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

Research domains

SATURN will improve methodological standards, conduct research and lead specific projects that will help to better understand the impact of antibiotic use on acquisition, selection and transmission of antibiotic-resistant bacteria in different environments, by combining state-of-the-art analyses of molecular, individual patient-level and aggregate, group-level data. The suggested program and its anticipated results may ultimately help to reduce the burden of antibiotic-resistant infections in Europe and guide both clinical decision making and policy decisions in this area.

Two types of clinical research studies will be conducted:

  • First, a randomised multi-facility intervention study in the ICU setting will be performed to resolve an issue of high controversy: antibiotic cycling vs. mixing.
  • Second, 3 observational studies will be conducted to study important issues surrounding the effect of antibiotic usage that are not easily assessable through randomised controlled trials, due to the problem of rare outcomes and sample size requirements.

Observational cohort studies should complement controlled clinical trials dealing with AMR, because the latter have a limited ability to detect adverse effects such as acquisition of ARB, provide information only about patients who satisfy the criteria for study entry and often concentrate on the efficacy of specific agents rather than evaluate variations in the duration and pattern of antibiotic use. In addition, randomised trials do not provide data on the effect of therapeutics in actual clinical practice. In contrast to many previously reported clinical trials, the proposed observational studies will focus on critical issues that are unlikely to receive any industry funding in the near future. Overall, both types of studies (interventional vs. observational) will increase cohesiveness and cooperation nationally and internationally.

While a quantitative analysis from epidemiologic and clinical studies can inform about the increase and temporal persistence of ARB, the complementary molecular analysis will help assess the prevalence (and/or co-selection) of certain known or emerging AMR genotypes linked to a predominant use of particular antibiotics or antibiotic durations. Another key factor dictating the evolution/transmission of AMR is the fitness cost associated with carriage of a resistance gene or mechanism. This biological cost is one of the main determinants of how rapidly a resistant mutant will establish itself within a host population. However, fitness limitations in resistant strains may be overcome by the development of compensatory mutations that makes them almost as fit as sensitive strains in their dissemination capacity.

Work plan structure

A randomised multi-facility intervention study (WP2) in the critical care setting will be performed to resolve an issue of high controversy (antibiotic cycling vs. mixing).

Three observational clinical studies will be conducted (WP3, WP4 & WP5) to rigorously study important issues surrounding the effect of antibiotic usage that are not easily assessable through randomised controlled trials, due to the problem of rare outcomes and sample size requirements. These clinical studies will be linked to 2 complementary work packages (WP1 - Bacterial Genetics and Functional Studies and WP6 - Pharmacodynamics) that will perform additional investigations relevant to the purpose of this call.

An additional work-package (WP7 - Project management and dissemination) will assure the coordination of the work, its dissemination outside the consortium, proper exploitation, and transfer.

WP1 – Bacterial Genetics and Functional Studies

The general objective of WP1 is:

  • to study the abilities of various antibiotics to select for resistance in the respiratory and intestinal flora of patients (hospitalised or in the community) and their contacts or in non-antibiotic-treated controls and compare the persistence of the selected resistant bacteria over time following antibiotic administration;
  • to investigate the known and novel/emerging mechanisms of resistance in the bacteria selected by antibiotic use; and
  • to investigate the underlying basis for the global dissemination of certain clonal types by studying virulence, clonality and the fitness costs of resistance gene carriage in these successful clones.

WP2 – ICU Intervention Trial

WP2 will undertake a study of AMR in Enterobacteriaceae, P. aeruginosa and Acinetobacter species in 10 ICUs in different European countries:

  • to quantify the impact of antibiotic cycling and antibiotic mixing on overall antibiotic resistance levels;
  • to assess other epidemiologic factors associated with carriage of ARB;
  • to determine the impact of both strategies on the rates of endogenous and exogenous acquisition of ARB

WP3 – Community Study

WP3 will undertake an observational cohort study in a well-defined community population of patients with urinary tract infections in 3 European countries with the following primary objectives:

  • to determine the impact of various durations of antibiotic use on the carriage of resistant E. coli among individuals consuming antibiotics for suspected or confirmed urinary tract infections and their household members;
  • to assess other epidemiologic factors associated with carriage of resistant bacteria or changes in the resistance pattern of the commensal flora;
  • to determine the impact of antimicrobial use on the carriage of susceptible E. coli among individuals consuming antibiotics;
  • to genotype isolates recovered from patients and evaluate changes in pheno-and genotype in relation to antibiotic resistance and usage;
  • to link clonal grouping, virulence and antibiotic resistance in selected bacteria with prescribing habits and antibiotic consumption.

WP4 – Nosocomial Acquisition Study

The overall objective of the WP4 will be to compare rates of acquisition of MRSA and ESBL-producing gram-negative bacteria between different treatments groups and to define the temporal relationship between the start of antibiotic therapy, the acquisition of new colonisation in patients previously not colonised, and the development of a bacterial infection caused by the same strain isolated in a screening sample. This goal will be achieved by completing the following primary objectives:

  • to determine the rate of acquisition of target antibiotic-resistant bacteria by 1,000 antibiotic-days according to different classes of antibiotics, duration of therapy, and antibiotic combinations (monotherapy versus combinations);
  • to determine genotypic relation between colonising and infecting strain in the same patient and patients’ and hospital staff colonising strains;
  • to describe virulence and fitness of the isolates (i.e. new colonising strains) causing subsequent nosocomial infections;
  • to find risk factor associated with new colonisation by target antibiotic-resistance bacteria;
  • to predict the risk for nosocomial infections due to target ABR after a cycle of antibiotic therapy adjusted by length of hospitalisation and ward colonisation pressure.

WP5 – AMR Carrier Study

A prospective, observational longitudinal trial designed to examine the effect of various agents on selection and amplification of AMR organisms and resistance genes among carriers of these strains will be conducted in 4 European countries in which AMR is a prevalent problem with the following objectives:

  • to determine the effect of various antibiotics on amplification of AMR Enterobacteriaceae pathogens, i.e. ESBL producing Enterobacteriaceae and Carbapenem resistant Enterobacteriaceae (CRE), and on dissemination of resistance genes.
  • to determine the effect of duration of antibiotic therapy on amplification of AMR pathogens and on dissemination of resistance genes
  • to determine the PK/PD indices that influence the amplification of AMR pathogens and on dissemination of resistance genes
  • to correlate the effects of antibiotics on phenotypic and genotypic expansion of AMR
  • to determine the effects of various antibiotics on epidemicity and fitness of various ARB
  • to determine the correlation between amplification of AMR pathogens in the GI tract and environmental contamination
  • to study the impact of antimicrobial treatment on human microbiota, including composition and diversity of bacterial communities.

WP6 – Pharmacodynamics

The main purpose of WP6 is to establish relationships between exposure and emergence of resistance, both qualitatively as well as quantitatively. To that end, the data that will be collected in each of the WP2-5. Essentially, three sets of data will be required to establish these relationships: measures of exposure (pharmacokinetic profiles); measures of susceptibility (MIC; MPC) and measures of emergence of resistance.

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