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Resistance in Gram-Negative Organisms: Studying Intervention Strategies

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Intervention strategies against antibiotic resistance

Europe faces a dramatic increase in infections caused by drug-resistant bacteria. With very few anti-microbial agents in the drug discovery pipeline, effective measures are urgently needed to contain resistance and limit the spread of these pathogens.

Fundamental Research

Multidrug resistant Gram-negative bacteria (MDR-GNB) can cause serious infections that pose a threat to hospitalised patients and especially those in intensive care units (ICUs). The European Centre for Disease Prevention and Control and the European Medicines Agency estimated that nearly 200 000 patients were infected with MDR-GNB in 2007. With a striking lack of antimicrobial agents, new interventions are required to contain resistance and limit the spread of MDR-GNB. Towards this goal, the EU-funded R-GNOSIS project brought together leading experts in the field who developed cutting-edge interventions against MDR-GNB. Using highly innovative microbiology, mathematical modelling and data management, researchers performed five pivotal clinical studies that tested the efficacy of various approaches. “Our aim was to develop prophylaxis strategies and optimise treatment against MDR-GNB, avoiding the detrimental consequences of these bacteria on patient outcome,″ explains project coordinator Dr Marc Bonten. Approaches for containing drug resistance The injudicious prescription of antibiotics is to blame to a large extent for the emergence of MDR-GNB species. Therefore, improving antibiotic prescription in primary care is believed to alleviate the issue. For this purpose, R-GNOSIS partners developed point-of-care-tests (POCT) for optimising antibiotic prescription and prophylaxis before surgery. Since bacteria are capable of transferring drug resistance genes, the scientific teams of R-GNOSIS worked to identify the most effective measures for controlling genetic transmission. In particular, they investigated the critical molecular aspects for persistence and transfer of resistance genes in the human gut and used mathematical modelling to generate mechanistic and quantitative understanding of the ecological and evolutionary processes determining the dynamics of MDR-GNB in the host. Significant insight was also gained into how these organisms are transmitted in hospitals. R-GNOSIS included a clinical study involving gut decolonisation followed by faecal microbiota transplantation (FMT) for intestinal carriers of MDR-GNB, such as extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae. The study showed encouraging preliminary results, although technical challenges prohibited the recruitment of the necessary number of patients. Nonetheless, R-GNOSIS partners hope to continue these studies exploring the use of FMT without prior use of antibiotics. In a multicentre study, different patient isolation strategies were tested as an approach for reducing ESBL-Enterobacteriaceae acquisition among hospitalised patients, similar to what happens for MRSA. This study revealed no difference between two strategies that differed in the intensity of isolation measures. In another multicentre study, researchers tested various decontamination strategies for patients in ICUs as a means of eliminating bacteria from the airways and gut, and preventing hospital infections. This approach is standard of care in Dutch ICUs where the prevalence of antibiotic resistance is low. This study was based on 8 500 patients admitted to 13 ICUs in 6 European countries where the prevalence of antibiotic resistance was considerably higher than in Dutch ICUs. Two of these strategies included antibiotics and contrary to previous results obtained in Dutch ICUs they demonstrated no beneficial effect compared to standard care. This constitutes a strong argument against the use of decontamination strategies with antibiotics in ICUs with moderate to high prevalence of antibiotic resistance. The future of antibiotic resistance Dr Bonten views drug-resistant bacteria as “a formidable enemy, equipped with sophisticated molecular methods to express and exchange resistance genes, capable of colonising multiple reservoirs and harbouring a bewildering array of virulence factors to infect any suitable host.″ As a result, he emphasises the need for concerted efforts to improve diagnosis, antibiotic-prescribing practices and infection prevention strategies for tackling antibiotic resistance in the future. Recommendations derived from the R-GNOSIS results will undoubtedly contribute to all these, leading to better quality of patient care in Europe.


R-GNOSIS, drug resistance, MDR-GNB, faecal microbiota transplantation (FMT), POCT

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