evaluation of a pediatric antimicrobial stewardship program in a tertiary care medical center

117 Pages·2014·2.81 MB·English

by  Josh Lai

EVALUATION OF A PEDIATRIC ANTIMICROBIAL STEWARDSHIP
PROGRAM IN A TERTIARY CARE MEDICAL CENTER

By
Chou-Cheng Lai

A dissertation submitted to Johns Hopkins University in conformity with the requirements
for the degree of Doctor of Philosophy

Baltimore, Maryland
January, 2014
ABSTRACT

Background:
The problem of antibiotic resistance is increasing globally. The inappropriate use of
antibiotics has been linked to the emergence of antibiotic resistance and other adverse
effects. Antimicrobial stewardship programs (ASPs) have been developed to improve
antibiotic use, with the goals of maintaining the effectiveness of current antimicrobials and
improving patient safety and outcomes. There are several methods by which the use of
antimicrobials can be intervened upon by ASPs; most fall into two basic categories:
restriction of antimicrobial before they are dispensed initially, often called “prior approval”
and review and feedback regarding antimicrobial use sometime after prescription, often
called “post-prescription review.” Relatively few studies evaluating either approach have
been conducted in pediatric settings. This study aims to assess if a prior-approval program
combined with post-prescription review program decreases antimicrobial use, reduces the
proportion of inappropriate antimicrobial course and is associated with a higher
compliance rate with following recommendations compared to a prior-approval program
alone among pediatric inpatients. Additionally, the study aims to determine the frequency
and risk factors of inaccurate requests submitted in a pediatric web-based prior-approval
program.
Methods:
We conducted a prospective, randomized controlled study at the Johns Hopkins Children
Center a 180 bed tertiary pediatric center from September 2011 to November 2012.
Patients in 4 general pediatric floors who were assessed by ASP team to be receiving
inappropriate antibiotics after being on therapy within 25-96 hours were randomized to
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either receive the intervention (a phone call with the recommendations by ASP team to the
treating physician) or no additional feedback. Patients who were cystic fibrosis patients, in
oncology-hematology, ICU and patients for whom ID consult had been obtained were
excluded from the study. Data collected included days of antibiotic therapy, the proportion
of inappropriate antimicrobial course, the acceptance rate of ASP recommendations and
some patient’s outcome ( such as inconsistence between the antimicrobial susceptibilities
of any recovered organism and the recommended alternative therapy, any subsequent
infection after ASP's recommendation of stopping therapy) at follow up between the two
groups. Wilcoxon rank-sum test was taken to compare measures of antibiotic use. Chi-
square test was used to compare the proportion of inappropriate antimicrobial course and
the acceptance rate of ASP recommendations.

In addition, a retrospective review of patients whose providers ordered antimicrobial using
the web-based prior-approval program was carried out from December 2011 to March
2012 for 4 months to determine the frequency of inaccurate information contained within
the requests. Multivariate logistic regression was performed to evaluate potential risk
factors of inaccurate information in the prior-approval program.
Results:
The pediatric ASP team identified 60 pediatric patients (30 patients in the intervention
group and 30 patients in the control group) for whom use of restricted antimicrobials was
inappropriate. There were no significant differences of the amount of restricted
antimicrobial use between the intervention group and the control group (median DOTs: 750
vs. 816.7, p=0.932; median duration of antimicrobial agent per episode of infection (days):
3.5 vs. 5, p=0.094). In the comparison of total antimicrobial use, differences were also not
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significant. However, the prevalence of inappropriate antimicrobial use at follow up was
significantly lower in the intervention group than the control group (34.4% vs. 75.8%,
p=0.001). The acceptance rate was significantly higher in the intervention group (the
treating physician accepted the recommendation) than in the control group (the treating
physician auto-corrected antibiotic use so that it was the same as what would have
recommended by the ASP team) (67.6% vs. 22.9%, p<0.001).
In the retrospective study reviewing prior-approval requests, the result showed that
inaccuracy (discrepancies between requests and medical records) occurred in 101 out of
1159 (8.7%) requests. Patients on the surgical service, in the ICU unit, not on oncology
service and with “prophylaxis” as an indication for receiving their antimicrobials were
significantly more likely to have inaccurate antimicrobial requests in multivariate logistic
regression analysis (p=0.011, p=0.043, p=0.036, p=0.044, respectively). Inaccurate
information in the prior-approval requests could potentially affect the decisions of the
pediatric ID fellow’s approval in about 45% (45 out of 101) of inaccurate requests.
Conclusions:
Our study demonstrates that a post-prescription review program can successfully decrease
the number of inappropriate antimicrobial courses at our institution. These findings might
encourage other pediatric centers to pursue similar post-prescription review programs.
Although inaccurate information occurred not very frequently among all pediatric prior
approval requests, nearly half of them could have influenced pediatric ID fellows’ decision-
making regarding approval of the antimicrobial. Targeted review of requests for specific
antimicrobials, or for specific patient populations is warranted.

