C Difficile Near-patient Diagnostics
C Difficile Near-patient Diagnostics
The investigators will conduct a two-period, two-intervention, cluster randomized crossover
 (CRXO) designed study at Foothills Hospital. Each cluster (hospital ward) will receive each
 of the two interventions in a separate 6-month period of time leading to two
 "cluster-periods" with associated "wash-in" and "wash-out" periods attached. The two
 interventions are: 1) a rapid diagnostic test (RDT) using near-patient testing (NPT) for C.
 difficile infections (CDI); 2) testing for CDI using centralized testing facilities (standard
 operating procedure, 2 step algorithm).

 The investigators hypothesize that NPT for CDI will result in reduced patient isolation days
 in the hospital, decreased morbidity and mortality, reduced unnecessary antibiotic use and
 overall reduced costs to the health care system, including both hospital and laboratory.

 Our primary endpoint is to examine the differential effect of NPT on the duration of contact
 precautions (i.e. patient isolation days). Secondary outcomes will compare turn-around times
 from specimen submission to result, days of hospitalization, the number of days of antibiotic
 therapy, the incidence of CDI, severe CDI, and in-hospital mortality. A comprehensive
 economic evaluation will be performed to determine the cost of testing, patient isolation,
 and hospitalization for all patients in the control and treatment arms.
Clinical microbiologists have developed a two-step algorithm in which an EIA or a RDT is
 first used to screen stools for the presence of glutamate dehydrogenase (GDH) antigen derived
 from C. difficile. The GDH antigen test is very specific (> 95%) and negatives could be
 reported right away, only requiring GDH-positive toxin-positive specimens by EIA or RDT to be
 confirmed by NAAT. In Calgary, the two-step algorithm is performed for a population of close
 to 1.5 million people at an offsite Diagnostic and Scientific Centre (DSC). The use of a
 testing centre, however, undermines to some extent the advantages of the rapid testing
 methodologies developed in recent years, because of increased transportation and processing
 time.

 A key issue in many settings, including ours, is that testing falls into a separate budget
 from the treatment of patients with CDI infections. This has the potential to distort the
 decision of whether to run a test and, if so, what sort of test. The distortions are of two
 types. First, the hospital may decide to order more tests than is optimal, since the tests
 are perceived as "free" from the perspective of decision-makers. At the same time, the
 diagnostic facility may choose low-cost, slow diagnostics, because the costs associated with
 delays in test results are borne by the hospital. This is a classic case of silos in health
 care costs inefficiently distorting policy decisions, with potentially negative results for
 both patient health and costs.

 Many institutions follow the clinical practice guidelines provided by the Infectious Diseases
 Society of America for the management of C. difficile (Cohen et al., 2010). As part of
 routine Infection Prevention and Control (IPC) management, patients with acute diarrhea of
 unknown cause are pre-emptively placed in private rooms with additional contact precautions,
 which mandate the use of gowns and gloves for healthcare workers. This is also known as
 patient isolation. Investigation for gastrointestinal pathogens is typically initiated and
 the duration of patient isolation depends largely on the result of microbiological testing.
 When severe or complicated CDI is suspected, patients are initiated on empiric treatment as
 soon as the diagnosis is suspected. Generally, oral metronidazole is used for
 mild-to-moderate CDI and oral vancomycin for severe CDI. Among hospitalized patients with
 acute diarrhea, initiation of pre-emptive management for CDI is common.

 The intervention of interest is implementing a new RDT to Near Patient Testing (NPT); initial
 screening for CDI to be performed at the hospital rapid response laboratory (RRL) instead of
 the DSC. Techlab Inc. offers a lateral flow assay (C. DIFF QUIK CHEK COMPLETE® test) that
 detects both GDH and Toxin simultaneously and further simplifies the testing algorithm. As
 prescribed in the two-step algorithm, GDH and Toxin negatives will be reported out
 immediately as negative for CDI, while positive or discrepant results will be confirmed at
 the DSC using NAAT. The vast majority of requests for CDI testing are negative thus allowing
 a majority of results to be reported immediately without confirmation at the DSC.

 The Investigators will conduct a two-period, two-intervention, cluster randomized crossover
 (CRXO) design study at Foothills Hospital. Each cluster (ward) will receive each of the two
 interventions in a separate 6-month period of time leading to two "cluster-periods" with
 associated "wash-in" and "wash-out" periods attached. The interventions are RDT using NPT for
 CDI, and testing for CDI using our centralized testing facility.

 This study is cross-sectional CRXO in that, each cluster-period consists of different
 individuals (patients). The order in which the interventions are delivered to each cluster
 (ward) is randomized to control for potential period effects. Within Foothills Hospital there
 are 40 wards which will be observed over a 12-month period. Each ward is randomly assigned to
 administer one of the two interventions for the first 6-month period (Period 1). In the
 second 6-month period (Period 2), the ward will administer the other intervention. Within
 each ward (cluster) there are two cluster-periods. Study outcomes during Period 1 and Period
 2 intervention will be compared in both arms (NPT and centralized laboratory testing).

 NPT testing can deliver results within several hours, while typically off-site testing takes
 about one to two day. If NPT and the off-site testing deliver identical test results as our
 pilot data suggest, the investigators can follow the clinical outcomes for each arm without
 the confounder of differences in test performance. As a contingency, if variation in test
 performance characteristics is found, analysis of patient outcomes will take this into
 consideration.

