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Challenges in understanding the determinants of anti-infection agent escape

New antibiotic components are being developed and, provided the necessary investments are made, new antibiotics may therefore become available within the next few years. New vaccines and antimicrobial drugs may also become available, for controlling or minimizing the consequences of antimicrobial resistance. A recent example is provided by the seven-valent polysaccharide conjugate vaccine (PCV–7), with unexpected additional benefits due to the impact of herd immunity on severe pneumococcal sepsis in the elderly.

No matter how many new anti-infection molecules or vaccines become available in the future, new resistant microorganisms will almost certainly emerge.

However, a more thorough investigation of the factors determining the epidemic strength of resistant bacteria and of the interactions between exposure to multiple antibiotics and the diffusion of multidrug-resistant bacteria (MRB) is warranted. Additional efforts are also required to anticipate vaccine evasion, as recently reported in a population with a high level of conjugated pneumococcal vaccine coverage. Cell biology, immunology, genetics and molecular biology all contribute to our understanding of the biological mechanisms involved in antimicrobial drug evasion (e.g., the mechanisms of bacterial adaptation to a new environment, such as exposure to antibiotics). However, it is not possible to understand and to quantify these phenomena fully without investigations at the level of human populations.

The PhEMI research group thus carries out research on:

The influence of multiantibiotic selection on the spread and competitiveness of multidrug-resistant bacteria (MRB): methicillin-resistant Staphylococcus aureus (MRSA) and enterobacteria resistant to 3rd-generation cephalosporins (ER3GC)

Project leaders: D Guillemot, J Salomon

The specific challenges of this work are:

  • Elucidating the interaction between exposure to antibiotics and the risk of acquiring MRB, and analyzing the impact of these molecules on the duration of carriage and the risk of transmission     to the carrier’s family and friends;
  • Predicting the pattern of MRB diffusion in the hospital/community in the context of high levels of antibiotic use, taking competition between bacteria into account.

We will use data recorded in the ASAR, I-BIRD, and EßIC investigations.

Dynamic factors of underlying MRB (MRSA, in particular) dissemination: epidemicity, antibiotic exposure and between-individual contacts

Project leader: D Guillemot

Collaboration with: P-Y Boëlle, E Fleury, J-L Hermann, L Temime

We aim here to characterize the “intrinsic epidemicity” of the various clonal complexes of MRB circulating in hospitals. The fundamental goal is to improve our understanding of the determinants of nosocomial MRB dissemination. Ultimately, we aim to optimize strategies for controlling and reducing the spread of these bacteria. This project combines:

  • Investigation of the clone-specific epidemicity of MRSA and ER3GC with large-scale ambient dynamic networks and innovative devices for documenting contact frequencies and interactions     between medical and nursing staff and patients in hospital rehabilitation departments, together with antibiotic use, colonization with MRB strains, and clinical factors;
  • Simulation of the dynamics of MRB transmission by an innovative approach: individual-based modeling (link to chapter: 3. Improvement of statistical methods).

This project will be supported by the I-BIRD program.

Dynamics of human papilloma virus (HPV) interactions

Project leaders: E Delarocque-Astagneau, D Guillemot

Collaboration with: M Favre, I Heard

The introduction of vaccination against certain oncogenic genotypes of HPV raises questions about the impact of vaccination programs on the ecological evolution of these viruses in populations. Anticipating this evolution is a major public health issue, with possible consequences for the adaptation of vaccination strategies and the future development of vaccines. Indeed, the two oncogenic genotypes targeted by the vaccines should be gradually eliminated, potentially freeing a biological “niche” that may subsequently be occupied by non vaccine genotypes. The impact of anti-HPV vaccination on public health therefore depends heavily on the capacity of non vaccine genotypes to establish themselves in this niche. However, the likely speed and direction of these vaccine escape phenomena based on genotypic replacement remain unpredictable. Whatever the epidemiological reality (competitive, neutral or synergistic interactions between viruses), the nature and strength of interactions between viruses will determine the impact of vaccination. We aim here to characterize epidemiological interactions between different HPV genotypes.

