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Evaluation of the Impact of Pharmacist-Led Communication of the Clinical Pulmonary Infection Score (CPIS) on Antibiotic Prescribing in the Intensive Care Unit – A Pilot StudySt Joseph’s Healthcare Hamilton. Lanny Tran PharmD, RPh, ACPR Candidate

Submitted to the Pharmacy Residency Advisory Committee of St. Joseph’s Healthcare Hamilton in partial fulfillment of the requirements of the 2015-2016 Hospital Pharmacy Residency Program

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I would like to acknowledge the following individuals:

Angela Wright – for your unwavering support and diligence, from start to finish

Christine Wallace – for your expertise, patience and dedication

Dr. Phillippe El-Helou, Vida Stankus and Jennifer Lee – for your enthusiasm and support in initiating the project

My family and friends – for everything you do

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Abstract

Background:

Overprescribing of antibiotics for nosocomial pneumonia is the Intensive Care Unit (ICU) is a prevalent issue in antimicrobial stewardship. Use of the Clinical Pulmonary Infection Score (CPIS) to guide antibiotic discontinuation in patients with a low probability of nosocomial pneumonia had led to a reduction in antibiotics days, decreased costs and decreased antimicrobial resistance. However it is not known whether a similar pharmacist-led CPIS initiative would have the same impact.

Objectives:

The primary objective was to determine the feasibility of a pharmacist-led CPIS initiative at our institution. The secondary objectives were to determine the impact of this initiative on antibiotic prescribing, ICU length of stay and cost, and to discern prescriber rationale for Day 3 antibiotic continuation where patients are eligible for discontinuation.

Methods:

A prospective, interventional pilot study was conducted from March 21 to May 16, 2016 in the ICU at St. Joseph’s Healthcare Hamilton (SJHH). Patients who were being treated for nosocomial pneumonia in the ICU were included in the study. Pharmacists provided communication of the CPIS to the physician team on day 3 of antibiotic use for patients who had a low probability of nosocomial pneumonia (maintained a CPIS score less than or equal to 6 on day 1 and day 3 of antibiotic use). Descriptive data on prescriber rationale for continuing antibiotics beyond Day 3 for these patients was also recorded. . Comparisons were drawn between the study period and data collected previously as part of the local antimicrobial stewardship program (ASP), where there was no pharmacist intervention.

Results:

Eleven patients met the inclusion criteria over the eight-week study period. Barriers identified during the study included a lack of prescriber familiarity with the CPIS and unavailability of pharmacists on weekends. Of the six eligible patients in each period, there were two antibiotic discontinuations with Pharmacist communication in the study period while

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there were none during ASP data collection. There were significantly fewer ICU antibiotic days during the study period as opposed to the ASP period: 11.17 days (95% CI 4.41, 17.93) versus 22.67 days (95% CI 19.03, 26.31). Prescriber rationale for antibiotic continuation beyond Day 3 related to treatment of positive sputum cultures and treatment of extra-pulmonary infections.

Conclusions:

The pilot study demonstrated feasibility of a pharmacist-led CPIS intervention, but also identified some barriers that may have affected the impact of this initiative. The pharmacist-led CPIS intervention resulted in trends towards shorter lengths of ICU stay, shorter intubation durations and increased antibiotic discontinuation, while significantly decreasing antibiotic days. Given the pilot’s small sample size, further larger studies may provide more insight into the potential impact of a pharmacist-led CPIS intervention.

Background

The overuse of antibiotics in the intensive care unit (ICU) for suspected pneumonias is a prevalent issue in antimicrobial stewardship (ASP).1 It is estimated that up to 49% of antibiotic use in the ICU is prescribed for presumed respiratory tract infections.2 However, most cases of pulmonary infiltrate in the ICU are not caused by pneumonia but rather by non-infectious pathology such as pulmonary edema, atelectasis, alveolar hemorrhage or pulmonary infarction. As such, this is identified as an area for quality improvement.3,4

One reason for this trend towards indiscriminate antibiotic use for respiratory infection may be the fact that there is no gold standard of diagnosis established for nosocomial pneumonias.1,3 Clinical criteria such as a fever over 38°C, leukocytosis or leukopenia, purulent secretions are sometimes used in tandem with a radiographic infiltrate to diagnose pneumonia. However, this overall lack of standardization in diagnostic criteria may contribute to frequent diagnosis of pneumonia among inpatients.5

To address the shortcomings in the diagnosis of ventilator-associated pneumonia (VAP), Pugin et al. developed the Clinical Pulmonary Infection Score (CPIS - see Appendix 1) in 1991 which incorporates six variables (leukocyte count, oxygenation, tracheal secretions, body temperature, radiographic infiltrate and cultures) to determine the probability that a patient’s symptoms are due to a pneumonia.6 Originally, the CPIS was

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proposed to indicate a pneumonia when the score is higher than six.6

However, the CPIS has been shown to have poor sensitivity and specificity, with no superiority to clinical criteria4,7 Given that the CPIS is typically more time-consuming to determine, some argue that there is no evidence to recommend this score in routine diagnosis of nosocomial pneumonia.4 The Canadian Critical Care Trials Group tested the discriminative power of the CPIS to provide a diagnosis of VAP in a multicenter study involving 739 patients.4,9 Overall, it indicated that the CPIS had no improved ability to predict VAP than that afforded by chance.9 Other criticisms of the CPIS include the fact that it attributes equal significance to each of its elements (e.g. leukocytosis versus a pulmonary infiltrate) and that some of its components are subjective (e.g. a chest x-ray interpretation and sputum volume).8

Rather than implementing the CPIS for diagnostic purposes, the CPIS has instead been most successfully utilized in guiding clinical decisions for patients with a low likelihood of nosocomial pneumonias, not limited to VAP.10 Singh et al. explored the idea that the CPIS can be used for ASP purposes and investigated its use as a tool to identify patients for whom a shorter course of antibiotic therapy for nosocomial pneumonia might suffice.3 In this randomized controlled trial, patients with a CPIS less than or equal to six maintained at both Days One and Three either continued with standard therapy (choice and duration of antibiotics at the discretion of prescribers) or had antibiotic therapy discontinued.3 They demonstrated that discontinuation of antibiotics in those with a CPIS less than or equal to six maintained through to Day Three of antibiotic therapy resulted in lower rates of antibiotic use with no differences in mortality and length of stay. The emergence of antibiotic resistance was also lower in the group with early discontinuation of antibiotics at Day Three.3 Singh et al. also showed that in 79% of patients, the CPIS remained under or equal to six at three days, concluding that antibiotics can be safely stopped in the majority of ICU patients and that antibiotic discontinuation did not lead to worse outcomes.3

Literature supports that the accuracy of the CPIS score is improved on Day Three as opposed to the first day of treatment.3,4,13 In a prospective cohort study by Tan et al. involving patients with presumed VAP, sensitivity and specificity on Day One of treatment were found to be 35.3% and 95.7% respectively.4 On Day Three however, the score was much improved, with sensitivity and specificity findings of 78.3% and 81.3% respectively.4 This temporal improvement in performance may have been missed in previous meta-analyses seeking to address the CPIS’ diagnostic accuracy, as these typically looked only at Day One performance.12

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Another reason for applicability of the Day Three score may lie in the fact that sterilization of lung tissue has been demonstrated to be achieved with three-day antibiotic treatment for those with VAP.3,13 Singh et al. advise against using the CPIS as a tool to withhold therapy at Day One.3 They reason that although possible that the CPIS could rule out nosocomial pneumonia at this stage, it is also conceivable that patients with an initial CPIS below or equal to a threshold of six had a mild infection (e.g. mild pneumonitis or tracheobronchitis) that resolved with three days of antibiotic therapy.3

A three-day discontinuation timeline also allows for culture data to be available.3 The original six-component CPIS conceived by Pugin et al. has a low diagnostic accuracy as it does not include culture data,.14 However, by including Gram staining or culture data, the CPIS’ accuracy improves significantly (sensitivity and specificity of 85% and 49% versus 78% and 56%, respectively).14

Current clinical practice guidelines support the use of the CPIS. The Clinical Practice Guidelines for Hospital-Acquired Pneumonia and Ventilator-Associated Pneumonia in Adults prepared jointly by the Association of Medical Microbiology and Infectious Disease Canada (AMMI) and the Canadian Thoracic Society (CTS) support the practice of early discontinuation of antibiotics at Day Three when the CPIS is equal to or below a threshold of six.11 In the same way, these guidelines state that a CPIS on Day One is not sufficiently accurate to drive clinical decisions, describing Singh et al.’s approach as a sensible compromise.11 The guidelines also suggest using components of the CPIS to arouse clinical suspicion of hospital-acquired pneumonia (HAP) or VAP, stating that either could be suspected in patients, whether ventilated or not, if two or more of the following clinical features are present: temperature greater than 38°C or less than 36°C; leukopenia or leukocytosis; purulent tracheal secretions and decreased partial pressure of oxygen in arterial blood.11 As these clinical criteria are largely similar to that of the CPIS, it is argued that the CPIS should thus be applicable to both disease states. The AMMI/CTS guidelines go on to plainly recommend that in the presence of two or more of the aforementioned clinical abnormalities, the CPIS should be calculated regardless of whether or not the patient is in the ICU or mechanically ventilated.11

Gorman et al. conducted a 6-month observational study in the intensive care unit, where pharmacists retrospectively calculated the CPIS for patients with VAP.15 They found that at Day 3, 17 (35%) of 49 patients were eligible for early discontinuation of antimicrobial therapy but therapy was actually discontinued in only 2 (12%) of these 17 patients.15 Therefore,

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the authors highlighted a significant opportunity to reduce antimicrobial prescribing in the ICU in this regard.15 During the data collection phase of this pilot study, Oxman et al. subsequently conducted a before and after prospective observational study with an intervention. Their study demonstrated that pharmacist intervention improved the rate in which antibiotics were targeted to culture results. They also attempted to use the CPIS to suggest early Day 3 discontinuation of antibiotics but were unable to demonstrate that pharmacist intervention improved this outcome. However, the landmark study by Singh et al. implied that discontinuation at Day 3 was appropriate for both HAPs and VAPs alike, not solely VAPs as was explored by Oxman et al. Furthermore, Oxman et al. conducted their study in a surgical ICU and over the course of nearly 2.5 years, there were only a total of 48 cases of VAP where pharmacists could intervene and communicate a recommendation for discontinuation.16 Thus it was felt that a pilot study including patients with both HAP and VAP in the ICU at SJHH with a mixed surgical and medical population might provide some insight into the feasibility and potential impact of a pharmacist-led CPIS initiative.

