Charles Frenette

Continuous Proton Pump Inhibitor Therapy and the Associated Risk of Recurrent Clostridium difficile Infection

IMPORTANCE Clostridium difficile infection (CDI) is associated with significant morbidity, mortality, and a high risk of recurrence. Proton pump inhibitor (PPI) use is associated with an initial episode of CDI, and PPIs are frequently overprescribed. For many, the use of PPIs could likely be discontinued before CDI recurrence. OBJECTIVES To determine whether PPI use was associated with a risk of initial CDI recurrence, to assess what proportion of patients who developed CDI were taking a PPI for a non-evidence-based indication, and to evaluate whether physicians discontinued unnecessary PPIs in the context of CDI. DESIGN, SETTING, AND PARTICIPANTS We conducted a retrospective cohort study of incident health care-associated CDI cases to determine the association between continuous PPI use and CDI recurrence within 90 days. The setting was 2 university-affiliated hospitals, the 417-bed Montreal General Hospital (Montreal, Quebec, Canada) and the 517-bed Royal Victoria Hospital (Montreal, Quebec, Canada). The cohort consisted of 754 patients who developed health care-associated CDI between January 1, 2010, and January 30, 2013, and who survived for a minimum of 15 days after their initial episode of nosocomial CDI. EXPOSURE Continuous PPI use. MAIN OUTCOMES AND MEASURES Recurrence of CDI within 15 to 90 days of the initial episode. RESULTS Using a multivariable Cox proportional hazards model, the cause-specific hazard ratios for recurrence were 1.5 (95% CI, 1.1-2.0) for age older than 75 years, 1.5 (95% CI, 1.1-2.0) for continuous PPI use, 1.003 (95% CI, 1.002-1.004) per day for length of stay, and 1.3 (95% CI, 0.9-1.7) for antibiotic reexposure. The use of PPIs was common (60.7%), with only 47.1% of patients having an evidence-based indication. Proton pump inhibitors were discontinued in only 3 patients with CDI. CONCLUSIONS AND RELEVANCE After adjustment for other independent predictors of recurrence, patients with continuous PPI use remained at elevated risk of CDI recurrence. We suggest that the cessation of unnecessary PPI use should be considered at the time of CDI diagnosis.

Seasonal Variations in Clostridium difficile Infections Are Associated with Influenza and Respiratory Syncytial Virus Activity Independently of Antibiotic Prescriptions: a Time Series Analysis in Québec, Canada

ABSTRACT Seasonal variations in Clostridium difficile-associated diarrhea (CDAD), with a higher incidence occurring during winter months, have been reported. Although winter epidemics of respiratory viruses may be temporally associated with an increase in CDAD morbidity, we hypothesized that this association is mainly due to increased antibiotic use for respiratory infections. The objective of this study was to evaluate the effect of the two most frequent respiratory viruses (influenza virus and respiratory syncytial virus [RSV]) and antibiotics prescribed for respiratory infections (fluoroquinolones and macrolides) on the CDAD incidence in hospitals in the province of Québec, Canada. A multivariable Box-Jenkins transfer function model was built to relate monthly CDAD incidence to the monthly percentage of positive tests for influenza virus and RSV and monthly fluoroquinolone and macrolide prescriptions over a 4-year period (January 2005 to December 2008). Analysis showed that temporal variations in CDAD incidence followed temporal variations for influenza virus (P = 0.043), RSV (P = 0.004), and macrolide prescription (P = 0.05) time series with an average delay of 1 month and fluoroquinolone prescription time series with an average delay of 2 months (P = 0.01). We conclude that influenza virus and RSV circulation is independently associated with CDAD incidence after controlling for fluoroquinolone and macrolide use. This association was observed at an aggregated level and may be indicative of other phenomena occurring during wintertime.