This project will make use of the DyPAVIR–ISHARE cohort.

Challenges in public health research

Impact of French public health policies for controlling bacterial resistance in the community

Project leaders: D Guillemot, L Watier

Collaboration with: L Gutmann, P Ricordeau, E Varon

We are analyzing changes in the invasive pneumococcal community in relation to the public health interventions implemented in recent years: the national “Keep Antibiotics Working” and pneumococcal vaccination programs (the PHI–CARE program).

Risk factors for empyema in the pediatric community

Project leader: D Guillemot

Collaboration with: A Ferroni, L Gutmann, M Le Bourgeois, M Leruez, E Varon

Through the ChANCE program, we are currently testing the hypothesis of an association between the use of non steroidal anti-inflammatory drugs (NSAIDs) without antibiotics after viral respiratory infections and the risk of empyema in children.

Incidence rate and risk factors for the infection of children with antibiotic-resistant bacteria in low-income countries

Project leaders: E Delarocque-Astagneau, D Guillemot

Collaboration with: C Delval, B Garin, M Seguy

We aim here to initiate a new research project for estimating the incidence of bacterial infections resistant to antibiotics in children living in low-income countries (i.e., neonatal and childhood infections). We also aim to investigate the bacterial etiologies and consequences (in terms of mortality and morbidity) and the vertical versus horizontal transmission of multiresistant bacteria in newborns (i.e., from the mother versus from the environment/other people).

This project will benefit from the ChARLI program.

Social resistance to innovations for controlling infectious diseases: application to the case of the anti-human papillomavirus (HPV) vaccine

Project leader: A Opinel

We aim to investigate the relationships, in the exposed population’s opinion, between HPV and the risk of cancer for oneself or others together with the risk of non malignant diseases for their partner and the community. Assessments of the volume and impact of the knowledge of the patient’s close social circle (family and friends) concerning HPV infections and the risks incurred are required. The transmission of suspicious or confident attitudes is a critical parameter that must be assessed in the context of disease knowledge. This collective or individual knowledge, whether acquired or transmitted, should provide insight into behavior with respect to vaccination and the development of schemes of resistance to vaccination. We will also need to evaluate the degree of confidence individuals have in their family and general practitioners and the opinions of these general practitioners concerning anti-HPV vaccination and risk perception.

This project will make use of the DyPAVIR–ISHARE cohort.

Improvement of statistical methods

Project leaders: A Thiébaut, L Watier

Collaboration with: J Benichou

Modeling epidemiological longitudinal data

As far as individual data are concerned, we aim to evaluate statistical methods for estimating complex hazard functions, such as those encountered in pharmacoepidemiology in general and, more specifically, in relation to anti-infection drugs, after taking the lack of independence between individuals into account. We also aim to develop approaches for estimating the risk of resistance acquisition attributable to exposure to anti-infection drugs. These developments will be useful for the analysis of the ASAR, I-BIRD, and EßIC data.

As far as aggregated data are concerned, we aim to evaluate approaches for analyzing the association between two time-series showing common seasonality patterns: ways of eliminating season, the choice of Poisson or Gaussian regression, and the robustness of the results to the assumption of a linear association. Those developments will be useful within the PHI–CARE program.

Modeling measurement error

We aim to investigate not only measurement error on the exposure variable, but also measurement error on the response variable, as often encountered in pharmacoepidemiology, in situations in which the event of interest is defined on the basis of the prescription of tracing drugs or, more specifically, with respect to the acquisition of resistance, with carriage status assessed by collecting samples several days apart.

Mathematical modeling of interactions between pathogens, within hosts

Project leader: L Opatowski

Collaboration with: P-Y Boëlle, C Fraser, J Legrand, V Letort, L Temime

This project aims to investigate the interactions between pathogens and to assess the epidemiological impact of such interactions. It includes two sections: a methodological section based on the development of mathematical models and a more applied section addressing biological and epidemiological issues.