Rationale

Mitigating antibiotic overuse is a patient safety priority at St. Joseph’s Healthcare Hamilton (SJHH). Given the high mortality, frequency, and high cost associated with nosocomial pneumonias in ICUs, this has been identified as an area of quality improvement and the Quality and Patient Safety Steering Committee is exploring Antimicrobial Stewardship (ASP) to assist in this endeavor. Evidence presented has demonstrated that the implementation of the CPIS in the ICU curbs antibiotic use, reduces costs and results in less frequent emergence of resistant organisms.1,2 However, at present, there is no formalized initiative at SJHH involving the CPIS. Therefore it was important to determine whether or not the utilization of this strategy as part of ASP may potentially affect antibiotic prescribing in the ICU. At the time the study was being designed and conducted, we were not aware of any evidence relating to an assessment of its implementation in clinical practice by pharmacists or its acceptance by prescribers.3,10 The objective of this study was to specifically explore whether or not pharmacist-led communication of the CPIS calculation to prescribers may potentially serve as an effective tool in minimizing antibiotic overuse in the ICU. This pilot study also attempts to determine the feasibility for a subsequent, larger study and whether there is potential for uptake by intensivists. This study also examined prescriber acceptance of this

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endeavor and the impact of this strategy on patient-important outcomes, such as intubation duration.

Aim of the Study

The study allowed for assessment of the feasibility and the effectiveness of a pharmacist-led initiative using the CPIS in reducing antibiotic prescribing for presumed pulmonary infections in the ICU. Specifically we sought to examine whether pharmacist-led communication of the CPIS score to prescribers on Day Three of antimicrobial treatment for ICU patients with a diagnosed nosocomial pneumonia affects antimicrobial discontinuation.

Population: Patients admitted to the ICU receiving antibiotic treatment for presumed nosocomial pneumonia

Intervention: Pharmacist-led communication of the CPIS score to the prescriber on Day Three for patients with a CPIS less than or equal to six, and rationale behind early antibiotic discontinuation

Comparison: Data gathered historically by ASP from December 7, 2015 to January 22, 2016, where there was no formalized CPIS initiative

Outcome: Proportion of patients (with CPIS less than or equal to six) where antibiotics are discontinued on or prior to Day Three

Study Objectives

Primary Objective

To broadly assess the feasibility of the project in terms of recruitment potential and acceptance of the clinical intervention (i.e. communication of the score to prescribers)

Outcome:

o Rate of patient recruitment o Proportion of patients eligible for interventiono Rate of prescriber acceptance for antibiotic discontinuationo Descriptive summaries of barriers encountered during the

pilot study

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Secondary Objectives

To determine the impact of a pharmacist-led CPIS initiative on ICU antibiotic prescribing and patient-important outcomes

To discern prescriber reasoning behind uptake or resistance to the use of the CPIS in clinical practice

Outcomes:

o Mean number of days in hospital where patients receive an antibiotic prescribed for a nosocomial pneumonia

o Mean per patient cost of antibiotics o Mean number of days where patients are intubatedo Mean length of stay in ICUo Proportion of patients where antibiotics prescribed for a

nosocomial pneumonia are discontinued on or prior to Day Three.

o Descriptive summary of prescriber rationale for continuation or discontinuation of antibiotics

Methods

Study Design

This project was a prospective interventional study conducted to assess the feasibility, acceptance and performance of a new pharmacist-led CPIS strategy, with comparisons to previously extracted historical data. It was conducted in the ICU of SJHH’s Charlton Campus from February to April, 2015. For comparison purposes, the study utilized data collected previously under the authority of SJHH’s ASP initiative, where there was no communication of CPIS to prescribers.

Study Population

All patients admitted to the ICU with antibiotics prescribed for a presumed nosocomial pneumonia were included in this study. Given that the monitoring of antibiotic use and communication of recommendations relating to antibiotic discontinuation are within the scope of practice and

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circle of care of the ICU pharmacist, consent was not sought. This study sought only to collect data on the actions and resulting impact of ICU pharmacist recommendations.

Exclusion criteria included: patients less than 18 years of age, patients with chemotherapy-induced neutropenia, HIV infection, patients being treated for a pneumonia with antibiotics for over 24 hours prior to ICU admission, patients previously included in the data collection period conducted by ASP when there was no implementation of a formalized pharmacist-led CPIS strategy and patients with a Day 3 CPIS less than or equal to 6 on a Saturday or Sunday when unit pharmacists were not available.

Data Collection and Outcome Measures

Data was collected prospectively for an eight-week period. Prior to the commencement of this period, critical care prescribers were acquainted with the objectives of the CPIS strategy and this study. An in-service presentation relating to the project and supporting evidence was conducted during ASP rounds and a summary sheet was circulated throughout the ICU (Appendix 10).

Patients with newly prescribed antibiotics in the ICU were identified by pharmacists using ASP auditing lists and Horizon Meds Manager (HMM) software daily.

CPIS Calculation

Pharmacists conducted CPIS calculations for study patients on Days One and Three (see Appendix 1). For patients who began antibiotic therapy on weekends when pharmacists were not present, a retrospective calculation for Day One CPIS was performed. Days One and Three were defined in this study as the first and third days of prescribed antibiotic therapy for a presumed pulmonary infection.

A number of sources were used to extract data in order to calculate the CPIS on Day One and Day Three, as summarized in Table 1. For both Day One and Day Three CPIS calculations, the value with the most derangement from a stable clinical picture within 24 hours was selected. For patients without an arterial line where a direct SaO2 is not available, the surrogate measure of a SpO2 correlated with an estimated PaO2 was utilized (Appendices 2 and 3). Oxygen saturation was not adjusted for temperature

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or pH, in alignment with common clinical practices. The CPIS on Day Three accounted for whether or not the pulmonary infiltrate on the radiograph has worsened. This was sourced from communication at rounds or direct inquiry. In addition to the previously mentioned information repositories, data was additionally sourced from the pharmacist’s knowledge of the patient.

Table 1: Information sources used for patient-specific CPIS calculationsCPIS Component Information SourceTemperature Philips® IntelliVue Critical Care and Anesthesia

(ICCA) softwareLeukocyte count Philips® IntelliVue Critical Care and Anesthesia

(ICCA) softwareTracheal Secretions Philips® IntelliVue Critical Care and Anesthesia

(ICCA) softwareOxygenation Philips® IntelliVue Critical Care and Anesthesia

(ICCA) software1

Pulmonary radiographs McKesson’s® Horizon Physician Provider Portal1

Culture information McKesson’s® Horizon Physician Provider Portal1

1 – PaO2 will be used when provided. Otherwise, a surrogate measure of SpO2 correlated with an estimated PaO2

is utilized

Intervention

The algorithm for pharmacist communication of the CPIS and recommendations to the prescribers in this study is highlighted in Figure 1. If a pharmacist calculated the CPIS to be less than or equal to six on both Day One and Day Three of antibiotic therapy, pharmacist communication was then conducted at daily rounds on Day Three. This communication was comprised of the patient-specific score, discussion of relevant components, in addition to a suggestion of antibiotic discontinuation. The prescriber’s decision specific to antibiotic therapy, as well as the rationale for their decision for continuation of antibiotics was documented, if applicable.

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Documentation

Data collection sheets were used by pharmacists for documentation and provided to the investigator upon completion (Appendix 4). Patient identifiers were removed and replaced with a unique study ID number. The subject log that links the study ID number and patient identifiers were stored separately.

Data collection forms were kept either in a locked filing cabinet in the pharmacy department or within a locked office space accessible to only the unit pharmacist in the ICU. Data were kept on a password-protected hard drive within a secure network, accessible only by the investigator. Initials were safeguarded by a coding system and kept as a paper file in a locked area and on a secured hard drive.

Comparison of Results to Historical ASP Data

The results of the study were compared with historical ASP data. In a similar fashion to this study, during historical ASP data collection, patient-specific CPIS values were calculated on Days One and Three by Antimicrobial Stewardship team members, using information gathering strategies identical to those described previously. However, there was no pharmacist-led communication of a CPIS to prescribers, as is the usual standard practice in the ICU. This ASP data collection period will henceforth be referred to as the ASP period. Analysis of patient

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characteristics and outcomes was performed only for patients who maintained a CPIS of less than or equal to 6 on Days 1 and 3 in either the study period or the ASP period.