Antibiotic Self-stewardship: Trainee-Led Structured Antibiotic Time-outs to Improve Antimicrobial Use

Antibiotic resistance is a major public health issue that substantially affects patient outcomes and costs (1). With new antimicrobials few in number and far off in development (2), we need to maximize the effectiveness of todays therapy and preserve it for tomorrow by preventing resistance. This and the prevention of Clostridium difficile infection are 2 of the main goals of antimicrobial stewardship. There are several methods of stewardship (3); one of the most effective, prospective audit and feedback, uses consultants in infectious diseases or trained pharmacists to review use case by case (4). The expertise required limits the implementation of such programs (3, 4). Given that the Centers for Disease Control and Prevention (CDC) suggests that nearly 50% of antimicrobial use is unnecessary or inappropriate (5), it is clear that widely available methods of stewardship need to be developed. In an online campaign called Get Smart for Healthcare, the CDC suggests that clinicians take an antimicrobial time-out to review the dose, duration, and indication when cultures and new clinical information become available (6). While planning our local stewardship program, we recognized that our resources were limited and our needs great. Although it seemed logical that time-outs could lead to reduced antibiotic use, we believed that without education and a formal structure, they would be forgotten or underutilized. We developed an educational curriculum and electronic checklist to provide structure and subsequently implemented mandatory time-out audits on our internal medicine clinical teaching units. These time-out audits were integrated into routine clinical practice by our senior residents, who performed a process that we called antimicrobial self-stewardship. Methods Setting The study was conducted in two 23-bed internal medicine clinical teaching units in the Montreal General Hospital, a 417-bed tertiary care hospital. Each unit has an attending physician, a senior resident (second-year), 2 first-year residents, and 2 medical students. A third-year resident is shared between the teams who focuses their time on quality improvement projects, teaching, and procedural support. Attending physicians work a variable number of 2-week blocks per year. Resident physicians have three to four 1-month rotations per year. Interventions The study investigators included consultants in infectious diseases, critical care medicine, and general internal medicine with expertise in the management of hospitalized patients. Through consensus, we developed a 30-minute teaching session (Data Supplements 1 and 2) that addressed the importance of antibiotic stewardship, our guidelines for the most common infectious diseases encountered, and how to perform self-stewardship. These sessions were given monthly to all rotating housestaff. Data Supplement 1. Antimicrobial Self-Stewardship: Putting the CDCs antibiotic timeouts to work Data Supplement 2. Antimicrobial Self-Stewardship: How to use the online tool Our stewardship team (Drs. Lee and Frenette) developed an online checklist (Data Supplement 3) that formalized each time-out audit into a step-by-step process meant to approximate how an infectious diseases specialist might approach prospective audit and feedback. We specifically targeted 4 key antimicrobials: 1) carbapenems, which were the most expensive class with the broadest spectrum of activity; 2) moxifloxacin, which was chosen to reduce C. difficile infection and to reduce gram-negative exposure to the quinolones; 3) piperacillintazobactam, which is the most widely used broad-spectrum antibiotic at our institution; and 4) vancomycin, because it is potentially overused in patients without risk factors for infection with -lactamresistant gram-positive organisms and is associated with nephrotoxicity. Data Supplement 3. Stewardship checklist To limit workload, we chose to implement audits twice weekly. On each audit day, the senior resident would apply the checklist to all patients receiving antibiotics. Each unit audited required 30 minutes to complete. Residents were reminded to perform the audits by the unit pharmacists, but performance was not directly observed. At the end of each month, antibiotic use was reviewed using the qualitative data from the audits and the results were fed back. Measurements Information on antibiotic use from 1 April 2010 to mid-January 2012 (control period) and from mid-January 2012 until the beginning of June 2013 (intervention period) was obtained from the pharmacy as World Health Organization defined daily doses (DDDs) (7). The DDDs were available by fiscal period (13 periods per year, beginning in April) and were standardized per 1000 patient-days. Cost was standardized to the June 2013 price per DDD in Canadian dollars. Because an automatic substitution from ticarcillinclavulanate to piperacillintazobactam occurred in mid-2011, the lower price was used for both. Only antibacterial agents were included. Rates of nosocomial C. difficile infection were calculated as the number of polymerase chain reactionpositive cases per 10000 patient-days. In keeping with Quebec reporting standards, a nosocomial case was identified when symptoms occurred more than 3 days after admission or symptoms caused readmission in a patient who had been hospitalized on our unit within the previous 2 months and who was not a resident in a long-term care facility. Primary outcomes were the cost and quantity of antibiotics used both overall and with a focus on our targeted drugs, and rates of C. difficile infection per 10000 patient-days. Secondary outcomes were length of stay, number of monthly intensive care unit (ICU) transfers, and mortality per 10000 patient-days. McGill University Health Center ethics approval was obtained. Statistical Analysis We conducted segmented regression analysis of an interrupted time series, as described by Wagner and colleagues (8). Models were created for total antibiotic use and for each of the 4 targeted drugs or classes. Each interrupted time series can be specified as E(Y) = constant + 0*t + 1*X1+ 2 *t*X1, where Yt is the dependent variable (antibiotic use), t indicates the order of the observations (fiscal period), and X1 is a dummy variable indicating whether the observation was taken before or after the intervention. In this method, we use the preintervention period as the control for the postintervention period. If 1 differs statistically from zero, this implies that there was a change in the absolute level of use of the drug after intervention. If 2 differs statistically from zero, this implies that there was a change in the trend of use (slope of the line) after intervention. The time-series analyses were done using the tsset and regress commands. Autocorrelation in the residuals was evaluated by using the DurbinWatson method (estat dwatson command). Rates of C. difficile infection and mortality before and after intervention were compared by using the Z test for incidence rate ratios. Before-and-after comparisons in the average length of stay and the median monthly number of ICU transfers were compared by using the 2-tailed t test and Wilcoxon rank-sum test, respectively. All comparisons were performed by using Stata, version 11 (StataCorp). Role of the Funding Source This project was completed without any funding. Faculty members donated their time. Resident physicians were paid their usual salary because the time-out audits were considered clinical work. The monthly faculty time required was 1 hour, and the monthly resident time totaled 8 hours (108 hours per year). Results During the intervention period (mid-January 2012 to the start of June 2013), 23 staff physicians attended a median of 6 weeks each. There were 15 senior residents who worked a median of 12 weeks each. There were a total of 1548 admissions, with 1513 time-out audits performed on 1062 unique infections involving 679 unique patients. Auditing was performed on 80% of assigned days. Pneumonia was the most common infection (25%), followed by urinary tract infection (12%), C. difficile (9%), and cellulitis (7%). The top 5 classes of antibiotics used at the time of initial time-out audit were antipseudomonal penicillins (23%), fluoroquinolones (16%), glycopeptides (13%), narrow-spectrum -lactams (12%), and third-generation cephalosporins (7%). The initial time-out led to a change in antibiotic therapy in 15% (154) of infections audited. Among these changes, 55% involved dose or duration only and the other 45% involved a change in therapy. Changes were less frequent in subsequent audits (9%). These data are presented in Table 1. Changes were more common in patients receiving piperacillintazobactam (20%), a fluoroquinolone (20%), or vancomycin (14%) than in those receiving a carbapenem (6%) (Table 2). Changes or cessations that occurred before or between the time-outs were not captured. Table 1. Antibiotic Changes Made During the First and Subsequent Audits Table 2. Antibiotic Changes Made During the First Audit, by Initial Antibiotic Choice The total annual standardized cost of antibiotics for the units decreased from

