Ecological Effects of Decolonisation Strategies in Intensive Care
Ecological Effects of Decolonisation Strategies in Intensive Care
Previous research has shown that applying certain treatments can reduce both the number of
 infections and the presence of resistant bacteria in the intensive care (ICU) and its
 patients. These treatments have been used as standard care throughout the world for many
 years, but they have not been compared to each other yet. The investigators aim to evaluate
 the effect of 3 different treatments on the occurrence of resistant bacteria and bacterial
 infections in the ICU and to establish which treatment is the best.

 All adult patients undergoing mechanical ventilation are eligible for this study and will
 receive treatment according to the study scheme. Twice weekly, sputum and rectal samples will
 be obtained to measure the effects.

 All ICU-patients will receive standard treatment, consisting of daily body washing with an
 antiseptic (chlorhexidine 2%), oral care and a hand-hygiene program for health care workers
 as endorsed by the WHO. According to 4 different study periods, each participant will receive
 one of the following extra treatments depending on his or her admission date:

 -  Standard treatment only (this is the control group)

 -  Chlorhexidine 1% oral gel, this is an antiseptic.

 -  Antibiotic mouth paste containing 3 different antibiotics (selective oropharyngeal
 decontamination, SOD).

 -  Antibiotic mouth paste and suspension for the stomach and intestines containing 3
 different antibiotics (selective digestive decontamination, SDD).

 All treatments will be given 4 times daily with the purpose of killing harmful bacteria in
 the mouth (CHX, SOD,SDD) and digestive tract (SDD).

 During the study the investigators will examine the effect of these treatments on:

 -  the occurrence of blood stream infections with certain bacteria

 -  cross-transmission of certain bacteria between patients

 -  presence of these bacteria in the respiratory tract of the patients

 -  patient survival

 Benefits: Previous research has shown that these interventions can reduce infections in
 intensive care patients.

 Risks: The interventions performed (both cultures and treatment) are considered safe and are
 already given as standard care in many ICUs throughout the world. There is a slight risk that
 bacteria become resistant to antibiotics: this will be monitored closely during the trial.
Introduction

 The "R-GNOSIS: Ecological Effects of Decolonization Strategies in Intensive Care" study
 assesses three decolonization interventions against standard care to evaluate unit wide
 ecological effects and compare effectiveness.

 Previous studies have demonstrated that decontamination interventions were beneficial to
 individual patients but also influence ICU ecology, affecting patients who do not receive the
 intervention. Decolonization with antibiotics have been shown to reduce the prevalence of
 resistant bacteria during treatment [de Smet et al. NEJM 2009]. Reducing the presence of
 these bacteria in some patients (that are decolonized), reduces cross transmission and is
 therefore beneficial to all patients in the unit. The decolonization strategies therefore
 represent an intensive care unit population rather than an individual patient intervention.
 In this respect the study represents a cluster-cluster randomized clinical trial which
 requires the intervention is undertaken on the whole ICU population [Edwards et al. BMJ
 1999].

 As decolonization strategies represent an ecological intervention on the whole critical care
 population, all patients meeting inclusion/exclusion criteria will be entered into the study
 according to ethics approval in each participating country. Each participating ICU will use
 three decolonization strategies in a randomised order. The interventions are administered
 four times daily to ventilated patients until extubation. The interventions will be compared
 to a 6 month baseline period consisting of standard care only.

 Standard operating procedures

 Standard care

 The baseline period is the first 6-month period and will be used to implement universal
 "standard care":

 -  Chlorhexidine 2% body washings (CHX-BW) for all ICU patients. CHX-BW ensures state of
 the art standard of care to prevent carriage and transmission of (resistant) gram
 positive bacteria commonly residing on body surface, such as Staphylococcus aureus and
 Enterococci.

 -  A hand hygiene improvement program (HHIP) based on the program designed by the World
 Health organisation (WHO). Implementation of the hand hygiene program derived from the
 WHO hand hygiene program ensures state of the art standard of care for transmission
 prevention of all relevant pathogens.

 -  Standard oropharyngeal care consists of oral washing with sterile water (3-4 times
 daily) and tooth brush twice daily.

 "Standard care" will be the only protocolised intervention in the baseline period and will be
 used throughout the entire study.

 Intervention periods

 After the baseline period, the first decolonization regimen will be implemented. The order of
 regimens per ICU is decided by randomization. The three regimens are:

 -  Chlorhexidine oral care (CHX-Oro) with chlorhexidine 1% oromucosal gel.