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COMMITTEE OF FINAL THESIS READERS

Kenrad Nelson, M.D.
Professor and Chair
Department of Epidemiology

Ruth Karron, M.D.
Professor and Dissertation Advisor
Department of International Health
Sara Cosgrove, M.D., M.S.
Associate Professor
Department of Medicine, School of Medicine

Lawrence H. Moulton, Ph.D.
Professor
Department of International Health

ALTERNATE THESIS READERS
William Moss, M.D., M.P.H.
Professor
Department of Epidemiology

Andrea Ruff, M.D.
Associate Professor
Department of International Health
Aaron Milstone, M.D., M.H.S.
Assistant Professor
Department of Pediatrics, School of Medicine

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ACKNOWLEDGEMENTS
First and foremost, I would like to express my deepest gratitude to my advisor, Dr. Ruth
Karron. I am really fortunate to have such a great advisor. Her continuous guidance,
encouragement, patience and immense knowledge always helped me through a lot of
obstacles from the beginning of exploring the research topic to every stage of writing the
thesis.
I cannot thank Dr. Sara Cosgrove enough. Dr. Cosgrove led the intervention project and
tutored me in antibiotic stewardship, providing numerous suggestions and answers to my
questions about the antimicrobial stewardship program. I would also like to thank Dr. Larry
Moulton for his insightful comments and criticisms at different stages of my research. I also
truly appreciate the efforts of Dr. Tamma and Dr. Jehn-Hsu, who despite large workloads of
their own, completed the post-prescription reviews, helped me collect the data and
provided lots of support during the whole process.
I am very grateful to my parents, my wife and daughter for their unlimited love, support,
and encouragement to pursue my academic career and my good friends Wei-Ju, Yea-Jen,
Hsin-Jen, Yi-Fang and Tsung for their continuous support.
It is a privilege and wonderful journey to be in the Johns Hopkins University. I will never
forget this experience and I could not have finished my thesis without the contributions of
so many people in my life.