Data Analyses and Sample Size

The sample size was one of convenience. All patients in the ICU who met the established eligibility criteria listed above were included in the study. The seven-week ASP period collected data from 12 patients. It was thus anticipated that there would be a similar number in the study period.

Descriptive statistics (means and proportions) were used to present data related to patient demographics and outcomes of interest. Graphs were generated using GraphPad Prism® software. As this study is a pilot, and thus not powered to detect differences, statistical hypothesis tests were not calculated. Instead, where appropriate, 95% confidence intervals were calculated, which allowed for some comparison between the study period and the ASP period and to provide some estimate for future study. Given the exploratory nature of this pilot study, it was felt that confidence intervals also share additional information relating to the direction and strength of effects, not readily identifiable from a p-value. When the 95% confidence intervals for estimates did not cross, this was identified as a statistically significant difference. The formula for calculating confidence intervals for

proportions was x±n×1.96×√ p(1−p)n, where x is the number of patients equal

to the proportion in question, p is the proportion expressed as a decimal and n is the number of patients. When the proportion was zero, the rule of 3

( 3n ) was utilized for the calculation of the confidence interval. For means,

the confidence interval was calculated as mean±1.96× SD√n , where SD is the

standard deviation. In consideration of future study and potential need to calculate a pooled estimate of variance, outcomes of interest were reported with their standard deviation. For the component of results relating to prescriber rationale behind antibiotic prescribing, descriptive statistics were used for summary.

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Results

Feasibility

Table 2 presents the outcomes for study feasibility. In the span of eight weeks, there were 18 patients that met the inclusion criteria, i.e. were prescribed an antibiotic regimen for the treatment of a nosocomial pneumonia in the ICU (Figure 2). Seven patients of these patients were removed based on exclusion criteria, and 11 patients were admitted to the study. Of these, six patients maintained a CPIS of 6 or lower on both Days 1 and 3 of therapy and therefore were eligible for pharmacist intervention. Subsequently, two of these six patients had their antibiotics actually discontinued on Day 3 of treatment.

Figure 2 – Study flow diagram.

11 patients captured in the study overall

6 patients eligible for intervention (data presented)

7 patients excluded:

Treatment for pneumonia with antibiotics for over 24 hours prior to ICU admission (n = 4)

Day 3 CPIS less than or equal to 6 on a Saturday or Sunday when pharmacists were not available (n =

2)

HIV infection (n = 1)

18 patients prescribed antibiotic therapy for a nosocomial pneumonia in the ICU

March 21, 2016 to May 16, 2016

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Table 2: Feasibility metrics for pharmacist-led CPIS initiative Feasibility Measure Value

Number of patients admitted to the ICU with antibiotics prescribed for presumed nosocomial pneumonia

18 patients

Number of eligible patients recruited 11 patientsNumber of patients recruited where a CPIS ≤ 6 was maintained on both days 1 and 3 6 patientsProportion of patients eligible for pharmacist intervention 6 of 11 patients (54.0%)Rate of prescriber acceptance for antibiotic discontinuation 2 of 6 patients (33.3%)

A number of barriers were experienced during the pilot’s execution (Table 3). Prescribers misused the CPIS as a screening tool rather than a guide for Day 3 antibiotic discontinuation. Furthermore, there were occasions where prescribers were unaware of what the CPIS calculation is and its implications. Extra-pulmonary antibiotic indications also limited the success of pharmacist interventions. There were also potential barriers that were hypothesized as being likely but not directly observed during study execution. These included subjective interpretations of sputum and chest x-ray by clinicians not involved in the CPIS study.

Table 3: Barriers encountered by pharmacists Barriers encountered

Lack of prescriber familiarity with CPIS:

Figure 2 – Study flow diagram.

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Unaware of significance of CPIS ≤6 on Days 1 and 3 Prescriber misuse of CPIS to decide on Day 1 antibiotic prescribingAdditional antibiotic indications: Pharmacist suggestion to discontinue antibiotics refused due to extra-pulmonary

infectionLack of weekend pharmacist availability: Patients with Day 3 CPIS on Sat/Sun were excluded from the study CPIS non-specificity: CPIS elements highly non-specific such that many patients had elevated scoresCompletion of CPIS calculation: Variability in radiologist interpretation of chest x-ray Variability in nursing interpretation of sputum

Patient Demographics

Patient demographics are presented in Table 4. Overall, patients were comparable between the study period and the ASP data collection period with regards to age and comorbidities (Table 5). During the study period, there were numerically more patients with renal failure (66.7%) and other infectious diagnoses (33.3%) in comparison with the ASP period (0% and 0%, respectively). Conversely, during the ASP period, there were more post-surgical patients (83.3%) and more patients with treatment of repeat pneumonias (66.7%), compared to the study period (16.7% and 16.7%, respectively).

Table 4: Patient demographics (CPIS ≤6 on Days 1 and 3)Patient Demographic Study Period, (n = 6) ASP Period, (n = 6)

Age, yr (mean ± SD) 61.83 ± 14.80 67.33 ± 8.07Proportion of patients with ARDS 0 (0.0%) 1 (16.7%)Proportion of patients with heart failure 2 (33.3%) 0 (0.0%)Proportion of patients with COPD 1 (16.7%) 1 (16.7%)Proportion of patients with renal dysfunction*

4 (66.7%) 0 (0.0%)Proportion of patients who were post-surgical 1 (16.7%) 5 (83.3%)Proportion of patients diagnosed with HAP 2 (33.3%) 3 (50.0%)Proportion of patients diagnosed with VAP 4 (66.7%) 3 (50.0%)Proportion of patients where antibiotics were prescribed for repeat pneumonias 1 (16.7%) 4 (66.7%)Proportion of patients with another infectious diagnosis 2 (33.3%) 0 (0.0%)Proportion of patients with antibiotic use in last 48 hours 0 (0.0%) 0 (0.0%)

ARDS=acute respiratory distress syndrome, ASP=antimicrobial stewardship, COPD = chronic obstructive pulmonary disease, CPIS=clinical pulmonary infection score, HAP=hospital-acquired pneumonia, ICU=intensive care unit, VAP=ventilator-associated pneumonia, SD=standard deviation

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*Renal dysfunction defined as creatinine clearance (eGFR) less than 30 mL/min

There were differences observed between those with and without antibiotic discontinuation during the study period (Table 5). The group with antibiotic discontinuation was numerically younger than the patients without discontinuation: 46.50 ± 6.36 versus 69.50 ± 10.78. Patients without discontinuation had higher proportions of heart failure, COPD, renal dysfunction, and extra-pulmonary infection.

Table 5: Patient demographics for study patients eligible for pharmacist intervention, with and without antibiotic discontinuation

Study Patient Demographic Day 3 Discontinuation, (n = 2)

Day 3 Continuation, (n = 4)

Age, yr (mean ± SD) 46.50 ± 6.36 69.50 ± 10.78Proportion of patients with ARDS 0 (0.0%) 0 (0.0%)Proportion of patients with heart failure 0 (0.0%) 2 (50.0%)Proportion of patients with COPD 0 (0.0%) 1 (25.0%)Proportion of patients with renal dysfunction* 1 (50.0%) 3 (75.0%)Proportion of patients who were post-surgical 0 (0.0%) 1 (25.0%)Proportion of patients diagnosed with HAP 1 (50.0%) 1 (25.0%)Proportion of patients diagnosed with VAP 1 (50.0%) 3 (75.0%)Proportion of patients where antibiotics were prescribed for repeat pneumonias 0 (0.0%) 1 (25.0%)Proportion of patients with another infectious diagnosis 0 (0.0%) 2 (50.0%)Proportion of patients with antibiotic use in last 48 hours 0 (0.0%) 0 (0.0%)

ARDS=acute respiratory distress syndrome, COPD = chronic obstructive pulmonary disease, HAP=hospital-acquired pneumonia, ICU=intensive care unit, VAP=ventilator-associated pneumonia, SD=standard deviation*renal dysfunction defined as creatinine clearance (eGFR) less than 30 mL/min

Assessment of CPIS Calculations

The comparison of the mean Day 1 and Day 3 CPIS calculations between the study and ASP groups is presented in Figure 3, while the CPIS calculations are presented in Appendix 6. There were six patients assessed in each group and the CPIS calculations were similar overall between the comparisons.

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The mean Day 1 and Day 3 CPIS calculations for study patients with and without antibiotic discontinuation are displayed in Figure 4. No difference was identified in the Day 1 scores. However, mean Day 3 scores were significantly lower in the antibiotic discontinuation group (2.50; 95% confidence interval [CI] 1.52-3.48) in comparison with the group without antibiotic discontinuation (5.25; 95% CI 4.31-6.19).