 -  Selective oropharyngeal decontamination (SOD) with antibiotics. SOD consists of
 application of a paste containing colistin, tobramycin in a 2% concentration and
 nystatin 1 x 10^5 units.

 -  Selective digestive decontamination (SDD), in which a 10 ml suspension via the
 nasogastric tube containing 100 mg colistin, 80 mg tobramycin and nystatin 2 x 10^6 i.u.
 will be added to application of SOD paste.

 All intervention periods last 6 months and all regimens are applied four times daily.

 In contrast to some other SDD studies, systemic prophylaxis with Cefotaxime (or other broad
 spectrum cephalosporins) will not be implemented as part of SDD.

 Patient recruitment

 All patients in the ICU receive standard care and minor anonymized personal data are
 collected from them. Once monthly point prevalence cultures are collected from patients in
 the ICU on that day.

 Eligible patients in the ICU - in addition to the above mentioned - will receive one of the
 interventions and will undergo surveillance sampling. More anonymized personal data are
 collected (including some clinical culture results).

 A waiver of informed consent is in place, but patients can opt out for data collection.

 Culture sampling

 Point prevalence cultures are taken once monthly from each patient present in the ICU at that
 moment. These include a rectal swab and a respiratory sample and serve the purpose of
 monitoring and evaluating ecological changes during all regimens.

 Surveillance cultures are taken twice weekly from included patients and also include a rectal
 swab and a respiratory sample. The samples are collected to measure the treatment effect.

 Finally, results from regularly obtained cultures for clinical purposes (blood and
 respiratory samples) will be recorded to measure the treatment effect.

 Data-collection

 Data-collection can be performed by two methods. All data will be "anonymised" by recoding
 the patient identifier (ID) to a study patient ID and by removing their personal identifiers.

 1. A web based electronic case report form (ECRF) has been designed within "Research
 Online". This system meets all requirements according to International Conference on
 Harmonisation Good Clinical Practice (ICH-GCP)standards for electronic data entry with
 respect to safeguarding data integrity and data security regulations.

 2. Automatic extraction of data from electronic patient data dossiers may be performed if
 technically possible without harming the patients' privacy.

 Data dictionary

 -  Data from all patients admitted to the ICU include sex, age, disease severity score,
 admission/discharge date, mechanical ventilation (yes/no) and duration, ICU-survival.

 -  Data from included patients additionally include: hospital admission date, place before
 admission, reason for ICU admission, acute illness (yes/no), sites of organ failure,
 antibiotic use on ICU-admission (yes/no), comorbidity, ventilation data, disposition at
 28-days after ICU- admission, at ICU-discharge and at hospital-discharge, isolation
 precautions.

 -  Culture data include results from clinical respiratory and blood samples and
 surveillance cultures from included patients and point prevalence cultures (monthly)
 from all patients.

 -  Ward-level antibiotic use will be recorded per study period.

 Sample size calculation

 In a Dutch SDD ICU trial the day-28 mortality rate during the baseline period was 27.5% (3).
 Assuming a low level of cluster-effects, 2016 patients are needed in each phase to
 demonstrate a 10% relative reduction in day-28 mortality as compared to Standard Care
 (alpha=0.05; beta=0.8). We intend to include 2700 patients per arm. The margin of 600
 patients per arm is included to allow for adjustment for differences in baseline
 characteristics in a random-effects logistic regression model if needed, or to include
 cluster-effects. Of note, assuming day-28 mortality in standard care to be 27%, the absolute
 reduction that can be demonstrated is 2.7%. Day-28 mortality data will be derived from
 clinical data obtained as part of routine standard care.

 STATISTICAL ANALYSIS PLAN (updated October 2017)

 INTRODUCTION.

 Analysis will determine the effect of each intervention in the occurrence of bacteremia,
 patient survival, colonization rates, and the use of antibiotics. Statistical analysis of the
 primary objective and secondary objectives regarding mortality, bacteremia and ward-level
 colonization with antibiotic resistant bacteria will account for ICU-level clustering and the
 statistical methods used are described in detail in below. The use of antibiotics will be a
 descriptive statistic.

 All available data on patient colonization with MDR-GNB (both from screening and clinical
 cultures) will be used to determine, as carefully as possible, the extended-spectrum
 beta-lactamase (ESBL) colonization status of each patient on every study day. Nosocomial
 transmission capacities (RA-values) for different species of MDR-GNB during study regimens
 will be quantified. As a secondary aim species-specific RA values will be compared between
 wards. Available data will be used to quantify incidences of cross-transmission in both study
 periods, using sophisticated modeling approaches.

