FP7 logo euThe SATURN project has received funding from the European Community's Seventh Framework Programme [FP7/2007-2013] under grant agreement n°241796

Impact of Specific Antibiotic Therapies on the Prevalence of Human Host Resistant Bacteria

Main findings & results

WP2 – Antibiotic rotation strategies to reduce antibiotic resistance in the Intensive Care Unit: A cluster randomized, crossover study

2.210, 4.237 and 4.711 patients were enrolled during standard care, cycling and mixing respectively, with comparable baseline characteristics. During cycling the study-preferred antibiotic was the most prescribed of the 3 rotated antibiotics in 72% of the 6-weekly cycling periods. Diversity of prescribed study antibiotics changed considerably between interventions with mixing having more stable- and cycling having a more varied prescription pattern. In the cycling versus mixing period, resistance prevalence for the composite endpoint was 22,7% and 21,5% (170/750 and 187/869, p=.578) respectively, with no statistically significant differences for subgroups of resistance types. Antibiotic consumption was 1,53 and 1,69 DDDs per admission day for baseline- and combined intervention periods respectively. The largest proportional changes of overall antibiotic use between standard care and the combined intervention periods were meropenem (+1.6%) and cefepime (-1.0%) consumption. In preliminary, unadjusted analysis there were no statistically significant differences in the prevalence of antibiotic resistance during mixing and cycling interventions, in which antibiotic diversity differed markedly. More sophisticated analyses will incorporate potentially confounding factors such as patient characteristics, hand hygiene adherence, isolation measures and indwelling devices.

WP3 – A prospective, observational multi-centre cohort study of antimicrobial resistance in E.coli and other clinically relevant enteric bacteria in a well-defined community population

The data resulting from the study are novel in presenting an alarmingly high prevalence of colonisation by ciprofloxacin-resistant Enterobacteriaceae in the European community. Exposure to fluoroquinolones clearly increased the risk of colonisation by ciprofloxacin-resistant Enterobacteriaceae, and this effect is likely to by mediated – at least in part – by the impact of this antibiotic on the gastrointestinal microbiota. The duration of treatment did not appear to significantly modify this effect. By contrast, nitrofurantoin had minimal impact on commensal microbiota and was not associated with emergence of resistance. Interestingly, we did not demonstrate an association between exposure to antibiotics and colonisation by ESBL-producing Enterobacteriaceae. Household clustering was noted for both ciprofloxacin resistant and ESBL-producing Enterobacteriaceae. Interruption of household transmission therefore represents a potential opportunity for interventions to reduce the community-based spread of antibiotic resistant Enterobacteriaceae.

WP4 – A multicenter prospective cohort study to compare nosocomial acquisition rates of MRSA and ESBL-GNB

This is the largest prospective study (more than 10 000 patients with more than 55 000 samples) designed to assess the acquisition of antibiotic-resistant microorganisms in hospitalized patients on antibiotics. This is also the first study in the field of nosocomial acquired infections, in which supervised learning models (support vector machines) were used, associated with learning algorithms to analyze data and recognize patterns. The study shows that 4.2% of patients were newly colonized by MRSA and 23.5% by ESBL-GNB after starting antibiotic therapy. The rate of acquisition is still significantly higher also after adjusting for colonisation pressure and rate of acquisition in patients not undergoing antibiotic therapy. The combinations of antibiotics most associated with the acquisition of ESBL were carbapenems and macrolides, linezolid and quinolones while cephalosporin and piperacillin significantly increased the risk for MRSA development. These results clearly underline that the new acquisition of colonisation due to MDR bacteria should be considered as a common (according to the WHO definition) adverse event of antibiotic therapy. The information about the risk related to single, combination and sequential therapy has also an immediate clinical application in selecting therapies with the lowest risk to produce resistance according to patients´ comorbidities, duration of hospitalisation and previous antibiotic therapy (free app almost completed to be available on the SATURN website). Importantly the study also provides microbiological and molecular evidence that the infections in patients developing new colonisation after antibiotic therapies are the same of those responsible for infections in the same patienst. These data could be used to design new studies with interventions (i.e. screening or colonisation) that could prevent the development of infections in high risk hospitalised patients.