Antibiotics continued on Day 3 (n =4)

Antibiotics discontinued on Day 3 (n =2)

Day of Therapy

Figure 3 – Comparison of mean CPIS calculations between study (n=6) and

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Assessment of Impact of the Pharmacist-Led CPIS Initiative

Table 6 provides estimates for measures of central tendency for the outcomes of interest between the study period and ASP period groups (see Appendix 5 for full ASP data). There appeared to be a trend toward a shorter length of stay in the ICU in patients during the study period compared to the ASP period. The mean number of antibiotic days in the ICU appeared to be significantly shorter in patients during the study period as opposed to the ASP period: 11.17 (4.41-17.93) days versus 22.67 (19.03-26.31) days. This trend appeared to hold true for all antibiotic days in the hospital, although the confidence intervals overlapped in this outcome. Overall, there were two antibiotic discontinuations during the study, while there were none in the ASP period.

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Table 6: Comparison of pharmacist-led CPIS initiative versus ASP

Measurement Study Period,(n = 6)

ASP Period,(n = 6)

Length of ICU stay (days)mean, SD (95% CI)

30.17, 25.82(9.51-50.83)

83.83, 79.46 (20.25-147.41)

Duration where patients were intubated (days) mean, SD (95% CI)

13.00, 16.66 (0.00-26.33)

20.33, 28.66 (0.00-42.93)

Number of antibiotic days during ICU stay (days) mean, SD (95% CI)

11.17, 8.45 (4.41-17.93)

22.67, 6.80 (19.03-26.31)

Number of antibiotic days in hospital (days) mean, SD (95% CI)

11.50, 9.07 (4.24-18.76)

22.00, 7.29 (16.16-27.84)

Proportion of patients where antibiotics were discontinued on or prior to Day 3 (%; 95% CI)

33.3%(0.00-4.26)

0.0% (0.00-0.50)*

Cost of antibiotics ($)mean, SD (95% CI)

142.22, 186.09 (0.00-291.12)

69.11, 51.90(27.58-110.64)

ASP=antimicrobial stewardship, CI=confidence interval, CPIS=clinical pulmonary infection score, ICU=intensive care unit, SD=standard deviation* As calculated by the rule of 3 (3/n) for CI of a proportion of 0.

Similar data were analyzed between patients with and without antibiotic discontinuation upon pharmacist intervention (Table 7). There were two individuals with antibiotic discontinuation and four patients without. There were significant differences observed between these groups in terms of length of stay: 2.50 (1.52-3.49) days versus 44.00 (25.77-62.23) days. In addition, there was also a significant difference observed in the number of antibiotic days in the ICU: 2.50 (1.52-3.48) days versus 15.50 (9.02-21.98) days. This was also true for the number of antibiotic days within the hospital: 2.50 (1.52-3.48) days versus 23.00 (12.00-34.00) days. There was no difference observed in medication costs, although this appeared to trend lower in the Day 3 discontinuation group: $37.44 (0.00-85.64) versus $194.61 (0.00-405.56).

Table 7: Impact of early antibiotic discontinuation

Measurement Day 3 Discontinuation, (n = 2) Day 3 Continuation, (n = 4)

Length of ICU stay (days) mean, SD (95% CI)

2.50, 0.71 (1.52-3.48)

44.00, 18.60 (25.77-62.23)

Duration where patients were intubated (days) mean, SD (95% CI)

1.50, 2.12 (0.00-4.44)

18.75, 18.14 (0.98-36.52)

Number of antibiotic days during ICU stay (days) mean, SD (95% CI)

2.50, 0.71 (1.52-3.48)

15.50, 6.61 (9.02-21.98)

Number of antibiotic days in hospital (days)mean, SD (95% CI)

2.50, 0.71 (1.52-3.48)

23.00, 11.22 (12.00-34.00)

Cost of antibiotics ($) mean, SD 37.44, 34.78 194.61, 215.25

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(95% CI) (0.00-85.64) (0.00-405.56)CI=confidence interval, CPIS=clinical pulmonary infection score, ICU=intensive care unit, SD=standard deviation

Prescriber Rationale

Table 8 presents the prescriber rationales documented when a recommendation was made to discontinue antibiotics and the prescriber chose to continue antibiotic therapy. This occurred on four separate occasions during the study period, due to one or more of the following: an ongoing infectious process (2 responses), worsening status (1 response), positive sputum culture (1 response), or guarded prognosis (1 response).

Table 8: Prescriber rationales for continuing antibiotics (CPIS ≤6 on both Days 1 and 3)

Rationale Number of responses

Antibiotics are continued given that the patient now has a documented infection at another source, e.g. blood, urinary tract 2The prescriber (additionally) feels that antibiotics should be continued given a positive sputum culture 2Patient’s status is worsening despite 3 days of antibiotic therapy, e.g. remains febrile, became hypotensive, declining respiratory status 1Patient’s prognosis is guarded; the prescriber therefore feels that finishing the course of antibiotics is most judicious 1

Discussion

Overall, the pilot study demonstrated that examining the impact of pharmacist-led communication of the CPIS strategy in the ICU may be feasible. Furthermore, it also showed that it is possible that pharmacist intervention may be a useful strategy associated with improvements in both antibiotic prescribing and patient-important outcomes.

Feasibility

Feasibility metrics from the study period were integrated with similar metrics from ASP data collection (Table 9). Over this 15-week period (combined ASP and pilot study), there were 23 patients who were eligible for entry. Furthermore, 12 of these 23 patients maintained low CPIS scores such that pharmacist intervention would be possible. Over the 15-week period, this amounts to 0.80 patients per week. This is in contrast to Oxman et al.’s paper, in which there was an estimated 0.39 patients per week.16

Therefore this highlights that by increasing the scope of the patient

22

population to a mixed ICU patient group and expanding eligibility to both HAPs and VAPs, a higher rate of recruitment is likely possible.

Table 9: Combined ASP and project feasibility data for 15-week periodFeasibility Measure Value

Number of patients admitted to the ICU with antibiotics prescribed for presumed nosocomial pneumonia

33 patients

Number of eligible patients recruited 23 patientsNumber of patients recruited where a CPIS ≤6 was maintained on both Days 1 and 3 12 patients

Proportion of patients eligible for pharmacist intervention 12 of 23 patients (52.0%)

This pilot study demonstrated that there are large areas of opportunity for antibiotic discontinuation at the institution’s ICU for treatment of nosocomial pneumonia, given that there were two (9%) patients with a Day 3 discontinuation, but 11 (52%) patients were eligible. This is higher than the proportion reported in Gorman et al.’s non-interventional study, where 35% of patients maintained a CPIS ≤6 on both days one and three in VAP.15 Given that the present study expanded the patient population to those with HAP as well, it is possible that there is even more potential for antimicrobial stewardship than previously estimated in the area of ICU nosocomial pneumonias. This study also demonstrated that despite low recruitment numbers, there were trends towards significant differences in all outcomes of interest, with the exception of cost. Indeed, there was actually a statistically significant difference in terms of the number of antibiotic days despite the small sample size. Therefore, we are cautiously optimistic that future studies may be able to detect differences despite limitations in sample size.

To our knowledge, this pilot study is the first to evaluate the feasibility and effectiveness of a pharmacist-led CPIS initiative on antibiotic prescribing when used in a way that is realistic to everyday clinical practice. Our study also identified many barriers to acceptance of this initiative that may impact the feasibility. One of the prominent barriers included prescribers using the CPIS as a tool for decision-making at the point of prescribing rather than as a guide for Day 3 discontinuation. The practice of using the CPIS in this manner is contestable given its relative non-specificity9, while use of the CPIS to reassess antibiotic prescriber at Day 3 is better evidenced.3,4,13 Given that pharmacists were not available for all sets of rounds during the day, it was also impossible to ascertain how frequently the CPIS was being utilized in this manner, thereby reducing the number of patients in which this study would have been most suited for. It

23

should also be noted that an education session was provided to a team of resident and attending prescribers, and materials were circulated throughout the ICU that described the drawbacks and potential utility of the CPIS (Appendix 7). However, it was not possible to convey this information to all prescribers in the ICU, especially given that the site is a teaching institution with a high turnover of learners. Thus, a suggestion for future study might be more intensive educational interventions prior to the initiation of the study. In the same way, pharmacists found that communication of the CPIS itself to medical residents was challenging in that residents were often unaware of what the CPIS is and its application to practice. This again highlights the importance of prescriber education in this endeavor.

Additional indications for antibiotics also proved problematic for the pilot study. Of the 23 patients from whom data was collected, 5 had extra-pulmonary infections. This may prove to be an obstacle in future studies, given that it became a prominent prescriber rationale for continuation of antibiotics beyond Day 3 (Table 8). In a similar study, Gorman et al. found that 16 of 92 patients had extra-pulmonary infection that required the same antibiotics as for the pneumonia.15 We chose to exclude patients that met these criteria. This highlights an important distinction that future studies should consider: given the potential for high rates of concomitant extra-pulmonary infection, it may be advisable to focus not on antibiotic discontinuation but to analyze for antibiotic de-escalation on Day 3.

Furthermore, lack of pharmacist availability on weekends such that Day 3 interventions could not be communicated also led to two patients being excluded from the study. Although the literature suggests Day 3 discontinuation as being most evidenced, future studies are thus advised to allow for some flexibility in this regard.3 Similarly, pharmacists encountered difficulties in determining eligibility for the study when the patient was admitted over the weekend – there were several occasions on weekends where antibiotics were started by residents empirically without a true infectious diagnosis. Involving active ICU team members over the weekend could mitigate this issue.