 Investigators and the R-GNOSIS staff will make every attempt to collect complete data from
 all subjects enrolled in the study. Where possible, automatic extraction of data from
 hospital information systems will be used (without disclosing patient identifiers). There
 will be regular contact between the study coordinating centre and study sites to track and
 retrieve missing data. Should culture results be inadvertently lost, those data will be
 treated as missing at random. All inferential analyses will be based on available data.

 The detailed statistical analysis plan has been established prior to database lock and is
 divided into two parts.

 PART 1: Clinical outcomes (patient data)

 The data

 The data analysis will be performed on all patients included during the baseline period, the
 last 2 weeks of the wash-out/in periods and those included during one of the three
 intervention periods. Two ICU admissions of the same patient with less than 3 days in between
 will be merged and analyzed as one ICU admission.

 The following cohorts will be made for analysis of the following clinical outcomes:

 1. Cohort "ICU-admissions": ICU-acquired bacteremia, ICU survival.

 2. Cohort "Hospital-admissions": Hospital survival

 3. Cohort "first ICU-admissions", excluding re-admissions to the ICU within 30 days after
 prior ICU-discharge: 28-day survival

 Missing data.

 Missing data will be retrieved where possible, after which a complete case analysis will be
 performed.

 Statistical models.

 To adjust for potential selection bias in this cluster randomized trials with crossover
 (without blinding), the statistical analysis will be performed using doubly robust
 estimation. [Funk MJ et al. Am J Epidemiol 2011]

 Propensity score model.

 The propensity score model will include the following a priori selected confounders:

 -  Age

 -  Gender

 -  Disease severity (either APACHE II or SAPS II score)

 -  Use of antibiotics upon ICU-admission

 -  Prior location before ICU-admission

 -  Admission type (medical/surgical/trauma)

 -  Charlson comorbidity score

 -  Hospital of recruitment (hospital) As two different scoring methods , APACHE II or SAPS
 II, have been used to determine disease severity by different hospitals, two separate
 propensity score models will be fitted (one for hospitals that recorded APACHE II and
 one for hospitals that recorded SAPS II).

 These propensity score models will be fitted in the cohort "ICU-admissions" using the
 R-package 'twang'. [McCaffrey Stat Med. 2013] This package uses generalized boosted models
 machine learning techniques to calculate weights for each patient. The resulting weights
 represent the inverse probability for a patient to be included in the baseline, CHX, SOD or
 SDD arm and will be used to weigh the data in the outcome models , creating
 pseudo-populations with an equal distribution of the specified covariates over treatment
 groups.

 Outcome models.

 Separate models will be fitted per endpoint, as specified in table 1. All models will include
 the inverse probability weights, the confounders included in the propensity score model and
 the mean hand hygiene compliance per study period per hospital (hand hygiene compliance might
 differ per study period and act as a confounder on all outcomes) to obtain doubly robust
 estimators. A dummy variable indicating the measure of disease severity (APACHE II or SAPS
 II) will be included as an interaction with the standardized disease severity to overcome
 different hospital having registered different measures. In addition, two levels of
 clustering will be taken into account, as follows:

 -  Hospital of recruitment: fixed effect, acknowledging that the risk of the outcome
 differs per hospital

 -  Cluster period (i.e. periods 1-4 per hospital): random intercept, acknowledging that
 patients recruited in different periods within hospitals may be more alike with regard
 to the risk of the outcome.

 Table 1. Outcome models per endpoint

 -  ICU-acquired bacteremia Model: Cox proportional hazard (hazard ratio) Competing
 endpoints: ICU discharge, death in ICU

 -  ICU survival Model: Cox proportional hazard (hazard ratio) Competing endpoint:
 ICU-discharge

 -  ICU survival Model: Cox proportional hazard (hazard ratio) Competing endpoint:
 hospital-discharge

 -  28-day survival Model: generalized linear model (odds ratio) Family: (quasi)binominal
 Link: logit

 Results will be presented as hazard ratios or odds ratios with 95%-CI. R and STATA will be
 used to perform the analyses specified above.

 Sensitivity analysis.

 As eligibility in this open cluster-randomized study was defined as "Expected length of MV
 >24h", selection bias may have occurred (as discussed under 'confounding adjustment'). To
 quantify this potential bias a sensitivity analysis will be performed in which patients who
 left the ICU within 2 days after study inclusion are excluded, as these patients could not
 reach the ICU-acquired bacteremia primary endpoint (which requires at least three days in
 ICU).

 Exploratory analysis.

 As an exploratory analysis the treatment effect on 28-day survival and ICU-acquired
 bacteremia per ICU will be visualized in Forest plots, in which ICUs are ranked on the
 prevalence of bacteremia with highly resistant micro-organisms (HRMO) during the baseline
 period.

