During the first 4 years of the R-GNOSIS programme, efforts have been focused on:
In parallel to the progress of the studies, WP7 (Microbiology), WP8 (Mathematical Modelling) and WP9 (Data Coordination Centre) started their work related to WP2-WP6 studies.
Progress on the work of is as follows:
In WP2 – “Primary care”, the stage 2 Observational study was conducted in Wales, England, Spain and the Netherlands where GPs registered sequential patients with UTI symptoms, recorded their usual-care diagnostic procedures, treatment and sampling. This stage will allow enumeration of existing diagnostic strategies and antibiotic prescribing practice. Urine samples were collected from patients for assessing the incidence of uropathogens in the community, their resistance rates and to study risk factors for resistance in the community. Final statistical analyses of this stage are underway.
The stage 3 randomised controlled trial (RCT) was conducted in the same countries where registered GPs randomised patients to usual care, or to use of the Point-of-care Test – Flexicult. This stage is now completed, and final statistical analyses are underway.
The performance of the Flexicult point-of-care test (POCT) will be compared to routine laboratory based culture which is the currently used procedure for urine samples referred from women with a urinary tract infection (UTI). This evaluation will take place in part during the stage 3 RCT. In addition to the RCT, further evaluation of the Flexicult POCT has already been conducted in the microbiology laboratory. In this evaluation, the Flexicult POCT was compared to routine microbiology tests for 200 urines submitted routinely to an NHS microbiology laboratory.
Initial results from the RCT showed no additional benefit of using the POCT, therefore the focus of stage 4 was adjusted so that the barriers and facilitators of use of the POCT could be understood through interviewing clinicians who took part. Analysis is underway, and is due to be completed by December 2015.
WP3 – “Decolonization/recolonisation in carriers of ESBL- and carbapenemase producing Enterobacteriaceae” underwent significant changes in its design, which was needed as the development program of the proposed investigational products was discontinued. The original plan was to decolonize patients with high concentrations of topical antibiotics and subsequently to recolonize them with an antibiotic-susceptible E. coli strain. Yet, recent studies suggested carcinogenic effects of the intended recolonisation strain. It was agreed to change the intervention to fecal transplantation, a procedure recently demonstrated to be highly effective for preventing recurrent infections with Clostridium difficile. New laboratory and study protocols have been developed and submitted to the local ethical committees and national authorities. All four sites have now obtained approval from their local ethical committees and national authorities, the recruitment period has started during the end of the 4th period.
WP4 – “Surgical prophylaxis” is in progress in all 3 study sites. As of the end of September 2015, 434 patients were included for Phase 1 and 172 patients for Phase 2 in the study group. The percentage of ESBL positive patients calculated from the first screening performed is 20% in Tel Aviv, 12% in Geneva and 12.5% in Belgrade.
The feasibility of using a rapid test in Phase 2 was discussed. For the only available rapid test (made by Checkpoint) the full evaluation using clinical specimens is not yet complete. Test operating characteristics (complexity of performing the test and time to result which does not fit working hours) make it difficult to use as a real time test in the study centers and make it unsuitable for general use in the study sites. WP4 are therefore considering evaluating the performance of checkpoint in selected nested study on selected patients. Regarding possible alternatives to rapid screening a decision was made to replace rapid screening by early screening at the pre-surgery visit. This strategy has been implemented in Phase 2.
WP5 – “Patient isolation strategies for ESBL-E carriers in medical and surgical hospital wards” is in progress: the first intervention period has been completed in all participating sites (in 20 wards). In the first half of 2015 all wards were due to switch to the second infection control strategy and to change infection control procedures for ESBL-E-patients accordingly. The monitoring of adherence to the protocol with regard to the use of gloves, gowns and alcoholic hand rub continued as in the previous intervention year.
The electronic upload of screening compliance data and ESBL-E-patients’ data was prepared and started for all sites. Manual entry of data on ESBL-patients’ infection and antibiotic use and compliance data was started as well.