The non-specificity of the CPIS was certainly observed during the study, with the mode score for tracheal secretions, leukocytes and oxygenation amongst all calculations being two, the maximum allotted (see Appendix 9). This was problematic for the study given that it severely limited the number of patients for whom pharmacists could intervene to 12 of 23 patients.

24

A potential barrier that was not directly observed by the study authors but hypothesized as being problematic was the subjective interpretation made by other clinicians for several components of the CPIS. Some prescribers initially expressed that radiologist interpretation is subjective and that they might on occasion agree with some reports more than others. It was also observed during rounding that sometimes intensivists would analyze chest x-rays themselves and therefore may arrive at diverging interpretations. Therefore, future studies are encouraged to utilize the prescribing prescriber’s chest x-ray interpretation. Similarly, tracheal secretion interpretation was completed by a large number of nurses. Involvement of a smaller number of nursing colleagues in this interpretation for the study could reduce potential subjectivity. Table 10 summarizes the aforementioned strategies to potentially overcome the identified barriers for future studies.

Table 10: Suggestions for future studiesSuggestion for future studiesAdditional prescriber education

Capture antibiotic de-escalation rather than strict discontinuationAllow for flexibility with regards to the timing of pharmacist intervention

Involvement of the ICU teamProtocol to suggest pharmacist ensure diagnostic orders completed

Utilize prescribing prescriber’s interpretation of chest x-ray Limit the number of nurses in interpretation of sputum

Impact of the Pharmacist-Led CPIS Initiative

This pilot study generated estimates as to the effect of the pharmacist-led CPIS initiative on antibiotic prescribing in the ICU. When comparing these outcomes between study patients with and without antibiotic discontinuation, there were significant differences in length of stay and antibiotic days. This is similar to what was observed by Singh et al., in which there was also a reduction in antibiotic days.3

Additionally, comparisons were made in these outcomes between the study period and ASP period. Overall, these patients appeared to be similar in terms of their baseline demographics. There were trends towards shorter length of stay and duration of intubation during the study period as opposed to the ASP period, although not significant. There was also a trend towards having a larger proportion of antibiotic discontinuations. Although these patterns can be attributed to changes in the institution, not related to the intervention itself, there was also a significant reduction in the number of antibiotic days between the ASP period and the intervention period. Taken

25

together, these trends towards reduction in antibiotic prescribing suggest potential effects from pharmacist intervention.

This is in contrast with the results from Oxman et al. which reported no difference in the proportion of patients where antibiotics were discontinued between their observational and intervention phases (19% and 23% respectively).16 Indeed, when compared to a similar non-interventional study by Gorman et al., there was a similar rate of discontinuation at 12%, despite a lack of pharmacist communication. There are many reasons as to why this difference may have been observed. Both this pilot study and the study by Oxman et al. have small sample sizes overall, and as such, the differences may simply be spurious. However, the present study also detailed an educational component to ICU prescribers, supported by the antimicrobial stewardship team. Pharmacists also communicated the actual CPIS value to the prescribers. This usually entailed detailing the components of the CPIS to the prescriber as well. Overall these details may have provided a more persuasive basis for discontinuation. Furthermore, the secondary outcome estimates provided by this pilot suggest that although Oxman et al. may have demonstrated that there is potentially no benefit in terms of actual antibiotic discontinuation, there may yet be positive effects from an antimicrobial stewardship perspective, particularly in the reduction of antibiotic days. This suggests that although prescribers may not agree to discontinue antibiotics on Day 3, pharmacist intervention does prompt prescribers to critically re-evaluate and truncate antibiotic therapy.

Prescriber Attitudes towards the Early Discontinuation of Antibiotics

Of the two patients where prescribers agreed to discontinue antibiotics during the study period, both were also transferred to medicine units on Day 3 as they were deemed to have improved significantly. Other similarities between these two patients were that they were younger and had significantly lower Day 3 CPIS values, compared to patients where a recommendation was made and antibiotics were continued. Therefore this suggests that prescribers had a very high threshold of clinical stability that needed to be met prior to agreeing to discontinue antibiotics. This threshold was not necessarily met by maintaining a CPIS less than or equal to six on Days 1 and 3. This clearly suggests that larger studies are warranted to analyze the effect and uptake of CPIS implementation into everyday practice in the ICU, as prescriber comfort with early discontinuation is not necessary in line with Day 3 antibiotic discontinuation as suggested by the landmark study of Singh et al.3

26

Collection of prescriber rationales for antibiotic continuation beyond Day 3 in patients where there was pharmacist intervention also provides some insight into prescriber attitudes towards early discontinuation of antibiotics. Of the rationales collected, it appears that having extra-pulmonary infections was often considered a reason to continue antibiotics. In fact, the two patients where antibiotics were discontinued notably did not have concomitant infections. This again does support the idea of examining antibiotic de-escalation rather than strict discontinuation in everyday ICU practice for future studies. Furthermore, the responses collected also highlight that some prescribers attribute more value to certain components of the CPIS than others, namely the sputum culture component. On two occasions, the prescriber felt continuation of antibiotics was justified because of this, despite maintaining a low CPIS otherwise. In a survey of 30 inpatient prescribers by Livorsi et al., participants similarly indicated that they were most comfortable with antibiotic de-escalation based on culture results.18

Filice et al. demonstrated that a correct diagnosis was critical to the selection of optimal inpatient antimicrobial use and suggested that antimicrobial stewardship strategies help providers in avoiding diagnostic errors and to discern when antimicrobial therapy can be safely withheld.19

Similarly, Livorsi et al. highlighted that antibiotic overuse was often driven by diagnostic uncertainty.18 Expert commentary from the NEJM also underscores that dual process theory plays a role in decision-making in any situation, including diagnoses, and argued for an elimination of cognitive bias by transitioning from intuitive processes to conscious, deliberate and more reliable analytic processes.20 It was hoped that the CPIS would serve as a tool in both of these aspects, by reducing diagnostic uncertainty and serving as a cue to encourage evidence-based diagnoses and antimicrobial prescribing. Some of the prescriber responses highlighted in this study echo the themes captured by Livorsi et al. in which providers prescribed antibiotics in fear of missing infection, especially in the critically ill. However, the trends towards improved antibiotic prescribing practices seen in this study suggest that the CPIS may potentially mitigate this type of thinking and move prescribers towards more analytic processes of decision-making.

Overall, there is literature to support strong rates of prescriber adherence to an infectious disease service’s recommendation.21,22 Therefore there is some credibility to suggest that in future studies, pharmacists may want to consult with infectious disease services in a coordinated fashion to communicate the message of antibiotic discontinuation. However, it was also demonstrated in one study that when a primary service chooses not to

27

follow a therapeutic recommendation, it was most often a refusal to stop an antibiotic regimen.22 In this way, it is not unanticipated that ICU pharmacists face resistance from intensivists when suggesting early antibiotic discontinuation.

In the study by Singh et al., the treatment arm consisted of Day 3 antibiotic discontinuation in patients with CPIS values ≤6 on days one and three, while the standard therapy arm allowed for antibiotic duration at the prescriber’s discretion.3 They noted that the prescribers began to reduce their duration of therapy in the standard therapy arm.3 They attributed this to the un-blinded nature of the study - prescribers under standard therapy protocols observed that there were no adverse effects with truncated therapy and thus began to shorten therapy too.3 This effect was not seen with our study given that it was conducted for only eight weeks and there was no protocol that mandated early discontinuation. However, this highlights that prescribers may become more accepting of early discontinuation should they observe successes of this intervention more gradually in a longer study.

Value of the CPIS

This pilot study also highlighted the value of and potential roles for the CPIS in the ICU. In spite of the issues highlighted with regards to feasibility, overall the secondary outcomes in this pilot study are not in disagreement with those reported by Singh et al., given that within the group where antibiotic discontinuation was achieved, there were reduced antibiotic days and a trend towards reduced costs.3 Therefore, there is a potential that even without the strict rigidity of a study environment, the CPIS may yet be able to achieve some improvement in this outcome when communicated as a recommendation from pharmacist to prescriber.

A particular role for the CPIS underscored by this study is potentially one that operates as a cue for intensivists in the diagnosing of nosocomial pneumonias. There were two occasions where individual diagnostic components of the CPIS were not completed during the study period (e.g. a Day 1 or Day 3 x-ray or a sputum culture), however on these occasions the CPIS values for the other criteria were >6, and therefore did not impact upon antibiotic recommendations. Given that currently the diagnosis of HAP and VAP is an area of clinical uncertainty1,3, the CPIS could thus prompt clinicians to, at the very least, complete diagnostics that will allow for comprehensive decision-making.

Limitations

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Limitations of our pilot study include that this was conducted at a single center and that it was held over a short period of time with a limited sample size. Although there were many suggestive trends in the secondary outcomes, the nature of the study design is such that there may be additional unidentified institutional or practice-based factors (e.g. inter-physician variability, comfort with early antibiotic discontinuation) that may have contributed to the results. Again, the pilot study’s goal was to provide estimates of feasibility and secondary outcomes of interest but it should not be interpreted as an attempt at hypothesis testing.

Future DirectionsGiven the feasibility and secondary outcome data generated from this

pilot study, future studies in this area should likely be conducted in a mixed ICU population and in both HAP and VAP cases. We have outlined other suggestions that may be considered in order to avoid potential pitfalls as outlined in Table 10.

