnosis, management or treatment of the patients will be required on behalf of the investigation. Any formal presentation or publication of data collected from this study will be considered as a joint publication by the participating physician(s) and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE) for authorship. Trial registration number NCT02709408.