 For patients without CDI, the antibiotics, and in many cases, the isolation, is unnecessary.
 NPT testing has the potential to avoid this unnecessary use of antibiotics and to avoid
 costly isolation procedures for the day+ that standard testing requires. It also enables a
 better-directed diagnostic process for the cause of diarrhea. For patients who are positive
 for CDI, the earlier test result will influence downstream events such as initiation of
 antibiotic therapy, resolution of disease, hospitalization days, and other clinical outcomes.

 The investigators hypothesize that NPT for CDI will result in reduced patient isolation days
 in the hospital, decreased morbidity and mortality, reduced unnecessary antibiotic use and
 overall reduced costs to the health care system, including both hospital and laboratory.

 Previous data at this facility has indicated that the mean number of patients per ward is
 39/month (SD=43) for a total of 1578 patients in a 6-month period and the mean number of
 negative patients is 33/month (SD=34) for a total of 1300 negative pts in a 6-month period
 The inclusion criteria will be diarrhea in adult patients admitted to four acute care
 hospitals in the Calgary region being tested for CDI. Outpatients and patients in the
 emergency room will be excluded.

 Our primary endpoint is to examine the differential effect of NPT on the duration of contact
 precautions (i.e. patient isolation days). Secondary outcomes will compare turn-around times
 from specimen submission to result, days of hospitalization, the number of days of antibiotic
 therapy, the incidence of CDI, severe CDI, and in-hospital mortality. A comprehensive
 economic evaluation will be performed to determine the cost of testing, patient isolation,
 and hospitalization for all patients in the control and treatment arms.

 Contact precautions (i.e. patient isolation) due to CDI will be defined as an order by
 healthcare workers for contact precautions within the 7-day infection window of a CDI
 diagnosis. The length of time on contact precautions will be defined as the calendar date
 contact precautions are completed or patient discharge date minus the calendar date contact
 precautions are ordered. Data on contact precautions will be extracted from the clinical
 patient management system in Calgary, known as Sunrise Clinical Manager (SCM). It is used
 extensively in all Calgary acute care facilities and emergency departments. These data
 include patient identifiers (e.g. patient health number, names, date of birth), start and
 stop dates of isolation, facility, and patient care unit where isolation order was placed,
 and the reason for isolation (e.g. CDI, diarrhea). These data will be linked to the specimen
 results tested for CDI by the patient's Personal Health Number (PHN). Turn-around times from
 specimen submission to result will be provided by Calgary Laboratory Services. Days of
 hospitalization will be defined as the difference between the admission and discharge date.
 The specimen results will be linked to the Discharge Abstract Database using the patient's
 PHN to determine during which acute care encounter the specimen was collected and the
 admission/discharge dates of that encounter. Antibiotic therapy will be defined as the
 administration of antibiotics initiated on the day of and up to 48 hours after specimen
 collection for CDI testing. Total days of antibiotic therapy during the acute care encounter
 will be defined as the calendar date antibiotic therapy is completed minus the calendar date
 antibiotic therapy is ordered. The data will be extracted from SCM.

 The investigators will also account for the severity of CDI. The epidemiological definition
 for severe CDI is that primarily proposed by Cohen et al. This definition has been used by
 infectious disease specialists in Alberta to guide the management and treatment of patients
 with CDI. Patients with severe CDI will have leukocytosis with a white blood cell (WBC) count
 >15,000 cells/µL OR an elevated serum creatinine (i.e. 200 µmol/L or greater). The inpatient
 laboratory results that will be considered to meet the definition for severe CDI will be
 those collected within a 7-day infection window around the date the laboratory tested
 positive for C. difficile. The presence of either measure meeting the criteria within the
 defined infection window will qualify as meeting the definition of severe CDI. If either
 criterion is measured more than once during the infection window, the highest value will be
 used to represent the severity of CDI. The laboratory values will be provided by Calgary
 Laboratory Services and linked to the positive C. difficile test results. In-hospital,
 all-cause mortality will be defined as death occurring during the acute care encounter where
 specimens were collected for C. difficile testing.

 The investigators predict that, given the large number of patients and randomized study
 design, matching of patients by age, gender, and co-morbidities is not required. Potential
 hurdles in the study model are logistical challenges associated with building a testing and
 reporting system for a hospital on 24hrs/7 days per week basis. The strength of the proposal
 lies in the scale and nature of the study which seeks to establish the medical and economic
 benefit of NPT versus centralized testing. The results could dramatically influence public
 health policy in this country and seek to bridge traditional silos, namely the laboratory and
 hospital budgets. Data on costs will be furnished by our partners at Calgary Laboratory
 Services/Alberta Health Services (Infection Prevention and Control).

 Beyond evaluating the relative merits of NPT versus centralized testing, studies will also
 look at the microbiology of CDI in this study. Specifically, the investigators will conduct
 several laboratory methods to examine antibiotic resistance and genetic variation in CDI. For
 example, whole genome sequencing of cultured CDI isolates may inform us about the
 transmission of specific strains in our setting. Indeed, certain strains and states of gut
 dysbiosis may result in increased morbidity and mortality (Shahinas et al., 2012). The
 investigators will look at the microbiome of patients in this study to determine if dysbiosis
 contributes to adverse clinical outcomes. The investigators will also correlate the strain
 types with the results of testing to determine if genetic variation affects test performance.
 Cultured toxin-producing CDI isolates will serve as a gold standard to evaluate test
 performance.
Inclusion Criteria:

 -  Patients located on inpatient wards for whom C. difficile test is ordered at Foothills
 Medical Center. Usually defined by having 3 or more loose bowel movements in a 24 hour
 period.

 Exclusion Criteria:

 -  No diagnostics for C. difficile requested. Inpatient at a different facility. All
 outpatients.