Future studies should also examine effects on antibiotic discontinuation more distal from the date of HAP or VAP diagnosis. Gorman et al. documented that there was only one additional case where antibiotics were discontinued by Day 7 as opposed to Day 3, with an average duration of treatment that was unexpectedly high at 15 days in length.15 Given that our pilot study highlights the reduced number of antibiotic days overall with the pharmacist-led CPIS intervention, this is a secondary outcome worth exploring. Integrating additional information from other studies about the CPIS can also make a more robust intervention. For example, Joung et al. demonstrated that a Day 5 CPIS of 7 to 9 was not associated with increased mortality, while scores of 10 or more did appear to correlate with this.23

Providing this information to providers with a Day 5 CPIS could also allow for another interface at which prescribers could be asked to re-evaluate therapy. Luna et al. demonstrated that a fall in the CPIS from Day 1 to Day 3 as well as the Day 3 oxygenation components differentiated survivors from non-survivors of VAP.24 This could be integrated into the pharmacist intervention component of a future study, as it may help hesitant prescribers with their decision-making.

ConclusionsAlthough Singh et al. were able to demonstrate that mandating early

antibiotic discontinuation for HAPs and VAPs was associated with benefits3,

29

our pilot study suggests that translating this to clinical practice is met with some resistance and barriers. However, by increasing the scope of the study population, we were able to demonstrate that a future study in this area is potentially viable, given the statistically significant reduction in antibiotic days observed between the ASP and study period. Certainly, this pilot study does suggest that pharmacist communication of the intervention appears to be at least somewhat valuable from an ASP perspective. Future studies with larger sample sizes should be able to further clarify this issue.

References

1. Kollef, MH. 1994. Antibiotic use and antibiotic resistance in the ICU: are we curing or creating disease? Heart Lung 23:363–367.

2. Bergmans DC, Bonten MJ, Gaillard CA, et al. Indications for antibiotic use in ICU patients: a one-year prospective surveillance. J Antimicrob Chemother. 1997;39(4):527-35.

3. Singh N, Rogers P, Atwood CW et al. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. Am J Respir Crit Care Med. 2000;162:505-511.

4. Tan JC, Guzman-Banzon A, Ayuyao F et al. Comparison of CPIS and clinical criteria in the diagnosis of ventilator-associated pneumonia in ICU complex patients. Phil Heart Center J. 2007;13(2):135-138.

5. Fagon JY, Chastre J, Hance AJ, Domart S, Trouillet JC, and Gibert C. 1993. Evaluation of clinical judgement in the identification and treatment of nosocomial pneumonia in ventilated patients. Chest 103:547–553.

6. Pugin, J, Auckenthaler R, Mili N, Janssens JP, Lew RD, and Suter PM. 1991. Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic “blind” bronchoalveolar lavage fluid. Am. Rev. Respir. Dis. 143:1121–1129.

7. Rea-Neto A, Youssef NCM, Tuche F, et al. Diagnosis of ventilator-associated pneumonia: a systematic review of the literature. Critical Care. 2008;12:R56.

8. Hunter JD. Ventilator associated pneumonia. Postgrad Med J 2006;82:172-178.

9. Lauzier F, Ruest A, Cook D, et al. The value of pretest probability and modified clinical pulmonary infection score to diagnose ventilator-associated pneumonia. J Crit Care. 2008;23(1):50-7.

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10. Zilberberg MD and Shorr AF. Ventilator-associated pneumonia: the Clinical Pulmonary Infection Score as a surrogate for diagnostics and outcome. Clin Infect Dis. 2010;51(S1):S131-S135.

11. Rotstein C, Evans G, Born A, et al. Clinical practice guidelines for hospital-acquired pneumonia and ventilator-associated pneumonia in adults. Can J Infect Dis Med Microbiol. 2008;19(1):19-53.

12. Shan J, Chen HL, Zhu JH. Diagnostic accuracy of clinical pulmonary infection score for ventilator-associated pneumonia: a meta-analysis. Respir Care. 2011;56(8):1087-94.

13. Montravers P, Fagon JY, Chastre J, et al. Follow-up protected specimen brushes to assess treatment in nosocomial pneumonia. Am Rev Respir Dis. 1993;147(1):38-44.

14. Napolitano LM. Use of severity scoring and stratification factors in clinical trials of hospital-acquired and ventilator-associated pneumonia. Clin Infect Dis. 2010;51 Suppl 1:S67-80.

15. Gorman SK, Stewart LM, Slavik RS, et al. Identifying missed opportunities to curtail antimicrobial therapy for presumed ventilator-associated pneumonia using the clinical pulmonary infection score. Can J Hosp Pharm. 2009;62(3):217-25.

16. Oxman DA, Adams CD, Deluke G, et al. Improving Antibiotic De-Escalation in Suspected Ventilator-Associated Pneumonia: An Observational Study With a Pharmacist-Driven Intervention. J Pharm Pract. 2015;28(5):457-61.

17. Thabane L, Ma J, Chu R, et al. A tutorial on pilot studies: the what, why and how. BMC Med Res Methodol. 2010;10:1.

18. Livorsi D, Comer A, Matthias MS, Perencevich EN, Bair MJ. Factors Influencing Antibiotic-Prescribing Decisions Among Inpatient Physicians: A Qualitative Investigation. Infect Control Hosp Epidemiol. 2015;36(9):1065-72.

19. Filice GA, Drekonja DM, Thurn JR, Hamann GM, Masoud BT, Johnson JR. Diagnostic Errors that Lead to Inappropriate Antimicrobial Use. Infect Control Hosp Epidemiol. 2015;36(8):949-56.

20. Croskerry P. From mindless to mindful practice--cognitive bias and clinical decision making. N Engl J Med. 2013;368(26):2445-8.

21. Sellier E, Pavese P, Gennai S, Stahl JP, Labarère J, François P. Factors and outcomes associated with physicians' adherence to recommendations of

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infectious disease consultations for inpatients. J Antimicrob Chemother. 2010;65(1):156-62.

22. Lo E, Rezai K, Evans AT, et al. Why don't they listen? Adherence to recommendations of infectious disease consultations. Clin Infect Dis. 2004;38(9):1212-8.

23. Joung MK, Lee JA, Moon SY, et al. Impact of de-escalation therapy on clinical outcomes for intensive care unit-acquired pneumonia. Crit Care. 2011;15(2):R79.

24. Luna CM, Blanzaco D, Niederman MS, et al. Resolution of ventilator-associated pneumonia: prospective evaluation of the clinical pulmonary infection score as an early clinical predictor of outcome. Crit Care Med. 2003;31(3):676-82.

List of Appendices

Appendix 1: Clinical Pulmonary Infection Score Calculation

Appendix 2: Algorithm for the selection of values used for oxygenation components of the CPIS

Appendix 3: Oxygen-hemoglobin curve comparing SaO2 and PaO2

Appendix 4: Patient-Specific Data Collection Form

Appendix 5: Data Collected Under the Auspices of ASP Prior to Study Initiation

32

Appendix 6: Completed CPIS Calculations

Appendix 7: ICU Educational Handout

Appendix 1 – Clinical Pulmonary Infection Score Calculation

- Temperature (ºC)o ≥ 36.5 and ≤ 38.4 = 0 pointso ≥ 38.5 and ≤ 38.9 = 1 pointo ≥ 39 or < 36.5 = 2 points

- Blood and leukocytes (number per mm3)o ≥ 4x109 and ≤ 11x109 / L = 0 points

33

o < 4x109 or > 11x109 / L = 1 point + band forms ≥ 50% = add 1 point

- Tracheal secretionso Absence of tracheal secretions = 0 pointso Presence of non-purulent tracheal secretions = 1 pointo Presence of purulent tracheal secretions = 2 points

- Oxygenation (PaO2/FiO2, mm Hg)o > 240 or ARDS (ARDS defined as PaO2/FiO2 > 200, pulmonary

arterial wedge pressure ≤ 18 mm Hg, and acute bilateral infiltrates) = 0 points

o ≤ 240 and no ARDS = 2 points- Pulmonary radiography

o No infiltrate = 0 pointso Diffuse (or patchy) infiltrate = 1 pointo Localized infiltrate = 2 points

- Progression of pulmonary infiltrateo No radiographic progression = 0 pointso Radiographic progression (after exclusion of CHF and ARDS) =

2 points- Culture of tracheal aspirate

o Pathogenic bacteria (being the predominant organism in the culture) in rare or light quantity or no growth = 0 points

o Pathogenic bacteria cultured in moderate or heavy quantity = 1 point

o Same bacteria seen on Gram stain = add 1 point

Adapted from: Singh N, Rogers P, Atwood CW et al. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. Am J Respir Crit Care Med. 2000;162:505-511.

34

Appendix 2: Algorithm for the selection of values used for oxygenation components of the CPIS

To obtain the appropriate PaO2/FiO2 value for calculation of the CPIS, use the following algorithm:

1) If there is a PaO2/FiO2 value reported in ICCA, use this value for CPIS scoring

2) If there is no PaO2/FiO2 value reported (i.e. there is no arterial line):a) Use the reported SpO2 to estimate the PaO2 with the following

table*:

SpO2 (%)

Approximated PaO2 (mm Hg)

65 3469 3672 3875 4077 4280 4482 4684 4885 5087 5289 5690 5891 6093 6594 7095 7597 9098 11099 175

b) Divide the PaO2 selected by the FiO2 reported in ICCA (as “oxygen %”).