 PART 2: Antibiotic resistance (ward level data)

 The data.

 The monthly point prevalence screenings on both included and non-included patients will be
 analyzed on two levels, each including outcomes for individual HRMO (e.g. carbapenem
 resistant GNB, MRSA, etc.) and the aggregate "any HRMO".

 1. Cohort "respiratory tract"

 2. Cohort "digestive tract"

 Missing data.

 If a patient or tractus was not sampled, it will be excluded from the analysis (and the
 denominator). If an antibiotic susceptibility result was missing, the highest susceptibility
 result from the same species in the same tractus 7 days prior or after the point prevalence
 date was "imputed", if available. Completeness of susceptibility testing will be reported as
 a descriptive statistic.

 Since monthly point prevalence measurements are taken on fixed days (i.e. first Monday,
 occasional exceptions accepted) on all patients present in the ward (both included and
 non-included) we do not expect bias due to selective inclusion per study period (as in the
 analysis of the clinical outcomes).

 Final models.

 We will perform logistic regression analyses with a log-link for each endpoint and include
 terms for underlying time-trend per hospital (months since study start * hospital) and
 time-trend per intervention (months since start study period * study period) and correct for
 repeated measurements on the same patient (corrected standard errors with sandwich
 estimator). Results will be presented as risk ratio's with 95%-CI.

 Quality and safety assurance plan

 The quality of the study will be assured by two methods.

 1. An external safety committee (SCom) consisting of three experts has the objective to
 guard the ecological safety during the study. During the intervention periods (CHX-Oro,
 SOD, SDD), the SCom will issue recommendations to continue or stop the study on a
 quarterly basis (three monthly), based on the results of monthly point prevalence
 cultures and input by participating ICUs.

 The primary safety measure to detect an increase of anti-microbial drug resistant
 bacteria is performing point prevalence cultures in all patients in the participating
 ICUs. The purpose of these cultures is to evaluate and ensure ecologic safety. Analysis
 will detect any multi-drug resistant gram negative bacteria (MDR-GNB), vancomycin
 resistant enterococci (VRE) or methicillin-resistant Staphylococcus aureus (MRSA)
 isolates. Also, susceptibility of /MDR-GNB to colistin, both used in SDD and SOD, will
 be tested. This way, any increase in the number of resistant isolates will be detected
 early.

 2. Guidelines for reporting suspected unexpected serious adverse reactions (SUSAR's) have
 been developed. In ICU patients, co-morbidity and the natural history of the underlying
 critical illness can cause events which would meet the definition of (serious) adverse
 events. Given the natural occurrence of these events and the low risk for adverse drug
 reactions based on the broad experience with the current study medication, only the
 following adverse events will be recorded:

 1. Adverse events possibly related to the medication (as judged by medical and
 scientific judgement) AND

 2. Deemed serious by medical or scientific judgement (as judged by either the
 investigator of treating physician) AND

 3. Not part of the natural history of the underlying critical illness

 Adverse events meeting these criteria should be reported by the local investigator
 within the following time limits:

 -  to the coordinating investigator within 24 hours

 -  to the accredited Institutional Review Boar (IRB) that has approved the protocol in
 that country (within 7 days if the event is life-threatening or fatal, within 15
 days if the event is not life-threatening or fatal)

 -  to the competent authority of that country (within 7 days if the event is
 life-threatening or fatal, within 15 days if the event is not life-threatening or
 fatal)

 3. A monitoring plan has been developed, in which:

 1. The SPONSOR completes a central monitoring form for each participating hospital
 every three 3 months. This form registers for example the quality of transferred
 data, recruitment rate and the occurrence of site specific problems.

 2. Each participating hospital completes a site self-monitoring form every three
 months. This form registers the completeness of the Investigator Site File,
 completeness of drug accountability and the correct reporting of suspected
 unexpected serious adverse reactions (SUSAR's).
Inclusion Criteria:

 -  mechanical ventilation (only invasive ventilation: i.e. intubated patients or patients
 with tracheostomal ventilation)

 -  no planned extubation within 24 hours When mechanical ventilation is not started
 directly after admission but later in the course of their ICU stay, patients are still
 eligible to participate.

 Exclusion Criteria:

 -  patients under the age of 18

 -  patients with known allergy to any of the medications or agents used (i.e. colistin,
 tobramycin, nystatin or chlorhexidine )

 -  pregnancy

 Participation ends as soon as the patient is extubated or after tracheostomal ventilation
 has stopped (weaning completed).