WP5 – A prospective, observational longitudinal study to examine the effect of various agents on selection and amplification of AMR organisms and resistance genes among carriers of these strains

Main steps and findings:

  • Development of new methodology to detect and quantify resistance organisms and genes using rectal swabs
  • Analyze and description of the clonal dissemination and success of various carbapenem resistant enterobacteriaceae
  • The draft genome sequence of the K. pneumoniae ST258 XDR clinical strain
  • Detection of 9 ertapenem-resistant, carbapenemase-negative K. pneumoniae (ERCNKP) belonged to ST-258
  • Description of the molecular epidemiology of Carbapenem-resistant E.coli
  • Description of carbapenem-resistant KPC-2-producing K. pneumoniae
  • Presumably unique genes of KPC-KP ST-258/512 were examined in a large international collection of strains
  • Characterization of the prevalence of carbapenemase-producing Enterobacteriaceae (CPE) carriage in post-acute-care hospitals (PACH)
  • Description of the clonal structure and resistance mechanisms of K. pneumoniae carbapenemase-producing E. coli (KPCEC) in a multicenter study
  • Study and description of the natural history of carriage of CRE, length of carriage and progression to infection
  • Development of methodologies and establishment of the importance and magnitude of environmental contamination with CRE in the hospital setting and establishment of the relation between gut CRE concentration, antibiotic use, and dissemination
  • Description of the emergence and spread of new mechanisms of resistance to carbapenemes and their dissemination by gene, plasmid and clonal spread
  • Identification of 5 VIM producing Carbapenem-resistant Aeromonas caviae belonging to four different pulsotypes

WP1 – Bacterial Genetics and Functional Studies

These translational studies provided unprecedented knowledge on pathogen and antibiotic resistance genes dynamics at baseline and under pressure of various antibiotics both in the European community and in hospitalized patients. We also identified identify antibiotic efflux to be a major mechanism selected under ciprofloxacin treatment in vivo in the oropharyngeal flora. Molecular studies identified the overexpressed efflux pump as a novel ABC transporter in S. mitis strains. Studies on MRSA, ESBL-carbapanenemase-harboring, and fluoroquinolone-resistant Enterobacteriaceae, and MDR Acinetobacter and Pseudomonas spp. mapped important clones in European hospitals and fundamental work on these strains identified important genes involved in virulence, biofilm formation, and biological fitness which are important determinant of their pathogenetic success. Such a bedside-bench-bedside approach have made these studies truly translational, and in the long term likely to impact both antibiotic use guidelines and hospital policies on breaking transmission routes of these important pathogens.

WP6 – Pharmacodynamics study

The program developed in order to determine the individual exposure in each patient allows the user to enter individual patient primary pharmacokinetic parameters as well as the MIC of the relevant micro-organism or Ct value and then automatically calculates the secondary pharmacokinetic parameters and the pharmacodynamic indices (fAUC/MIC, fCmax/MIC and %fT>MIC). The program was validated and used to determine pharmacodynamic indices in a population of intensive care (ICU) patients and in a population with community acquired pneumonia (CAP), for ceftazidime, ceftobiprole and ceftriaxone. The exposure response (ER) analysis focused on ceftriaxone, amoxicillin/lavulanic acid, ciprofloxacin and levofloxacin. All antibiotics showed significant correlations between exposure and ESBL colonization. Subsequent CART analysis showed that the ESBL colonization rate was significantly higher between 75% and 99% and there by resembled an inverted U-shape related to the %fT>4 mg/L for ceftriaxone. Of the patients that became colonized there was also a strong association between exposure and whether or not the micro-organism was susceptible or resistant. Similar associations were found for the two quinolones ciprofloxacin and levofloxacin. Interestingly, in the ciprofloxacin group the colonization ratio was significantly higher than in the levofloxacin group (25% vs 13%). For both drugs, there was a correlation with fAUC/MIC, but it differed for each drug in the initial analyses. Currently, these data are analyzed more in depth. For amoxicillin-clavulanic acid, higher exposures resulted in a slightly but significantly elevated colonization rate.

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