*Adapted from Severinghaus JW. Simple, accurate equations for human blood O2 dissociation computations. J Appl Physiol Respir Environ Exerc Physiol. 1979;46(3):599-602.

35

Appendix 3: Oxygen-hemoglobin curve comparing SaO2 and PaO2

Adapted from “Hemoglobin.” The Free Dictionary. 2015. Available at: http://img.tfd.com/ggse/5f/gsed_0001_0006_0_img1136.png. Accessed on December 9, 2015.

36

Appendix 4: Patient-Specific Data Collection Form (Page 1 of 5)Before completing this form, please ensure the patient meets eligibility criteria listed

in Section 1.

General Demographic Information

Patient Code: _______________________________________

Reason for ICU admission: ______________________________

Date of ICU admission (MM/DD/YYYY)]: _________________________________

Date of ICU discharge (MM/DD/YYYY): _________________________________

Age: ___________

ARDS: □ No □ Yes

Heart failure: □ No □ Yes

COPD: □ No □ Yes

Renal dysfunction]: □ No □ Yes

Post-surgical: □ No □ Yes

Infectious diagnoses and intubation

Choose from one of the following presumed diagnoses:

□ aspiration □ HAP □ VAP □ other please specify: __________________

Are there other concurrent infectious diagnoses?

□ No □ Yes please specify ___________________________

Are we treating a repeat pneumonia in the ICU?

□ No □ Yes

Is the patient intubated?

□ No □ Yes

How long has the patient been intubated? ____________ days

Antibiotic prescribing

Describe the patient’s antibiotic regimen: _____________________________________________

Has the patient been given antibiotics in the last 48 hours prior to starting antibiotics for pneumonia (excluding for surgical prophylaxis)?

□ No □ Yes

Were antibiotics discontinued on day 3?

□ No □ Yes

What were the total number of antibiotic days for pneumonia in the ICU? ___________________

37

What were the total number of antibiotic days for pneumonia in ICU and once transferred? _____________

Patient-Specific Data Collection Form Continued (Page 2 of 5)

Day 1 CPIS CalculationDate (MM/DD/YYYY): ________________________________

Please consult Section 2 for scoring information if needed.

For the following components, please use the value that is the most out of range within the last 24 hours (i.e. giving the “worst possible” CPIS score):

Temperature (most out of range in last 24 hours): _____________________

Points: _____

Leukocytes: ______________________

Points: _____

Tracheal secretions: _____________________________________

Points: _____

Oxygenation: __________________*

Points: _____

Pulmonary radiograph: ____________________________________

Points: _____

Culture of tracheal aspirate: ____________________________________

Points: _____

Total CPIS: _________________________

* If the PaO2/FiO2 ratio is not directly stated in ICCA, please consult Section 3.

38

Patient-Specific Data Collection Form Continued (Page 3 of 5)

Day 3 CPIS CalculationDate (MM/DD/YYYY): ________________________________

Please consult Section 2 for scoring information if needed.

For the following components, please use the value that is the most out of range within the last 24 hours (i.e. giving the “worst possible” CPIS score):

Temperature: _____________________

Points: _____

Leukocytes: ______________________

Points: _____

Tracheal secretions: _____________________________________

Points: _____

Oxygenation: __________________*

Points: _____

Pulmonary radiograph: ____________________________________

Points: _____

Progression of pulmonary radiograph: ____________________________________

Points: _____

Culture of tracheal aspirate: ____________________________________

Points: _____

Total CPIS: _________________________**

* If the PaO2/FiO2 ratio is not directly stated in ICCA, please consult Section 3.

** For dates following February 2015, if the CPIS is less than or equal to six on both days one and three, please make a recommendation to the prescriber regarding the discontinuation of antibiotics on Day Three. Please summarize prescriber’s reasoning behind the resulting decision: ____________________________________________________________

Please describe any discrepancies or issues with data collection below:

39

Collected by: ______________________________

Patient-Specific Data Collection Form Continued (Page 4 of 5)

Section 1 – Eligibility Criteria

Inclusion criteria: o Patients in the ICU with antibiotics prescribed for a presumed pulmonary infection

Exclusion criteria: o Patients less than 18 years of age, o patients with chemotherapy-induced neutropenia, o HIV infection, o patients being treated for a pneumonia in the ICU with antibiotics having been

started on the transferring floor over 24 hours prior to ICU admission, o patients previously included in the data collection period conducted by ASP when

there was no implementation of a formalized pharmacist-led CPIS strategy,o patients with a Day 3 CPIS ≤6 on a Saturday or Sunday when pharmacists are not

available

Section 2 – Clinical Pulmonary Infection Score Calculation

- Temperature (ºC)o ≥ 36.5 and ≤ 38.4 = 0 pointso ≥ 38.5 and ≤ 38.9 = 1 pointo ≥ 39 or < 36.5 = 2 points

- Blood and leukocytes (number per mm3)o ≥ 4x109 and ≤ 11x109 / L = 0 pointso < 4x109 or > 11x109 / L = 1 point + band forms ≥ 50% = add 1 point

- Tracheal secretionso Absence of tracheal secretions = 0 pointso Presence of non-purulent tracheal secretions = 1 pointo Presence of purulent tracheal secretions = 2 points

- Oxygenation (PaO2/FiO2, mm Hg)o > 240 or ARDS (ARDS defined as PaO2/FiO2 > 200, pulmonary arterial wedge

pressure ≤ 18 mm Hg, and acute bilateral infiltrates) = 0 pointso ≤ 240 and no ARDS = 2 points

- Pulmonary radiographyo No infiltrate = 0 pointso Diffuse (or patchy) infiltrate = 1 pointo Localized infiltrate = 2 points

- Progression of pulmonary infiltrateo No radiographic progression = 0 pointso Radiographic progression (after exclusion of CHF and ARDS) = 2 points

- Culture of tracheal aspirate

40

o Pathogenic bacteria (being the predominant organism in the culture) in rare or light quantity or no growth = 0 points

o Pathogenic bacteria cultured in moderate or heavy quantity = 1 pointo Same bacteria seen on Gram stain = add 1 point

Adapted from: Singh N, Rogers P, Atwood CW et al. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. Am J Respir Crit Care Med. 2000;162:505-511.

Patient-Specific Data Collection Form Continued (Page 5 of 5)

Section 3 – Surrogate Measures for PaO2/FiO2

If there is no PaO2/FiO2 value reported (i.e. there is no arterial line):

a) Use the reported SpO2 to estimate the PaO2 with the following table*:

SpO2 (%)

Approximated PaO2 (mm Hg)

65 3469 3672 3875 4077 4280 4482 4684 4885 5087 5289 5690 5891 6093 6594 7095 7597 9098 11099 175

b) Divide the PaO2 selected by the FiO2 reported in ICCA (as “oxygen %”).*Adapted from Severinghaus JW. Simple, accurate equations for human blood O2 dissociation computations. J Appl Physiol Respir Environ Exerc Physiol. 1979;46(3):599-602.

41

Appendix 5: Data Collected Under the Auspices of ASP Prior to Study Initiation

Similar data were collected by ASP prior to the study’s implementation. These data are represented in the tables below. The proportion of ARDS, heart failure, COPD, renal dysfunction, post-surgical complications, HAPs and VAPs appeared similar across patients, regardless of their Day 1 and 3 CPIS values.

Table 1: Patient characteristics of the individuals examined by ASP prior to the study’s initiation

Patients who maintained CPIS ≤ 6 on both days 1 and

3(n = 6), (95% CI)

Patients who did not maintain a CPIS ≤ 6 on

both days 1 and 3(n = 6), (95% CI)

Age, yr(mean ± SD) 67.30 ± 8.22 68.00 ± 13.17

Proportion of patients with ARDS 1 (16.7%) 2 (33.3%)Proportion of patients with heart

failure 0 (0.0%) 1 (16.7%)Proportion of patients with COPD 1 (16.7%) 1 (16.7%)Proportion of patients with renal

dysfunction* 0 (0.0%) 0 (0.0%)Proportion of patients who were post-

surgical 5 (83.3%) 3 (50.0%)Proportion of patients diagnosed with

HAP 3 (50.0%) 1 (16.7%)†

Proportion of patients diagnosed with VAP 3 (50.0%) 3 (50.0%)†

Proportion of patients where antibiotics were prescribed for repeat

pneumonias4 (66.7%) 1 (16.7%)

Proportion of patients with another infectious diagnosis 0 (0.0%) 0 (0.0%)

Proportion of patients with antibiotic use in last 48 hours 0 (0.0%) 1 (16.7%)

Mean Day 1 CPIS ± SD 3.67 ± 1.40 6.83 ± 1.35Mean Day 3 CPIS ± SD 3.00 ± 2.12 5.67 ± 1.22

CI=confidence interval, CPIS=clinical pulmonary infection score, ICU=intensive care unit, SD=standard deviation*renal dysfunction defined as creatinine clearance less than 30 mL/min†There were 2 patients in whom prescribers were uncertain of whether the diagnosis was a HAP or VAP but the patient was still diagnosed as a nosocomial pneumonia

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During the ASP period, there were no antibiotic discontinuations on or prior to Day 3 of antibiotic therapy. During the ASP period, individuals who maintained a lower CPIS score on Days 1 and 3 also had significantly less costly antibiotic therapy compared to those with higher scores: $69.11 ($47.92-$90.30) versus $208.90 ($117.29-$300.51). Although not significant, these patients also had a trend towards shorter lengths of antibiotic therapy: 7.00 days (5.54-8.46) versus 10.33 days (4.09- 16.57).