Healthcare-associated bloodstream infections secondary to a urinary focus: the Québec provincial surveillance results.

149743 (January 2011 to December 2011) to

Healthcare-Associated Influenza in Canadian Hospitals from 2006 to 2012

80319 (January 2012 to December 2012), for a year-on-year savings of

Epidemiology of central line–associated bloodstream infections in Quebec intensive care units: A 6-year review

69424 (46% reduction). Of the savings,

Comparison of eight commercial enzyme immunoassays for the detection of Clostridium difficile from stool samples and effect of strain type

54150 (78%) was related to carbapenem use and

Central line-associated bloodstream infection in neonatal intensive care units.

15274 (22%) was due to other classes. On the basis of 108 physician-hours per year, this would represent a return of

First Canadian outbreak of Enterobacteriaceae-expressing Klebsiella pneumoniae carbapenemase type 3.

140 to

Positive cultures of organ preservation fluid predict postoperative infections in solid organ transplantation recipients.

640 per hour, excluding and including carbapenems, respectively. In the time-series analysis, the total monthly use of antibiotics was unchanged (P= 0.91 for level; P= 0.100 for trend) and averaged 720 DDDs per 1000 patient-days per period throughout the study (Figure 1). Figure 2 shows the monthly use per fiscal period in DDDs per 1000 patient-days for moxifloxacin, carbapenems, vancomycin, and antipseudomonal penicillins. The only reliable, statistically significant change was a reduction i