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Table of Contents
ABSTRACT ....................................................................................................................................... ii
ACKNOWLEDGEMENTS ................................................................................................................ vi
TABLES OF ABBREVIATIONS ........................................................................................................ x
LIST OF TABLES ............................................................................................................................ xi
LIST OF FIGURES ..........................................................................................................................xiii
1. Background ............................................................................................................................. 1
1.1. The Development of Antimicrobial Stewardship Programs (ASPs) ........................... 1
1.1.1. The Emergence of Antibiotic Resistance .............................................................. 1
1.1.2. The Significance of Antibiotic Resistance and Other Adverse Outcomes .......... 3
1.1.3. Antibiotic Use and Antibiotic Resistance .............................................................. 4
1.1.4. Adverse Effects of Inappropriate Antibiotic Use ................................................. 4
1.1.5. The Development of Antimicrobial Stewardship Programs ............................... 5
1.2. Overview of Antimicrobial Stewardship Programs ..................................................... 6
1.2.1. Active Strategies ..................................................................................................... 6
1.2.2. Supplemental Strategies ........................................................................................ 7
1.2.3. Current Status of Antimicrobial Stewardship Programs ..................................... 9
1.2.4. The Influence of Effective Antimicrobial Stewardship Programs .................... 11
1.3. Prior Approval Programs ............................................................................................. 13
1.3.1. Advantage of Prior Approval Programs ............................................................. 13
1.3.2. Limitations of Prior Approval Programs ............................................................ 14
1.4. Post-prescription Review Programs ........................................................................... 16
1.4.1. Advantages of Post-prescription Review Programs .......................................... 16
1.4.2. Limitations of Post-prescription Review Programs .......................................... 18
1.5. Pediatric Antimicrobial Stewardship Programs ........................................................ 19
1.5.1. Difference Between Pediatric Patients and Adult Patients ............................... 19
1.5.2. Antimicrobial Use in Children in the United States ........................................... 20
1.5.3. Review of Pediatric ASP studies .......................................................................... 20
1.5.4. Pediatric Prior Approval Programs in the Johns Hopkins Children’s Center .. 22
1.6. Rationale for this study ................................................................................................ 23
1.7. Hypothesis and Specific Aims ...................................................................................... 25
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1.7.1. Specific Aims ......................................................................................................... 25
2. Methods ................................................................................................................................. 27
2.1. Methods for Aim 1 and Aim 2 ...................................................................................... 27
2.1.1. Study Design ............................................................................................................. 27
2.1.2. Outcome Measures ............................................................................................... 33
2.1.3. Statistical Analysis ................................................................................................ 39
2.2. Methods for Research Aim 3 ....................................................................................... 41
2.2.1. Study Design ......................................................................................................... 41
2.2.2. Statistical Analysis ................................................................................................ 44
3. Results ................................................................................................................................... 46
3.1. Results for Aim 1 and 2 ................................................................................................ 46
3.1.1. Demographic Data ................................................................................................ 46
3.1.2. Comparison of antibiotic use (restricted and total) in the two study arms .... 49
3.1.3. Reasons for inappropriate antimicrobial use in two groups ............................ 56
3.1.4. Proportion of inappropriate antibiotic use on Days 2 and 3 after ASP team
review ………………………………………………………………………………………………………………………….58
3.1.5. Potential factors associated with inappropriate antimicrobial courses at Day 2
after the ASP team’s review ................................................................................................. 61
3.1.6. Rate of Compliance with the Recommendation at Day 2 and Day 3 after the
ASP team’s review ................................................................................................................ 61
3.1.7. Outcomes of patients when ASP team recommended alternative empiric
therapy or stopping therapy in two arms .......................................................................... 62
3.2. Results for aim 3 ........................................................................................................... 68
3.2.1. Demographic data ................................................................................................ 68
3.2.2. Types of inaccurate requests and examples ...................................................... 68
3.2.3. Potential Factors Related to Inaccuracy of Antimicrobial Requests ................ 72
3.2.4. Types of inaccurate requests and potential influences on the approvals of ID
fellows ………………………………………………………………………………………………………………………….77
4. Discussions and Recommendations .................................................................................... 80
4.1. Discussion ..................................................................................................................... 80
4.2. Strengths and Limitations of the Study ...................................................................... 86
4.3. Recommendations for Future Study ........................................................................... 88
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4.4. Conclusions ................................................................................................................... 89
5. References: ............................................................................................................................ 91
5.1. Appendix: ...................................................................................................................... 91
5.2. Bibliography: ................................................................................................................ 93
Curriculum Vita:……...…………………………………………………………………………………………..……… 115

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TABLES OF ABBREVIATIONS
Abbreviations Definition
aOR Adjusted odds ratio
ASP(s) Antimicrobial Stewardship Program(s)
CA-MRSA Community-acquired methicillin-resistant Staphylococcus
aureus
CDAD Clostridium difficile–associated disease
CDC Centers for Disease Control and Prevention
CF Cystic fibrosis
CIs Confidence intervals
CRE Carbapenem-resistant Enterobacteriacea
CRP C-reactive protein
CT Computed tomography
DDD Daily defined dose
DOT Day of therapy
EIN Emerging Infections Network
ESBL Extended-spectrum β-lactamase
ESR Erythrocyte sedimentation rate
GI Gastrointestinal
hrs Hours
ICU Intensive care unit
ID Infectious disease
IDSA Infectious Disease Society of America
KPC Klebsiella pneumonia carbapenemase
MALDI-TOF Matrix-assisted laser desorption ionization time-of-flight
mass spectrometry
MRSA Methicillin-resistant Staphylococcus aureus
NDM New Delhi metallo-beta-lactamase
NICU Neonatal intensive care unit
OR Odds ratio
PDRAB Pan-drug-resistant Acinetobacter baumannii
PICU Pediatric intensive care units
PIDF Pediatric infectious disease fellows
STRAMA Strategic Program for the Rational Use of Antimicrobial
Agents and Surveillance of Resistance
UTIs Urinary tract infections
WHO World Health Organization
yr Year-old

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