First shipments of locally confirmed ESBL-isolates from all sites to SERMAS for confirmation have already been analysed. Further microbiological analysis of locally identified ESBL-E including confirmation of ESBL-production as well as verification of transmission events was agreed upon with WP7.
Preliminary findings of the study suggest an unexpectedly high ESBL-E-incidence (ranging between 2 up to 6%) regardless of the study site beside the high ESBL-E admission prevalence (around 10%). Moreover, a large percentage of consecutive screening samples from identified ESBL-E-patients showed intermittent carriage after the first positive screening result (up to 30% in Berlin).
WP6 – “Decolonization strategies in Intensive Care” has experienced significant delay with the study start due to unexpected hurdles emerging in the process of obtaining ethical approval in several European countries.
In year 1, the study protocol and the data safety committee protocol were finalised, recruitment of the members of the data safety committee was performed and procurement and selection procedure of 15 eligible ICUs to participate in the study as well as procurement of logistic partners was started. In year two, agreements were made with the manufacturer of medication, logistic partners and the manufacturer of microbiological culture materials. The procurement and selection of eligible ICUs continued throughout the second year of the study. In the summer of 2013, sixteen hospitals had been visited and selected for participation and the study protocols had been submitted to the institutional review boards and regulatory authorities in the different hospitals and countries. Ethical approval – including a waiver for informed consent - was obtained in Belgium, Italy and Slovenia and denied in Hungary and the UK. The process of obtaining ethical approval took considerably more time than anticipated. In year 3, approval was obtained in Spain and still pending in the UK, France and Portugal. After a long period of review, ethical approval was eventually denied in France, for which we decided to recruit additional sites in Belgium and Spain (where the protocol had already been approved). At the end of year 3, patient recruitment had started in 8 hospitals in Belgium, Slovenia, Italy and Spain (MS22, partially completed), of which four (in Belgium and Slovenia) had completed the baseline period and started with the first intervention period.
The most important objective for year 4 was to initiate patient recruitment in 15 participating sites. Year 4 started with 8 actively participating sites and seven potentially participating sites. Ethical approval was obtained in the UK in April 2015 and in Portugal in July 2015 and 6 sites have initiated the baseline period during this reporting period. Two UK sites eventually declined to participate due to time constraints; the process of obtaining ethical approval had taken that much time that getting the study started within R-GNOSIS timelines was no longer feasible. In year 4, all 13 hospitals of the six European countries participating have progressed to the first intervention period, six hospitals started the second intervention and three are currently in the third (and final) intervention period.
At the start of year 4, oral mucosal adverse events were noticed in 9.8% of 295 patients treated with chlorhexidine 2% mouthwash. Following consultation with the study safety committee, this has led to the decision to discontinue the use of this product in the study. Instead, a chlorhexidine 1% oral gel has been implemented. Since this amendment >500 patients have been included in the CHX-oro arm without any notification of potential side-effects.
WP7 – “Functional microbiology and within-host transmission dynamics of genes, plasmids and clones of MDR-GNB” has continued,
WP8 – “Mathematical modelling” worked on developing between-host dynamic models for hospital transmission and estimating key epidemiological quantities. Based on mathematical modelling applied to longitudinal molecular microbiology screening data it was estimated that the maximum effect of horizontal gene transfer of blaOXA-48 originating from E. coliOXA-48 on the basic reproduction number (R0) is 1.9%, and it is, therefore, unlikely that phenotypically susceptible E. coliOXA-48 will contribute significantly to the spread of blaOXA-48. (Haverkate et PLoS One 2015). Prevalence of KPC in Long Term acute care hospitals in the Chicago region is high, primarily due to high admission prevalence and the resultant impact of high colonization pressure on cross transmission. In this setting, with an intervention in place, patient-to-patient transmission is insufficient to maintain endemicity. (Haverkate et al Infect Control Hosp Epidemiol 2015).
WP9 – “Data Coordination Centre” was maintained, data collection was performed using the data collection websites. The Electronic Data Capture system was adapted and maintained according to the data management implementation plan to enable the system to facilitate data collection of the various clinical studies.