Table 2: Measurements relating to antibiotic prescribing and patient-important outcomes for nosocomial pneumonia

Patients who maintained CPIS ≤ 6 on both days 1

and 3(n = 6), (95% CI)

Patients who did not maintain a CPIS ≤ 6 on

both days 1 and 3(n = 6), (95% CI)

Average length of ICU stay (days) ± SD 83.3 ± 81.06 17.67 ± 20.24

Mean duration where patients were intubated (days) ± SD 20.3 ± 29.24 4.83 ± 4.67

Mean number of antibiotic days during ICU stay (days) ± SD 22.67 ± 4.55 20.33 ± 7.80

Mean number of antibiotic days in hospital (days) ± SD 23.33 ± 5.05 20.33 ± 7.80

Proportion of patients where antibiotics were discontinued on or

prior to day 30 (0.0%) 0 (0.0%)

Mean cost of antibiotics ($) ± SD 69.11 ± 51.90 208.90 ± 114.48CI=confidence interval, CPIS=clinical pulmonary infection score, ICU=intensive care unit, SD=standard deviation†There were 2 patients in whom prescribers were uncertain of whether the diagnosis was a HAP or VAP but the patient was still diagnosed as a nosocomial pneumonia

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Appendix 6: Completed CPIS Calculations

The individual CPIS calculations for all patients captured during the study period are shown in Table 1. Most calculations involved a score of 2 from the categories of tracheal secretions and oxygenation. There were several occasions where components were given a value of zero points, only because there was no chest x-ray completed or because no sputum culture was ever ordered.

There were 6 patients who maintained a CPIS of 6 or less on days 1 and 3 of therapy, while there were 5 who did not. One patient did not have a CPIS calculation performed on Day 3 as the patient expired on Day 2. Overall, two patients had antibiotics discontinued during the study period within 3 days of therapy. Both had total CPIS calculations equal to or less than 6 maintained on both Days 1 and 3 of treatment.

Table 1: CPIS calculation data for all patients during the study period

Patient Day

Points from

temperature

Points from

leukocytes

Points from

tracheal secretion

s

Points from

oxygenation

Points from chest x-ray

Points from

chest x-ray

progression

Points

from cultu

re

Total

score

A 1 0 1 2 0 0 N/A 2 5A 3 0 0 1 0 0 0 2 3B 1 0 0 2 0 1 N/A 2 5B 3 0 0 2 0 1 0 2 5

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C 1 2 2 2 2 1 N/A 0 9C 3 0 2 2 2 1 0 2 9D 1 2 1 2 2 1 N/A 0 8D 3 1 1 2 2 1 0 0 7E 1 0 0 2 0 1 N/A 1 4E 3 2 0 2 0 0 0∆ 2 6F† 1 2 0 2 2 2 N/A 0 8G 1 0 0 0 2 1 N/A 0 3G 3 1 0 2 2 1 0 0 6H‡ 1 2 0 0 2 0 N/A 0 4H‡ 3 2 0 0 0 0 0 0∆ 2I* 1 2 0 2 0 1 N/A 0 5J 1 0 1 2 2 0 N/A 2 7J 3 0 1 2 2 0 0∆ 2 7

K‡ 1 0 1 1 2 0 N/A 2 6K‡ 3 0 1 0 0 0 0 2 3

†The CPIS score was not calculated on day 3 for this patient as the patient had already been transferred to another floor prior to day 3, with antibiotics purposefully discontinued prior to transfer.*The CPIS score was not calculated on day for this patient as the patient had expired prior to day 3.‡This patient had antibiotics discontinued prior to or on day 3. ∆The component of the score was designated as zero, given that the diagnostic procedure was not completed or cultures were not produced

As was observed in the study period, the most common score among all CPIS calculations performed during ASP data collection for the components relating to tracheal secretions and oxygenation was 2. Similarly, there were also several patients where a culture or chest x-ray was not performed, in which this component of the CPIS was designated as zero.

Table 2: CPIS calculation data for all patients examined by ASP

Patient Day

Points from

temperature

Points from

leukocytes

Points from

tracheal secretion

s

Points from

oxygenation

Points from chest x-ray

Points from

chest x-ray

progression

Points

from cultu

re

Total

score

L 1 0 0 2 0 0 N/A 0 2L 3 0 0 0 0 0 0 0 0M 1 2 1 1 0 0 N/A 0 4M 3 0 1 1 0 0 0 0 2N 1 2 1 1 2 0 N/A 0 6N 3 0 1 1 2 1 2 0∆ 7O 1 2 1 0 2 2 N/A 0 7O 3 0 0 1 2 2 0 0 5P 1 2 0 1 2 0 N/A 0 5P 3 0 0 2 0 0 0 0 2Q 1 0 1 2 2 0 N/A 0 5Q 3 0 0 2 2 0 0∆ 0 4R 1 0 0 1 2 2 N/A 0 5

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R 3 0 1 0 2 2 2 0 7S 1 2 1 2 2 2 N/A 0 9S 3 0 1 1 0 2 0∆ 0 4T 1 1 1 0 0 0 N/A 0 2T 3 1 1 0 0 0 0 2 4U 1 0 1 2 2 2 N/A 0 7U 3 0 0 2 2 2 0∆ 0∆ 6V 1 2 2 2 0 0 N/A 1 7V 3 0 1 2 0 0 0 2 5W 1 0 1 2 0 0 N/A 1 4W 3 2 1 2 0 0 0 1 6

∆The component of the score was designated as zero, given that the diagnostic procedure was not completed or cultures were not produced

Appendix 10: ICU Educational HandoutEvaluation of the Impact of Pharmacist-Led Communication of the Clinical Pulmonary Infection Score, (CPIS) on Antibiotic Prescribing in the Intensive Care Unit – A Pilot Study

Lanny Tran, Angela Wright, Phillippe El-Helou, Christine Wallace, Vida Stankus, Jennifer Sang-Mee Lee

Abstract

Background: The overuse of antibiotics in the intensive care unit (ICU) for suspected pneumonias is a prevalent issue in antimicrobial stewardship (ASP).1 Unfortunately, most cases of pulmonary infiltrate in the ICU are not caused by pneumonia but rather by non-infectious pathology such as pulmonary edema, atelectasis, alveolar hemorrhage or pulmonary infarction.2,3 To address

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the shortcomings in the diagnosis of ventilator-associated pneumonia (VAP), Pugin et al. developed the Clinical Pulmonary Infection Score (CPIS) to determine the probability that a patient’s symptoms are due to a pneumonia. The CPIS has been most successfully utilized in guiding clinical decisions for patients with a low likelihood of nosocomial pneumonias.10 Guidelines from the Association of Medical Microbiology and Infectious Disease Canada (AMMI) and the Canadian Thoracic Society (CTS) support the practice of early discontinuation of antibiotics at Day Three when the CPIS is maintained at a score equal to or below a threshold of six.4

Objectives and Outcomes: The primary objective of this project is to determine the impact of a new ASP initiative, comprising of CPIS strategy implementation in the ICU as led by pharmacists, on the discontinuation of antibiotics prescribed for nosocomial pneumonias. Specifically, the proportion of patients where antibiotics prescribed for a nosocomial pneumonia are discontinued on or prior to Day Three will be examined. The project will also investigate the impact on total number of total antibiotic days, duration of intubation, cost of antibiotics, and prescriber reasoning behind uptake or resistance to the use of the CPIS in clinical practice.

Study Design: This project is a prospective quality improvement study with comparisons to previously extracted historical data under the authority of SJHH’s ASP initiative, where there was no communication of CPIS to prescribers. Data will be collected for an eight-week period. Pharmacists will conduct CPIS calculations for patients on Days One and Three. If the score is less than or equal to six on both days, pharmacist communication will be conducted at daily rounds on Day Three. Additionally, the prescriber’s decision specific to antibiotic therapy, as well as the rationale for their decision will be documented.

Implications

The outcomes of this pilot study will indicate whether or not communication of the CPIS to ICU prescribers has value in reducing antibiotic prescribing, as indicated by the proportion of patients where antibiotics are discontinued and any observed changes in the total number of antibiotic days and total costs. This study will also illustrate potential barriers for this type of pharmacist-led ASP intervention and will potentially demonstrate insights into prescriber rationale in a clinically challenging area.

Contact Information

Lanny Tran (PrI)

PharmD, RPh

Ltran@stjoes.ca or 519-835-7546

References

1. Kollef, MH. 1994. Antibiotic use and antibiotic resistance in the ICU: are we curing or creating disease? Heart Lung 23:363–367.

2. Singh N, Rogers P, Atwood CW et al. Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. Am J Respir Crit Care Med. 2000;162:505-511.

3. Tan JC, Guzman-Banzon A, Ayuyao F et al. Comparison of CPIS and clinical criteria in the diagnosis of ventilator-associated pneumonia in ICU complex patients. Phil Heart Center J. 2007;13(2):135-138.

4. Rotstein C, Evans G, Born A, et al. Clinical practice guidelines for hospital-acquired pneumonia and ventilator-associated pneumonia in adults. Can J Infect Dis Med Microbiol. 2008;19(1):19-53.